A drug and its application

Abstract

This invention provides a safer drug and its application, and a safer drug combination and its application without sudden cardiac death toxicity. The safer drug provided by this invention is a combination preparation containing a serotonin receptor antagonist and diltiazem, which effectively avoids the possibility of ventricular depolarization and repolarization disorders caused by the serotonin receptor antagonist ondansetron, thereby preventing corresponding arrhythmias and sudden cardiac death. This application also provides the application of diltiazem in the preparation of drugs that improve cardiac electrical activity and corresponding treatment methods.

Description

Technical Field

[0001] This application belongs to the field of Western medicine. Specifically, this application relates to a safer drug and its application, particularly to a new compound drug containing ondansetron and diltiazem and its application, which can effectively avoid arrhythmia or sudden cardiac death caused by ondansetron. Background Technology

[0002] Ondansetron, chemically known as 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-one, has the chemical formula C2. 18 H 19 N3O is a highly selective serotonin (5-HT3) receptor antagonist with high potency and selectivity, effectively controlling vomiting induced by receptor stimulation in the small intestine and CTZ. Simultaneously, at antiemetic doses, ondansetron can enhance gastric emptying, helping to alleviate nausea; it also has an anxiolytic effect on the central nervous system, which helps inhibit the excitation of the vomiting center. Ondansetron is currently a first-line antiemetic drug used both domestically and internationally, and is widely used clinically for the prevention or treatment of nausea and vomiting induced by chemotherapy drugs (such as cisplatin, doxorubicin, etc.), radiotherapy, surgery, or anesthesia.

[0003] The QT interval is a key part of the surface electrocardiogram, and cardiac electrical activity disturbances are associated with a potentially fatal arrhythmia—torsades de pointes (TdP)—and sudden cardiac death. For every 10 ms increase in the QT interval, the risk of progressing 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.

[0004] Transient ECG changes, including cardiac electrical activity disturbances, have been reported in patients receiving ondansetron. Additionally, post-marketing case reports have included cases of torsades de pointes ventricular tachycardia in patients receiving ondansetron (the FDA issued a specific warning regarding this in 2012). Randomized, double-blind, crossover controlled clinical trials in the United States have confirmed that ondansetron-induced cardiac electrical activity disturbances are dose-dependent, particularly with a single intravenous dose of 32 mg. After baseline correction, the maximum mean difference in cardiac electrical activity disturbances compared to placebo was 20 ms, while at lower doses (8 mg), the maximum mean difference was 6 ms. Patients with high-risk factors for cardiac electrical activity disturbances (congenital cardiac electrical activity disturbance syndromes, congestive heart failure, bradyarrhythmias, or concurrent use of medications that can cause ventricular depolarization and repolarization disturbances) are more likely to experience serious arrhythmias or even sudden death when using ondansetron. Therefore, a single intravenous dose of ondansetron should generally not exceed 16 mg. GlaxoSmithKline and other companies have also revised the package insert for ondansetron, removing the 32mg single-dose intravenous injection dosage. See the following figures and tables (…). Figure 1 , Figure 11 The document presents adverse events related to Ondansetron and the FDA's responses.

[0005] like Figure 1 As shown, according to statistics from the eHealthMe website, which is based on medical big data and artificial intelligence algorithms, as of July 19, 2022, 83,849 people reported side effects while using ondansetron, of whom 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 deaths among them each year. Summary of the Invention

[0006] While the adjusted dosage can reduce the probability of ondansetron-induced arrhythmias to some extent, it does not fundamentally eliminate this possibility. Patients using this drug, especially high-risk individuals with congenital long QT syndrome or other underlying diseases, still face considerable risk.

[0007] To address the aforementioned issues, the applicant utilized a pluripotent stem cell cardiac electrophysiology research and development platform to design novel antiemetic drugs that eliminate the fatal cardiotoxic side effects of arrhythmias. They discovered that diltiazem can effectively prevent ondansetron-induced disturbances in cardiac electrical activity, thereby reducing the likelihood of arrhythmias and sudden cardiac death. Specifically, this application provides a novel and safe antiemetic drug (an improved new drug) that reduces cardiac electrical activity disturbances, comprising a serotonin receptor antagonist and diltiazem.

[0008] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

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

[0010] Furthermore, the aforementioned novel safe drug is a compound preparation.

[0011] Furthermore, the mass ratio of the 5-hydroxytryptamine receptor antagonist to diltiazem in the novel safe drug is 180:1 to 1:4.

[0012] Furthermore, the mass ratio of the 5-hydroxytryptamine receptor antagonist to diltiazem in the novel safe drug is 35:1 to 5:1.

[0013] Furthermore, the mass ratio of the 5-hydroxytryptamine receptor antagonist to diltiazem in the novel safe drug is 24:1 to 12:1.

[0014] Furthermore, the novel safe drug (improved new drug) may be 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.

[0015] On the other hand, this application provides the use of diltiazem in the preparation of a medicament for reducing cardiac electrical activity disorders.

[0016] Furthermore, the cardiac electrical activity disorder is a cardiac electrical activity disorder caused by 5-hydroxytryptamine receptor antagonism.

[0017] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

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

[0019] 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.

[0020] Furthermore, the dosage of diltiazem is 1-60 mg for a single oral dose or 0.0002-0.35 mg / kg for an injection.

[0021] Furthermore, the dosage of diltiazem is 1-30 mg for a single oral dose or 0.0005-0.15 mg / kg for an injection.

[0022] Furthermore, the blood concentration of diltiazem in the compound preparation after entering the human body is 0.4 μg / L-300 μg / L.

[0023] Furthermore, the blood concentration of diltiazem in the compound preparation after entering the human body is 2 μg / L-130 μg / L.

[0024] Furthermore, the blood concentration of diltiazem in the compound preparation after entering the human body is 4 μg / L-50 μg / L.

[0025] On the other hand, this application provides a method for reducing cardiac electrical activity disturbances, including administering diltiazem to subjects at risk of cardiac electrical activity disturbances or with symptoms of cardiac electrical activity disturbances.

[0026] Furthermore, the object is a person.

[0027] Furthermore, the subject is female.

[0028] Furthermore, the cardiac electrical activity disorder is a cardiac electrical activity disorder caused by 5-hydroxytryptamine receptor antagonism.

[0029] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

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

[0031] Furthermore, the dosage of diltiazem is 1-60 mg for a single oral dose or 0.0002-0.35 mg / kg for an injection.

[0032] Furthermore, the dosage of diltiazem is 1-30 mg for a single oral dose or 0.0005-0.15 mg / kg for an injection.

[0033] Furthermore, the frequency and duration of diltiazem application are once to six times a day for 1 to 14 consecutive days.

[0034] Furthermore, the frequency and duration of diltiazem application are once to four times a day for 1 to 7 consecutive days.

[0035] The English name of ondansetron in this application is Ondansetron, with CAS number 99614-02-5 and molecular formula C. 18 H 19 N3O; The English name of diltiazem in this application is Diltiazem, corresponding to CAS number 42399-41-7, and molecular formula C. 22 H 26 N2O4S; the above-mentioned various numbers, names, and various hydrochloride salts 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.

[0036] In this application, 5-hydroxytryptamine and 5-HT have the same meaning and can be used interchangeably.

[0037] Ondansetron and diltiazem in this application can be prepared in the same pharmaceutical composition; or can be provided as two drugs in the same package; or can be packaged separately and used in combination; all combinations known in the art are applicable to this invention.

[0038] The dosage forms applicable in this application include, but are not limited to, oral preparations and injections. The compound preparations, ondansetron preparations, and diltiazem preparations of this application can 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 ondansetron and diltiazem preparations are provided in the same package or in various packages, their dosage forms may be the same or different.

[0039] Depending on the dosage form used for preparation / application, various pharmaceutically acceptable excipients may be selected for the formulation, including but not limited to coating materials, solvents, solubilizers, binders, stabilizers, antioxidants, pH adjusters, and flavoring agents. These excipients can be selected by those skilled in the art based on pharmaceutical knowledge.

[0040] In addition to the excipients mentioned above, the formulations of this application may also include, or be provided alone, or may be administered simultaneously with, other known antiemetic drugs or therapies, including but not limited to other 5-HT receptor antagonists, NK-1 receptor antagonists, dopamine receptor blockers, glucocorticoids, such as granisetron, dolasetron, ramosetron, tropisetron, palonosetron, aprepitant, metoclopramide, dexamethasone, etc.; and other drugs or therapies that reduce cardiac electrical activity disturbances, including but not limited to β-blockers, sympathetic nerve blockers, such as propranolol, phenytoin sodium, reserpine, adrenaline, atropine, verapamil, sympathectomy, etc.

[0041] Beneficial effects:

[0042] 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.

[0043] 2. Retains ondansetron's effective efficacy in preventing and treating vomiting.

[0044] 3. For high-risk individuals with congenital long QT syndrome or other underlying diseases, patients taking other medications that cause cardiac electrical activity disturbances, or patients with electrolyte imbalances (hypokalemia, hypocalcemia, hypomagnesemia), liver and kidney dysfunction, existing heart failure, left ventricular hypertrophy, myocardial infarction, or other heart diseases that make them prone to arrhythmias, the drugs or methods described in this application are safer to use than ondansetron alone.

[0045] 4. Diltiazem has a certain effect in 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.

[0046] 5. Women have a higher risk of drug-induced TdP than men, and this invention provides more significant protection for female patients. Attached Figure Description

[0047] Figure 1 According to statistics from the eHealthMe website, which is based on medical big data and artificial intelligence algorithms, as of July 19, 2022, 83,849 people reported side effects while using ondansetron, of whom 3,448 (4.11%) died. A. Shows the number of people who reported side effects while taking ondansetron each year; B. Shows the number of deaths among them each year.

[0048] Figure 2 These are schematic diagrams of an electrocardiogram (ECG). A is a normal ECG of a healthy human individual. B is a schematic diagram of an ECG showing disordered cardiac electrical activity.

[0049] Figure 3 An electrocardiogram showing torsades de pointes (TdP) is obtained.

[0050] Figure 4 The field potential (FP) characteristics of hiPSC-CMs differentiated from pluripotent stem cells were recorded using a multi-electrode array (MEA). A represents a normal MEA signal recording of the field potential electrical signal of hiPSC-CMs; B represents a representative arrhythmic MEA signal recording of the field potential electrical signal of hiPSC-CMs, which can detect arrhythmic events; and C allows analysis of the MEA signal trajectory to obtain field potential parameters: field potential duration (FPD), beat cycle, and corrected field potential duration (FPDc).

[0051] Figure 5Diltiazem (modified new drug group) can effectively reverse the cardiac electrical activity disturbances in cardiomyocytes induced by ondansetron, thereby preventing the development of related arrhythmias and avoiding sudden cardiac death caused by drug side effects. A shows 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. B uses raw field potential recordings to show 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 heart rate corrected field potential, equivalent to the QT interval in an electrocardiogram. In this figure, the concentration of ondansetron in the modified new drug group is 120 μg / L, and the concentration of diltiazem is 8.29 μg / L.

[0052] Figure 6 This figure shows the effects of combining other drugs with ondansetron in the search for effective combinations. A indicates that atenolol cannot reverse the toxicity of ondansetron. B indicates that diazoxide cannot reverse the toxicity of ondansetron. In this figure, the concentrations of ondansetron are 120 μg / L, atenolol is 4.79 mg / L, and diazoxide is 6.92 mg / L.

[0053] Figure 7 This diagram illustrates the effects of combining other concentrations with ondansetron during the search for effective combination concentrations. A. Indicates that the concentration of diltiazem in the modified new drug other ratio-1 is too low to reverse the toxicity of ondansetron. B. Indicates that the concentration of diltiazem in the modified new drug other ratio-2 is too high and will excessively reverse the toxicity of ondansetron. In this diagram, the ondansetron concentration is 120 μg / L, the diltiazem concentration in the modified new drug other ratio-1 is 8.29 μg / L, and the diltiazem concentration in the modified new drug other ratio-2 is 24.87 μg / L.

[0054] Figure 8 The action potential duration in the ondansetron group, as shown in the computer-simulated in vitro arrhythmia model, was longer than that in the negative control group. There was no significant difference between the modified drug group and the negative control group. This indicates that the modified drug group can effectively avoid the myocardial action potential changes induced by ondansetron.

[0055] Figure 9 This section shows the incidence of arrhythmias in human cardiomyocytes under different drug concentrations. A. Shows the percentage of cardiomyocytes exhibiting arrhythmias under different concentrations of ondansetron. B. Shows the percentage of cardiomyocyte arrhythmias induced by high-dose ondansetron and its corresponding modified drugs. C. Shows the percentage of cardiomyocyte arrhythmias induced by 10-fold higher doses of ondansetron and its corresponding modified drugs.

[0056] Figure 10 The effects of light protection, high temperature, and light exposure on the formulation and components of the improved new drug were observed in an influencing factor experiment. API-1 was ondansetron, and API-2 was diltiazem. A. This shows that single-component API-1 and API-1 in the compound form are relatively stable under high temperature and light protection. B. This shows that single-component API-1 is unstable under light, while API-1 in the compound form is stable under light; therefore, single-component API-1 needs to be stored away from light. This indicates 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 exposure still shows a significant degradation trend, requiring storage away from light. C. This shows that single-component API-2 and API-2 in the compound form are unstable at high temperature but stable when protected from light. Under high temperature and light protection conditions, API-1 has virtually no significant effect on the stability of API-2. D. This shows that under light conditions, the compound form of API-2 is more stable than single-component API-2. This indicates that API-2 is unstable under both high temperature and light, and the compound form is unstable under both high temperature and light, requiring storage at low temperature and away from light.

[0057] Figure 11 The document demonstrates the FDA's response to different doses of ondansetron.

[0058] Figure 12 The stability of API-1 (Ondansetron) was demonstrated at 2-8°C and 25°C, with no significant changes in related substances. API-2 (Diltiazem) was relatively stable under storage conditions of 2-8°C, but at 25°C, the main degradation impurity, API-2F, was generated. API-2F is a metabolite in vivo, therefore its safety is very high. It is predicted that the combination drug will have good stability under light-protected and low-temperature (2-8°C) storage conditions, and its quality will meet the requirements (no new safety issues will arise due to impurities). Detailed Implementation

[0059] Example 1 Drug Screening

[0060] ECG and reference values ​​for normal individuals, cardiac electrical activity disorders, and Tdp. Figure 2 and Figure 3 As shown.

[0061] Utilizing induced pluripotent stem cell technology and integrating the latest international electrophysiology and pharmacology technologies, a pluripotent stem cell cardiac electrophysiology research platform has been established, focusing on world-leading precision drug screening and development. This platform enables the design of novel antiemetic drugs that eliminate the cardiotoxic side effects of fatal arrhythmias. The platform can record and analyze parameters such as heart rate, QT, QTc, and beating period; and analyze the effects of drugs on changes in these parameters.

[0062] The stem cell cardiac electrophysiology platform was used to screen drug combination regimens. The basic process is as follows:

[0063] (1) Thaw the human induced stem cell differentiated cardiomyocytes and seed them on a Multi-Electrode Array (MEA) cell culture plate, and change the cell culture medium daily.

[0064] (2) After about 4-8 days, start recording cardiac cell electrical signals. Record the baseline cardiac cell electrical signals before the addition of drugs, as well as the cardiac cell electrical signal data after the addition of drugs such as ondansetron and diltiazem.

[0065] (3) Compare the differences in electrical signals under the action of different drugs, analyze the data, and make graphs for comparison.

[0066] Figure 4 This study demonstrates the field potential (FP) characteristics of multi-electrode array (MEA) recording of cardiomyocytes differentiated from induced pluripotent stem cells (hiPSC-CMs).

[0067] Example 2: Effect of the compound drug of this application

[0068] Human-induced stem cell-differentiated cardiomyocytes (hiPSC-CMs) were thawed and seeded onto Multiple Electride Array (MEA) plates coated with a substrate containing hiPSC-CMs. The medium was changed using hiPSC-CMs maintenance medium, and subsequently, the cell culture medium was changed daily until drug administration and data recording were completed. Cardiomyocyte electrochemical signals (ECS) could be recorded 4-8 days after seeding on MEA plates. ECS data were recorded at the baseline before drug administration, after the addition of ondansetron, and subsequently after the addition of diltiazem and other drugs. The recorded ECS data were analyzed and exported to Excel, and then plotted using GraphPad.

[0069] Figure 5The results show that diltiazem (modified new drug group) can effectively reverse the cardiac electrical activity disturbances in cardiomyocytes induced by ondansetron, thereby preventing the development of related arrhythmias and avoiding sudden cardiac death caused by drug side effects. A shows 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. B uses raw field potential recordings to show 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 heart rate corrected field potential, equivalent to the QT interval in an electrocardiogram. In this figure, the concentration of ondansetron in the modified new drug group is 120 μg / L, and the concentration of diltiazem is 8.12 μg / L.

[0070] Figure 6 This diagram illustrates 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 diagram, the concentrations of ondansetron are 120 μg / L, atenolol is 4.79 mg / L, and diazoxide is 6.92 mg / L.

[0071] Figure 7 This diagram illustrates the effects of combining other concentrations with ondansetron during the search for effective combination concentrations. A. Indicates that the concentration of diltiazem in the modified new drug other ratio-1 is too low to reverse the toxicity of ondansetron. B. Indicates that the concentration of diltiazem in the modified new drug other ratio-2 is too high and will excessively reverse the toxicity of ondansetron. In this diagram, the ondansetron concentration is 120 μg / L, the diltiazem concentration in the modified new drug other ratio-1 is 8.29 μg / L, and the diltiazem concentration in the modified new drug other ratio-2 is 24.87 μg / L.

[0072] Figure 8 The action potential duration in the ondansetron group, as shown in the computer-simulated in vitro arrhythmia model, was longer than that in the negative control group. There was no significant difference between the modified drug group and the negative control group. This indicates that the modified drug group can effectively avoid the myocardial action potential changes induced by ondansetron.

[0073] Figure 9 This section shows the incidence of arrhythmias in human cardiomyocytes under different drug concentrations. A. Shows the percentage of cardiomyocytes exhibiting arrhythmias under different concentrations of ondansetron. B. Shows the percentage of cardiomyocyte arrhythmias induced by high-dose ondansetron and its corresponding modified drugs. C. Shows the percentage of cardiomyocyte arrhythmias induced by 10-fold higher doses of ondansetron and its corresponding modified drugs.

[0074] Figure 10 The effects of light protection, high temperature, and light exposure on the formulation and components of the improved new drug were observed in an influencing factor experiment. API-1 was ondansetron, and API-2 was diltiazem. A. This shows that single-component API-1 and API-1 in the compound form are relatively stable under high temperature and light protection. B. This shows that single-component API-1 is unstable under light, while API-1 in the compound form is stable under light; therefore, single-component API-1 needs to be stored away from light. This indicates 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 exposure still shows a significant degradation trend, requiring storage away from light. C. This shows that single-component API-2 and API-2 in the compound form are unstable at high temperature but stable when protected from light. Under high temperature and light protection conditions, API-1 has virtually no significant effect on the stability of API-2. D. This shows that under light conditions, the compound form of API-2 is more stable than single-component API-2. This indicates that API-2 is unstable under both high temperature and light, and the compound form is unstable under both high temperature and light, requiring storage at low temperature and away from light.

[0075] Figure 11 The document demonstrates the FDA's response to different doses of ondansetron.

[0076] Figure 12 Laboratory-optimal formulation stability test.

Claims

1. The use of a drug in the preparation of a drug for reducing arrhythmia, characterized in that, The arrhythmia is QT interval prolongation caused by ondansetron. The drug is a compound preparation, which includes ondansetron and diltiazem. The mass ratio of ondansetron to diltiazem is 35:1 to 5:

1.

2. The application according to claim 1, wherein the mass ratio of ondansetron to diltiazem is 24:1 to 12:

1.

3. The application according to claim 1 or 2, wherein the drug is an oral preparation or an injection.

4. In the application according to claim 3, the oral preparation is a capsule, oral liquid, or tablet; the injection is a liquid injection or a powder injection.

5. In the application according to claim 1, the blood concentration of diltiazem in the drug after entering the human body is 0.4 μg / L-300 μg / L.

6. In the application according to claim 5, the blood concentration of diltiazem in the drug after entering the human body is 2 μg / L-130 μg / L.

7. In the application according to claim 6, the blood concentration of diltiazem in the drug after entering the human body is 4 μg / L-50 μg / L.

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