WO2022228363A1

WO2022228363A1 - Medical use of composition

Info

Publication number: WO2022228363A1
Application number: PCT/CN2022/088904
Authority: WO
Inventors: 井上貴世; 卡瓦纳·约瑟夫; 李海燕; 王文首; 赖才达
Original assignee: 杭州剂泰医药科技有限责任公司
Priority date: 2021-04-27
Filing date: 2022-04-25
Publication date: 2022-11-03
Also published as: CN115245515A

Abstract

A use of a combination of dextromethorphan or a pharmaceutically acceptable salt thereof and quinidine and a pharmaceutically acceptable salt thereof in the treatment or relief of dysphagia and/or salivation in neurological diseases. The use can effectively treat or relieve dysphagia and/or salivation in patients with neurological diseases, avoid or reduce the occurrence of corresponding complications, and has very important significance for improving the quality of life of the patients.

Description

Medicinal use of a composition

This application claims the priority of the prior application with the patent application number 202110460793.5 and the invention titled "Medical Use of a Composition" filed with the State Intellectual Property Office of China on April 27, 2021. The entirety of said application is incorporated herein by reference.

technical field

The present invention relates to the field of medicine, in particular to a novel use of a combination of dextromethorphan or a pharmaceutically acceptable salt thereof and quinidine or a pharmaceutically acceptable salt thereof. More specifically, it relates to dextromethorphan or a pharmaceutically acceptable salt thereof in combination with quinidine or a pharmaceutically acceptable salt thereof for the treatment or alleviation of dysphagia and salivation in diseases.

Background technique

Dysphagia and salivation are common gastrointestinal problems associated with neurological diseases, with a high incidence. Studies have shown that the incidence of dysphagia in patients with Parkinson's disease is 11-87%. More than 50% of patients with acute cerebral infarction have different degrees of dysphagia. The incidence of dysphagia in stroke patients is approximately 51-73%. About one-third of people with multiple sclerosis have difficulty swallowing. Dysphagia often leads to serious complications, such as dehydration, malnutrition, airway obstruction, and aspiration pneumonia, which can even be life-threatening. In addition, since the main cause of salivation in patients with the above diseases is difficulty in swallowing saliva, rather than excessive salivation, salivation is often accompanied by dysphagia, which is a common symptom in patients with neurological diseases. Dysphagia and salivation not only affect the body, but also cause inconvenience in life and social activities, affect the patient's mood, lead to depression, and thus reduce the patient's quality of life.

Currently, as there are no drugs approved for the treatment or relief of dysphagia and salivation, dysphagia is often treated or improved through dietary modification, oral rehabilitation exercises, acupuncture, nasogastric tube, and deep brain stimulation. However, these methods have problems such as poor patient compliance, uncertain effectiveness, and limited scope of use, which cannot meet clinical needs.

In conclusion, the research on drugs related to dysphagia and/or salivation is of great clinical significance, and there is an urgent need to develop a drug that can treat or alleviate dysphagia and/or salivation in neurological diseases.

SUMMARY OF THE INVENTION

The purpose of the present invention is to solve the problems in the prior art, and to provide a method for treating or alleviating the symptoms of dysphagia and/or salivation in neurological diseases.

The object of the present invention can be realized through the following technical solutions:

The present invention provides a method of treating or alleviating symptoms of dysphagia and/or salivation in a disease, comprising administering an effective amount of:

Dextromethorphan, its isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs, or pharmaceutically acceptable co-crystals thereof; and

Quinidine, its isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs or pharmaceutically acceptable co-crystals;

Wherein, the disease is not amyotrophic lateral sclerosis.

In certain embodiments, a subject is administered dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-form thereof. Crystallization and administration to a subject of quinidine, an isotopically-labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, a polymorph, or a pharmaceutically acceptable co-crystal thereof, are performed substantially simultaneously . In certain embodiments, a subject is administered dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-form thereof. crystalline prior to administering to a subject quinidine, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof (e.g., 1 to 10 minutes, 10 to 60 minutes, 1 to 6 hours, or 6 to 24 hours ago). In certain embodiments, a subject is administered dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-form thereof. Crystalline after administration to a subject of quinidine, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof (e.g., 1 to 10 minutes, 10 to 60 minutes, 1 to 6 hours, or 6 to 24 hours later).

In certain embodiments, the disease is a neurological disease.

In certain embodiments, the disease is a neurodegenerative disease. In certain embodiments, the disease is Parkinson's disease, Alzheimer's disease, syringomyelia, Wolfram's syndrome, or Huntington's disease.

In certain embodiments, the disease is cerebrovascular disease. In certain embodiments, the disease is stroke or cerebral infarction.

In certain embodiments, the disease is an inflammatory disease. In certain embodiments, the disease is multiple sclerosis, Guillain-Barre syndrome, poliomyelitis, or Lyme disease.

In certain embodiments, the disease is a neuromuscular junction disease. In certain embodiments, the disease is myasthenia gravis or neurobehcet's disease.

In certain embodiments, the disease is an infectious disease.

In certain embodiments, the disease is a neoplastic disease. In certain embodiments, the disease is cancer. In certain embodiments, the disease is a cancer of the central nervous system. In certain embodiments, the disease is brain cancer. In certain embodiments, the disease is brainstem glioma. In certain embodiments, the disease is malignant meningitis. In certain embodiments, the disease is a high brainstem tumor.

In certain embodiments, the disease is a genetic disease. In certain embodiments, the disease is Kennedy's disease. In certain embodiments, the disease is acute intermittent porphyria.

In certain embodiments, the disorder is a psychiatric disorder. In certain embodiments, the disorder is autism. In certain embodiments, the disorder is major depressive disorder.

In certain embodiments, the disease is a metabolic disease. In certain embodiments, the disease is osmotic demyelinating syndrome.

In certain embodiments, the disease is selected from Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke, cerebral infarction, Huntington's disease, myasthenia gravis, or meningitis. Parkinson's disease, multiple sclerosis, stroke or cerebral infarction are preferred.

In certain embodiments, dextromethorphan, its isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs, or pharmaceutically acceptable co-crystals and quinidine, its isotopically labeled compounds, pharmaceutically acceptable The molar ratio of acceptable salts, solvates, polymorphs or pharmaceutically acceptable co-crystals is from 1:1 to 10:1. In certain embodiments, dextromethorphan, its isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs, or pharmaceutically acceptable co-crystals and quinidine, its isotopically labeled compounds, pharmaceutically acceptable The molar ratio of acceptable salts, solvates, polymorphs or pharmaceutically acceptable co-crystals is from 2:1 to 8:1. In certain embodiments, dextromethorphan, its isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs, or pharmaceutically acceptable co-crystals and quinidine, its isotopically labeled compounds, pharmaceutically acceptable The molar ratio of acceptable salts, solvates, polymorphs or pharmaceutically acceptable co-crystals is from 3:1 to 6:1. In certain embodiments, dextromethorphan, its isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs, or pharmaceutically acceptable co-crystals and quinidine, its isotopically labeled compounds, pharmaceutically acceptable The molar ratio of acceptable salts, solvates, polymorphs or pharmaceutically acceptable co-crystals is about 4:1.

In certain embodiments, dextromethorphan, its isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs, or pharmaceutically acceptable co-crystals and quinidine, its isotopically labeled compounds, pharmaceutically acceptable The mass ratio of acceptable salts, solvates, polymorphs or pharmaceutically acceptable co-crystals is from 1:2 to 10:1, for example 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1. In certain embodiments, dextromethorphan, its isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs, or pharmaceutically acceptable co-crystals and quinidine, its isotopically labeled compounds, pharmaceutically acceptable The mass ratio of acceptable salts, solvates, polymorphs or pharmaceutically acceptable co-crystals is from 1:1 to 5:1. In certain embodiments, dextromethorphan, its isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs, or pharmaceutically acceptable co-crystals and quinidine, its isotopically labeled compounds, pharmaceutically acceptable The mass ratio of acceptable salts, solvates, polymorphs or pharmaceutically acceptable co-crystals is from 1:1 to 2:1.

According to the present invention, the dextromethorphan (DM) is a compound of the formula:

Isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs or tautomers thereof. In certain embodiments, dextromethorphan consists of isotopes substantially in their natural abundance. In certain embodiments, the dextromethorphan isotopically-labeled compound is deuterated dextromethorphan (eg, mono-deuterated dextromethorphan, multi-deuterated dextromethorphan, or per-deuterated dextromethorphan). In certain embodiments, the dextromethorphan isotopically labeled compound is dextromethorphan labeled with one or ^more3H , one or ^more14C , one or ^more15N , and/or one or ^more18O .

In certain embodiments, the pharmaceutically acceptable salt of dextromethorphan is dextromethorphan hydrobromide, preferably, the pharmaceutically acceptable salt of dextromethorphan is dextromethorphan monohydrobromide. In certain embodiments, the pharmaceutically acceptable solvate of dextromethorphan is dextromethorphan hydrate (eg, dextromethorphan monohydrate). In certain embodiments, dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof is dextromethorphan Hydrate of a pharmaceutically acceptable salt of fen. In certain embodiments, dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof is dextromethorphan Fenmonohydrobromide monohydrate.

In certain embodiments, the amount of dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof is 15 to 150 μmol.

In certain embodiments, the amount of dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof is 30 to 100 μmol. In certain embodiments, the amount of dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof is 40 to 70 μmol. In certain embodiments, the amount of dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof is About 54 μmol.

In certain embodiments, the mass of dextromethorphan, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 5 to 150mg.

In certain embodiments, the mass of dextromethorphan, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 5 to 80 mg.

In certain embodiments, the mass of dextromethorphan, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 10 to 100 mg. In certain embodiments, the amount of dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof is 10 to 40 mg. In certain embodiments, the amount of dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof is 10 to 30 mg. In certain embodiments, the mass of dextromethorphan, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 20 to 60 mg. In certain embodiments, the amount of dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof is About 20mg. Quinidine is a compound of the formula:

Isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs or tautomers or tautomers thereof. In certain embodiments, quinidine consists of isotopes substantially in their natural abundance. In certain embodiments, the quinidine isotopically labeled compound is deuterated quinidine (eg, mono-deuterated quinidine, poly-deuterated quinidine, or per-deuterated quinidine). In certain embodiments, the quinidine isotopically labeled compound is quinidine labeled with one or ^more3H , one or ^more14C , one or ^more15N , and/or one or ^more18O . In certain embodiments, the pharmaceutically acceptable salt of quinidine is quinidine sulfate, preferably, the pharmaceutically acceptable salt of quinidine is quinidine hemisulfate. In certain embodiments, the pharmaceutically acceptable solvate of quinidine is quinidine hydrate (eg, quinidine monohydrate). In certain embodiments, quinidine, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof is quinidine A hydrate of a pharmaceutically acceptable salt of Ding. In certain embodiments, quinidine, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof is quinidine Butyl hemisulfate monohydrate.

In certain embodiments, the amount of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 4 to 40 μmol.

In certain embodiments, the amount of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 7 to 25 μmol. In certain embodiments, quinidine, or an isotopically labeled compound thereof, quinidine, or an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or pharmaceutically acceptable salt thereof An acceptable amount of co-crystal is 10 to 20 μmol. In certain embodiments, the amount of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is About 13 μmol.

In certain embodiments, the amount of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 2.5 to 150 mg.

In certain embodiments, the amount of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 10 to 150 mg.

In certain embodiments, the amount of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 10 to 100 mg.

In certain embodiments, the amount of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 10 to 60 mg.

In certain embodiments, the amount of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 2.5 to 40 mg.

In certain embodiments, the amount of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 5 to 30 mg. In certain embodiments, the amount of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 7 to 20 mg. In certain embodiments, the amount of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is 10 to 15 mg. In certain embodiments, the amount of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is About 10mg.

In a preferred embodiment, the dextromethorphan, its isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs or pharmaceutically acceptable co-crystals, and quinidine, its isotopically labeled compounds , pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, or pharmaceutically acceptable co-crystals thereof are administered orally, by injection or parenterally.

In certain embodiments, dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof, and quinidine D, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal are two separate dosage forms. In certain embodiments, dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof, and quinidine D, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable co-crystal is a single dosage form.

The present invention also provides a pharmaceutical composition comprising:

(i) Dextromethorphan, its isotopically labeled compounds, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, polymorphs, or pharmaceutically acceptable co-crystals thereof;

(ii) quinidine, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof.

In some aspects, the present invention provides the use of the pharmaceutical composition in the manufacture of a medicament for the treatment or alleviation of dysphagia and/or salivation symptoms in a disease.

In another aspect, the present invention provides dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof in the preparation of Use in a medicament for the treatment or alleviation of dysphagia and/or salivation symptoms in a disease.

In another aspect, the present invention provides quinidine, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof in the preparation of Use in a medicament for the treatment or alleviation of dysphagia and/or salivation symptoms in a disease.

According to an embodiment of the present invention, the disease is as defined above.

According to an embodiment of the present invention, the pharmaceutical composition contains about 15-150 μmol of dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph thereof, or its A pharmaceutically acceptable co-crystal.

According to an embodiment of the present invention, the pharmaceutical composition contains 10-150 mg of dextromethorphan, an isotopically-labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorphic form, or a pharmaceutical thereof acceptable co-crystals.

According to an embodiment of the present invention, the pharmaceutical composition contains about 4-40 μmol of quinidine, an isotopically-labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph thereof, or its A pharmaceutically acceptable co-crystal.

According to an embodiment of the present invention, the pharmaceutical composition contains 10-150 mg of quinidine, an isotopically-labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorphic form, or a pharmaceutical thereof acceptable co-crystals.

In certain embodiments, the pharmaceutical compositions of the present invention further comprise one or more pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition is in unit dosage form.

According to an embodiment of the present invention, the unit dose comprises: (1) about 15-150 μmol of dextromethorphan, its isotopically labeled compounds, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, polymorphs , or a pharmaceutically acceptable co-crystal thereof; (2) about 4-40 μmol of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, polymorph, or its pharmaceutically acceptable co-crystals.

According to an embodiment of the present invention, in the unit dose, dextromethorphan, its isotopically-labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable The co-crystal is preferably 30-100 μmol, more preferably 40-70 μmol; quinidine, its isotopically-labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, polymorph, or its pharmaceutical The acceptable co-crystal is preferably 7-25 μmol, more preferably 10-20 μmol.

According to an embodiment of the present invention, the unit dose comprises: (1) 15-150 mg of dextromethorphan, its isotopically labeled compounds, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, polymorphs, or a pharmaceutically acceptable co-crystal thereof; (2) about 10-150 mg of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, polymorph, or its A pharmaceutically acceptable co-crystal.

According to an embodiment of the present invention, in the unit dose, dextromethorphan, its isotopically-labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its polymorph, or its pharmaceutically acceptable The co-crystal is preferably 10-100 mg, more preferably 20-60 mg; quinidine, its isotopically-labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, polymorph, or its pharmaceutically acceptable The above acceptable co-crystal is preferably 10-100 mg, more preferably 10-60 mg.

According to an embodiment of the invention, the unit dose is suitable for oral or parenteral administration.

The compounds and pharmaceutical compositions of the present invention can be administered by any route, including enteral (eg, oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, Interdermal, rectal, intravaginal, intraperitoneal, topical (eg, by powder, ointment, cream, and/or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation and/or as an oral spray, nasal spray and/or aerosol. Particularly contemplated routes are oral administration, intravenous administration (eg, systemic intravenous injection), topical administration through the blood and/or lymphatic supply, and/or direct administration to the affected site. In certain embodiments, dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof, and quinidine One or both of D, its isotopically labeled compounds, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its polymorphs, or its pharmaceutically acceptable co-crystals, or both, are administered orally. In certain embodiments, dextromethorphan, an isotopically labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof, and quinidine Both of D, its isotopically labeled compounds, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its polymorphs, or its pharmaceutically acceptable co-crystals are administered orally. In certain embodiments, dextromethorphan, isotopically labeled compounds thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates, polymorphs, or pharmaceutically acceptable co-crystals thereof, and quinidine D, its isotopically labeled compounds, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, polymorphs, or one or both of its pharmaceutically acceptable co-crystals without oral administration .

In certain embodiments, the methods of the present invention further comprise administering surgery, radiation therapy and/or transplantation or additional pharmaceutical therapy to a subject in need thereof. Additional agents may be administered at the same time as, before, or after administration of the compounds or pharmaceutical compositions of the present invention.

In certain embodiments, the additional agent is an additional therapeutically active or prophylactically active agent, including but not limited to cytotoxic chemotherapeutic agents, epigenetic modifiers, glucocorticoids, immunotherapeutic agents, antiproliferative agents, anticancer agents agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressive agents, antibacterial agents, antiviral agents, cardiovascular drugs, cholesterol lowering agents, antidiabetic agents, antiallergic agents, contraceptives, pain relievers, and combinations thereof. In some embodiments, the additional agent is a topoisomerase inhibitor, MCL1 inhibitor, BCL-2 inhibitor, BCL-xL inhibitor, BRD4 inhibitor, BRCA1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor Inhibitors, CDK9 inhibitors, Jummonji histone demethylase inhibitors or DNA damage inducers. In certain embodiments, the additional agent is a binding agent or inhibitor of a kinase (eg, a tyrosine kinase). In certain embodiments, the additional agent is an antibody or fragment thereof (eg, a monoclonal antibody). In certain embodiments, the additional treatment is immunotherapy (eg, immunotherapeutic monoclonal antibodies). In certain embodiments, the additional agent is an immunosuppressive agent. In certain embodiments, the additional agent is an immune activator. In certain embodiments, the additional agent is an immune checkpoint inhibitor. In certain embodiments, the additional agent is a programmed cell death 1 protein (PD-1) inhibitor. In certain embodiments, the additional agent is a programmed cell death 1 protein ligand 1 (PD-L1) inhibitor. In certain embodiments, the additional drug is a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor. In certain embodiments, the additional agent is a T cell immunoglobulin and mucin domain 3 (TIM3) inhibitor, a lymphocyte activation gene-3 (LAG3) inhibitor, a V-SET domain-containing T Cell Activation Inhibitor 1 (VTCN1 or B7-H4) Inhibitor, Cluster of Differentiation 276 (CD276 or B7-H3) Inhibitor, B and T Lymphocyte Attenuating Factor (BTLA) Inhibitor, Galectin-9 (GAL9) ) inhibitors, checkpoint kinase 1 (Chk1) inhibitors, adenosine A2A receptor (A2AR) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, killer cell immunoglobulin-like receptors (KIR) inhibitors or IgV-domain inhibitors of T cell activation (VISTA) inhibitors. In certain embodiments, the additional agent is metformin. In certain embodiments, the additional agent is approved by a regulatory agency (eg, the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA)) for human and/or veterinary use. In certain embodiments, the compounds or pharmaceutical compositions of the present invention may be administered in combination with surgery, radiation therapy, and/or transplantation (eg, stem cell transplantation, bone marrow transplantation).

In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human 18 years of age or older. In certain embodiments, the subject is a human 21 years of age or older. In certain embodiments, the subject is a human between the ages of 12 and 18. In certain embodiments, the subject is a human between 2 and 12 years of age. In certain embodiments, the subject is a human who is 29 days old to less than 2 years old. In certain embodiments, the subject is a human less than 29 days old. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, eg, a rodent (eg, mouse, rat), dog, pig, or non-human primate. In certain embodiments, the subject is a genetically engineered animal. In certain embodiments, the subject is a transgenic animal (eg, transgenic mouse, transgenic pig).

The present invention provides a novel use of a combination of dextromethorphan or a pharmaceutically acceptable salt thereof and quinidine or a pharmaceutically acceptable salt thereof. The use is for the treatment or relief of dysphagia and salivation in diseases. In addition, the combination of dextromethorphan or a pharmaceutically acceptable salt thereof and quinidine or a pharmaceutically acceptable salt thereof provided by the present invention has high safety, can meet the medication requirements of patients, and can significantly improve the quality of life of patients.

Explanation of terms and scope, etc.

When a range of values ("range") is listed, it is intended to include every value and sub-range within that range. Unless otherwise stated, ranges include both ends of the range.

The terms "administering," "administering," or "administering" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or a pharmaceutical composition thereof.

The terms "condition", "disease" and "disorder" are used interchangeably.

The terms "compound of the present invention", "compound of the present invention", "active ingredient of the present invention", "active composition compound" and other terms include any pharmaceutically active ingredient that constitutes the pharmaceutical composition of the present invention/the combined treatment regimen of the present invention, and encompasses various modifications, forms of existence of these active ingredients, including, for example, dextromethorphan, its isotopically labeled compounds, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, polymorphs, or its pharmaceutically acceptable forms. an acceptable co-crystal; and/or quinidine, an isotopically-labeled compound thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, polymorph, or a pharmaceutically acceptable co-crystal thereof.

The term "isotopically labeled compound" refers to a compound having the same chemical structure as the chemical formula and the compound of the present invention, except that the isotopic composition at one or more positions differs from that of the compound of the present invention (eg, hydrogen versus deuterium). , at least one atom of the isotopically-labeled compound includes at least one atom that is enriched above its natural abundance (eg, enriched 3-fold, 10-fold, 30-fold, 100-fold, 300-fold, 1000-fold, 3000-fold, or 10,000-fold more enriched) ), wherein the compound consists of isotopes substantially in their natural abundance. The "isotopic labels" include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (eg, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ¹⁸ F, ³⁵ S and ³⁶ Cl) labeled compounds of the present invention. Isotopically labeled compounds of the present invention are useful in assays for the tissue distribution of the compounds and their prodrugs and metabolites; preferred isotopes for such assays ^include3H ^and14C . Furthermore, in some cases, substitution of compounds with heavier isotopes such as deuterium (2H or D) may provide more therapeutically advantageous effects such as increased metabolic stability, increased in vivo half-life or reduced dosage requirements, etc. . Isotopically labeled compounds of the present invention can generally be prepared according to the methods described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The term "pharmaceutically acceptable salt" means, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (eg, human) without undue toxicity, irritation, allergic reaction, etc., and with reasonable benefit / Risk ratio commensurate with the salt. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid salts are amino groups with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids or organic acids such as acetic, oxalic, maleic, tartaric, lemon acid, succinic acid or malonic acid), or salts formed by other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate , Glycerophosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobate, Lactate, Laurate, Laurane Sulfate, malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxy Naphthate, Pectate, Persulfate, 3-Phenylpropionate, Phosphate, Picrate, Pivalate, Propionate, Stearate, Succinate, Sulfate, Tartaric Acid salt, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, as appropriate, quaternary salts.

The term "solvate" refers to a form of a compound that is associated with a solvent, usually by a solvolysis reaction. This physical association can include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds of the present invention may be prepared, for example, in crystalline forms and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and also include stoichiometric and non-stoichiometric solvates. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of isolation. "Solvates" include solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates. The term "pharmaceutically acceptable solvate" means, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (eg, human) without undue toxicity, irritation, allergic reaction, etc., and with reasonable availability. A solvate with a commensurate benefit/risk ratio.

The term "hydrate" refers to a compound that is associated with water. Typically, the number of water molecules contained in a hydrate of a compound is in a specific ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R _· xH2O, where R is a compound and x is a number greater than zero. A given compound can form more than one type of hydrate, including, for example, monohydrate (x is 1), low hydrate (x is a number greater than 0 and less than 1, such as hemihydrate (R _0.5H2O ) ) and polyhydrates (x is a number greater than 1, such as dihydrate (R _· 2H2O) and hexahydrate (R _· 6H2O)).

The term "tautomer" refers to compounds that are interchangeable forms of a particular compound structure, as well as compounds that differ in the distribution of hydrogen atoms and electrons. Thus, through the movement of pi electrons and atoms (usually H), the two structures can reach equilibrium. For example, enols and ketones are tautomers because they interconvert rapidly by treatment with acids or bases.

The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature and other factors can cause one crystalline form to predominate. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

The terms "condition", "disease" and "disorder" are used interchangeably.

An "effective amount" of a compound/pharmaceutical composition of the present invention refers to an amount sufficient to elicit the desired biological response, ie relief of symptoms. The effective amount may vary depending on factors such as the desired biological endpoint, the mode of administration, and/or the age and health of the subject.

Furthermore, the invention covers all modifications, combinations and permutations in which one or more limitations, elements, clauses and descriptive terms from one or more listed claims are introduced into another claim. For example, any claim dependent on another claim may be modified to include one or more of the limitations found in any other claim dependent on the same base claim. If each element is presented in enumerated form, this disclosure also discloses each subgroup of the elements, and any element may be removed from that group. It should also be noted that the terms "comprising" and "comprising" are intended to be open ended and allow for the inclusion of additional elements or steps. Where ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and understanding of one of ordinary skill in the art, values expressed as ranges may employ any specific value or sub-range within the range in various embodiments of the invention, up to the lower unit of the range. One tenth, unless the context clearly dictates otherwise.

Description of drawings

Fig. 1 is a graph showing the water intake and licking rate of rats within 24 hours on the 16th day after induction in the Parkinson's disease model induced by 6-OHDA in Example 1 of the present invention;

Fig. 2 is the minimal current diagram of the swallowing reflex evoked on the 7th day of administration in the rat Parkinson's disease model induced by 6-OHDA in Example 1 of the present invention;

Figure 3 is a graph of the average number of TH-positive nuclei in the left and right substantia nigra after administration in the rat Parkinson's disease model induced by 6-OHDA in Example 1 of the present invention;

Fig. 4 is the total DAB positive optical density map of left and right striatum after administration in the rat Parkinson's disease model induced by 6-OHDA in Example 1 of the present invention;

Figure 5 is a graph of the licking rate of each group on the 6th day and the 14th day of administration in the MACO-induced stroke model in Example 2 of the present invention;

6 is a graph of the licking rate of each group on the 8th day and the 14th day of administration in the SOD1 transgenic-induced rat ALS model in Example 3 of the present invention;

Fig. 7 is the minimum current diagram of the swallowing reflex evoked in each group on the 14th day of administration in the SOD1 transgenic-induced rat ALS model in Example 3 of the present invention;

Figure 8 is a graph of the number of endophagy in 60s in each group on the 14th day of administration in the SOD1 transgenic-induced rat ALS model in Example 3 of the present invention.

Detailed ways

The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the intended protection scope of the present invention.

Unless otherwise stated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.

Example 1 6-hydroxydopamine (6-OHDA)-induced Parkinson's syndrome model in rats

Accurately weigh 100 mg of dextromethorphan hydrobromide and 100 mg of quinidine sulfate, add 10 mL of methylcellulose solution (1% w/v), and sonicate for 30 minutes to form a dextromethorphan quinidine suspension.

Dissolve 6-OHDA-HCl in saline containing 0.02% ascorbic acid, prepare a solution of 4.4 mg/mL (corresponding to 3.0 mg/ml free base 6-OHDA), and store at 0°C in the dark.

Male SD rats (n=30, 220-250 g) were housed for 7 days for acclimatization and baseline licking rates were recorded. Rats were randomly divided into blank group, model group and treatment group according to body weight and licking rate, with 10 rats in each group. The neurotoxin 6-hydroxydopamine (6-OHDA) was slowly injected into the right medial forebrain bundle of the rats in the model group and the treatment group (maximum rate: 1 μL/min, 18 μg/rat). From day 6 to day 16 after induction, the 24-hour water intake of rats in each group was measured every day. Two weeks after induction, rats were given 0.1 mg/kg apomorphine, and their apomorphine-induced rotational behavior was detected. The model group and treatment group were regrouped into 6-OHDA group-1 and 6-OHDA group-2 based on the results of the rotation test. group-1 is the new model group and group-2 is the new treatment group. The licking rate of each rat was measured on day 16. The 24-hour water intake and licking rate test results of each rat on the 16th day are shown in Figure 1, where POD refers to the day after the operation.

The results showed that on the 16th day after induction, the 24-hour water intake and licking rate of the rats were significantly lower than those of the blank group, indicating that the rats had difficulty swallowing.

On the 20th day after induction, dextromethorphan quinidine suspension (po, 5 mL/kg) was administered to the rats in the treatment group. On the sixth day after dosing, test rats were tested for licking rate to determine whether swallowing function improved. If the swallowing function improved, the bioelectric signal of the upper laryngeal nerve of each rat was measured by in vivo electromyography (EMG) on the 7th day of administration, and the minimum current that evoked the swallowing reflex was recorded. The results are shown in Figure 2. Since 6-OHDA is injected into the right medial forebrain bundle, the left somatic motor function will be impaired, and it has a certain compensatory effect on the right somatic function. The results in Figure 2 show that the minimum current arousing the swallowing reflex of rats in the model group is higher than that of the blank group. After treatment with dextromethorphan quinidine, the minimum current evoking the swallowing reflex in rats is significantly reduced, indicating that dextromethorphan quinidine can significantly reduce the swallowing reflex. Improve dysphagia symptoms.

The rats were sacrificed, and tyrosine hydroxylase positive staining (immunohistochemistry, DAB staining) was performed on the substantia nigra and striatum of the rats; the average number of TH-positive nuclei in the black substantia and the total DAB positivity in the striatum were detected Optical density was used to investigate the improvement of dopamine neuron morphology in the substantia nigra and striatum of PD rats after administration. The results are shown in Figures 3 and 4. The results showed that the levels of dopaminergic neurons in both the substantia nigra and striatum of rats were significantly increased after dextromethorphan quinidine treatment. Since the dyskinesias of Parkinson's disease are associated with depletion of dopamine in the striatum and substantia nigra regions, these results suggest that dextromethorphan quinidine can significantly improve the dyskinesias associated with Parkinson's disease.

Example 2 Middle cerebral artery occlusion (MCAO)-induced stroke model in rats

Male SD rats (n=30, 220-240 g) were housed for 7 days for acclimatization and baseline licking rates were recorded. Rats were randomly divided into blank group, model group and treatment group according to body weight and licking rate, with 10 rats in each group. Insert a sterilized filament into the external carotid artery (ECA) of the model and treatment groups and thread it anteriorly into the internal carotid artery (ICA) 18 ± 0.5 mm until the tip occludes the origin of the middle cerebral artery, resulting in blood flow cessation and infarction of the cerebral artery. After 1.5 hours the suture was retracted to the stump of the ECA to achieve reperfusion. Cerebral blood flow (CBF) was measured at baseline, after occlusion, and at reperfusion using laser Doppler flowmetry. Continued decrease in CBF (rCBF≥70%) was considered as a sign of successful MCAO model construction.

In a manner similar to Example 1, the 24-hour water intake and licking rate of each rat were regularly measured to confirm that the rats in the model group and the treatment group had dysphagia. On the 17th day after induction, the treatment group was given dextromethorphan quinidine suspension according to the administration mode in Example 1. On the 6th and 14th days after administration, the licking rate of the test rats was tested to determine whether the swallowing function was improved. The results are shown in Figure 5.

The results showed that on the 6th and 14th days after administration, the licking rate of the rats in the treatment group was significantly improved, indicating that the swallowing function of the rats in the DMQ treatment group was significantly improved.

Example 3ALS Model

Male SOD1 transgenic rats (disease rats, n=20) and wild-type rats (n=10) were housed for 7 days for acclimatization and baseline licking rates were recorded. The neuroscore (NS) of the transgenic rats was performed daily according to the hindlimb function, and the scoring criteria were as follows:

NS 0 (pre-symptomatic): normal opening of the hind limbs;

NS 1 (first symptom): abnormal opening of the hind limbs;

NS 2 (paralytic attack): partial or complete collapse of the hind limbs without much extension;

NS 3 (paralysis): stiffness and paralysis of the hind limbs or minimal joint movement;

NS 4 (artificial endpoint): stiffness and paralysis of the hind limbs.

Rats with NS of 0 and 4 were excluded. In a manner similar to Example 1, the 24-hour water intake and licking rate of each rat were regularly measured to confirm that the rats in the model group and the treatment group had dysphagia. After dysphagia, the treatment group was given dextromethorphan quinidine suspension according to the administration mode in Example 1. On the 14th day of administration, the licking rate of the test rats was tested, and the results are shown in FIG. 6 . On the 15th day of administration, in vivo electromyography (EMG) was used to measure the bioelectrical signal of the upper laryngeal nerve, and the minimum current to evoke the swallowing reflex and the number of swallows within 60s were recorded. The results are shown in Figures 7 and 8, respectively.

The results in Figure 6 show that on the 14th day after treatment with dextromethorphan quinidine, there was no significant difference in the licking rate between the treatment group and the model group.

The results in Figure 7 and Figure 8 show that the minimum current arousing the swallowing reflex and the number of swallowing times within 60 s of the rats in the model group were not significantly different from those in the healthy group. After treatment with dextromethorphan quinidine, the swallowing reflex was aroused in the rats There was no significant difference in the minimum current compared with the model group.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiments. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, equivalents to many of the specific embodiments herein. The scope of embodiments of the present invention is not intended to be limited by the specific description above, but is rather as set forth in the appended claims. It will be understood by those of ordinary skill in the art that various changes and modifications can be made in this specification without departing from the spirit or scope of the invention as defined in the appended claims, and any modifications, equivalent substitutions, improvements made etc., should be included within the protection scope of the present invention.

Claims

Use of a pharmaceutical composition in the preparation of a medicine for treating or relieving dysphagia and/or salivation symptoms in a disease, wherein the pharmaceutical composition comprises:

(i) Dextromethorphan, its isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs or pharmaceutically acceptable co-crystals thereof; and

(ii) quinidine, isotopically labeled compounds, pharmaceutically acceptable salts, solvates, polymorphs or pharmaceutically acceptable co-crystals thereof;

Wherein, the disease is not amyotrophic lateral sclerosis.
The use according to claim 1, wherein the disease is a nervous system disease.
The use according to claim 1 or 2, wherein the neurological disease is selected from Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke, cerebral infarction, Huntington's disease, myasthenia gravis or meningitis, preferably Parkinson's disease, multiple sclerosis, stroke or cerebral infarction.
The use according to any one of claims 1-3, characterized in that: the dextromethorphan, its isotope-labeled compound, pharmaceutically acceptable salt, solvate, polymorph or pharmaceutically acceptable co- The molar ratio of the crystal to quinidine, its isotopically labeled compound, pharmaceutically acceptable salt, solvate, polymorph or pharmaceutically acceptable co-crystal is from 1:1 to 10:1, preferably from 2:1 to 8:1, more preferably 3:1 to 6:1.
The use according to any one of claims 1-3, characterized in that: the dextromethorphan, its isotope-labeled compound, pharmaceutically acceptable salt, solvate, polymorph or pharmaceutically acceptable co- The mass ratio of the crystal to quinidine, its isotopically labeled compound, pharmaceutically acceptable salt, solvate, polymorph or pharmaceutically acceptable co-crystal is 1:2 to 10:1, preferably 1:1 to 5:1, more preferably 1:1 to 2:1.
The use according to any one of claims 1-5, characterized in that: the dextromethorphan, its isotope-labeled compound, pharmaceutically acceptable salt, solvate, polymorph or pharmaceutically acceptable co- The crystal is dextromethorphan monohydrobromide monohydrate.
The use according to any one of claims 1-6, characterized in that: the quinidine, its isotope-labeled compound, pharmaceutically acceptable salt, solvate, polymorph or pharmaceutically acceptable co- The crystal is quinidine hemisulfate monohydrate.
The use according to any one of claims 1-7, characterized in that: the dextromethorphan, its isotope-labeled compound, pharmaceutically acceptable salt, solvate, polymorph or pharmaceutically acceptable co- The amount of crystals is 15-150 μmol, preferably 30-100 μmol, more preferably 40-70 μmol.
The use according to any one of claims 1-7, characterized in that: the dextromethorphan, its isotope-labeled compound, pharmaceutically acceptable salt, solvate, polymorph or pharmaceutically acceptable co- The mass of the crystal is 10-150 mg, preferably 10-100 mg, more preferably 20-60 mg.
The use according to any one of claims 1-7, wherein the quinidine, its isotopically-labeled compound, pharmaceutically acceptable salt, solvate, polymorph or pharmaceutically acceptable co- The amount of crystals is about 4-40 μmol, preferably 7-25 μmol, more preferably 10-20 μmol.
The use according to any one of claims 1-7, wherein the quinidine, its isotopically-labeled compound, pharmaceutically acceptable salt, solvate, polymorph or pharmaceutically acceptable co- The mass of the crystal is 10-150 mg, preferably 10-100 mg, more preferably 10-60 mg.
The use according to any one of claims 1-11, wherein the dextromethorphan, its isotopically-labeled compound, pharmaceutically acceptable salt, solvate, polymorph or pharmaceutically acceptable Co-crystals, and one or both of quinidine, its isotopically-labeled compounds, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, or pharmaceutically acceptable co-crystals thereof Oral or parenteral administration.
11. The use according to any one of claims 1 to 11, wherein the method additionally comprises surgery, radiotherapy and/or transplantation or additional medical treatment.
The use of any one of claims 1-12, wherein the additional agent comprises a cytotoxic chemotherapeutic agent, an epigenetic modifier, a glucocorticoid, an immunotherapeutic agent, an antiproliferative agent, an anticancer agent agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressive agents, antibacterial agents, antiviral agents, cardiovascular drugs, cholesterol lowering agents, antidiabetic agents, antiallergic agents, contraceptives, pain relievers, and combinations thereof; preferred topologies Isomerase inhibitor, MCL1 inhibitor, BCL-2 inhibitor, BCL-xL inhibitor, BRD4 inhibitor, BRCA1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor, CDK9 inhibitor, Jummonji histone deactivator Methylase inhibitor or DNA damage inducer, antibody or fragment thereof, immunosuppressant, immune activator, immune checkpoint inhibitor, programmed cell death 1 protein inhibitor, programmed cell death 1 protein ligand 1 inhibitor , cytotoxic T lymphocyte-associated protein 4 inhibitor, T cell immunoglobulin domain and mucin domain 3 inhibitor, lymphocyte activation gene-3 inhibitor, T cell activation inhibitor 1 containing V-SET domain Inhibitors, Differentiation Antigen 276 Inhibitors, B and T Lymphocyte Attenuating Factor Inhibitors, Galectin-9 Inhibitors, Checkpoint Kinase 1 Inhibitors, Adenosine A2A Receptor Inhibitors, Indoleamines 2,3 - Dioxygenase inhibitors, killer cell immunoglobulin-like receptor inhibitors or IgV-domain inhibitors of T cell activation or metformin.