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WO2022228363A1 - 一种组合物的医药用途 - Google Patents

一种组合物的医药用途 Download PDF

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Publication number
WO2022228363A1
WO2022228363A1 PCT/CN2022/088904 CN2022088904W WO2022228363A1 WO 2022228363 A1 WO2022228363 A1 WO 2022228363A1 CN 2022088904 W CN2022088904 W CN 2022088904W WO 2022228363 A1 WO2022228363 A1 WO 2022228363A1
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Prior art keywords
pharmaceutically acceptable
inhibitor
quinidine
polymorph
dextromethorphan
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PCT/CN2022/088904
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English (en)
French (fr)
Inventor
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
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Publication of WO2022228363A1 publication Critical patent/WO2022228363A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • 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.
  • 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.
  • dysphagia is often treated or improved through dietary modification, oral rehabilitation exercises, acupuncture, nasogastric tube, and deep brain stimulation.
  • these methods have problems such as poor patient compliance, uncertain effectiveness, and limited scope of use, which cannot meet clinical needs.
  • 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 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;
  • the disease is not amyotrophic lateral sclerosis.
  • 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.
  • 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.
  • 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.
  • the disease is a neurological disease.
  • the disease is a neurodegenerative disease.
  • the disease is Parkinson's disease, Alzheimer's disease, syringomyelia, Wolfram's syndrome, or Huntington's disease.
  • the disease is cerebrovascular disease. In certain embodiments, the disease is stroke or cerebral infarction.
  • the disease is an inflammatory disease.
  • the disease is multiple sclerosis, Guillain-Barre syndrome, poliomyelitis, or Lyme disease.
  • the disease is a neuromuscular junction disease. In certain embodiments, the disease is myasthenia gravis or neurobehcet's disease.
  • the disease is an infectious disease.
  • 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.
  • the disease is a genetic disease. In certain embodiments, the disease is Kennedy's disease. In certain embodiments, the disease is acute intermittent porphyria.
  • the disorder is a psychiatric disorder. In certain embodiments, the disorder is autism. In certain embodiments, the disorder is major depressive disorder.
  • the disease is a metabolic disease. In certain embodiments, the disease is osmotic demyelinating syndrome.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the dextromethorphan is a compound of the formula:
  • dextromethorphan consists of isotopes substantially in their natural abundance.
  • the dextromethorphan isotopically-labeled compound is deuterated dextromethorphan (eg, mono-deuterated dextromethorphan, multi-deuterated dextromethorphan, or per-deuterated dextromethorphan).
  • the dextromethorphan isotopically labeled compound is dextromethorphan labeled with one or more3H , one or more14C , one or more15N , and/or one or more18O .
  • the pharmaceutically acceptable salt of dextromethorphan is dextromethorphan hydrobromide, preferably, the pharmaceutically acceptable salt of dextromethorphan is dextromethorphan monohydrobromide.
  • the pharmaceutically acceptable solvate of dextromethorphan is dextromethorphan hydrate (eg, dextromethorphan monohydrate).
  • 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.
  • 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.
  • 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 ⁇ mol.
  • 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 ⁇ mol. 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 ⁇ mol.
  • 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 ⁇ mol.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • quinidine consists of isotopes substantially in their natural abundance.
  • the quinidine isotopically labeled compound is deuterated quinidine (eg, mono-deuterated quinidine, poly-deuterated quinidine, or per-deuterated quinidine).
  • the quinidine isotopically labeled compound is quinidine labeled with one or more3H , one or more14C , one or more15N , and/or one or more18O .
  • the pharmaceutically acceptable salt of quinidine is quinidine sulfate, preferably, the pharmaceutically acceptable salt of quinidine is quinidine hemisulfate.
  • the pharmaceutically acceptable solvate of quinidine is quinidine hydrate (eg, quinidine monohydrate).
  • 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.
  • 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.
  • 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 ⁇ mol.
  • 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 ⁇ mol. 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 ⁇ mol. 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 ⁇ mol.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • a pharmaceutical composition comprising:
  • Dextromethorphan its isotopically labeled compounds, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, polymorphs, or pharmaceutically acceptable co-crystals thereof;
  • 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.
  • 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.
  • 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.
  • the disease is as defined above.
  • the pharmaceutical composition contains about 15-150 ⁇ mol 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.
  • 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.
  • the pharmaceutical composition contains about 4-40 ⁇ mol 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.
  • 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.
  • compositions of the present invention further comprise one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition is in unit dosage form.
  • the unit dose comprises: (1) about 15-150 ⁇ mol 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 ⁇ mol of quinidine, its isotopically labeled compound, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, polymorph, or its pharmaceutically acceptable co-crystals.
  • the co-crystal is preferably 30-100 ⁇ mol, more preferably 40-70 ⁇ mol; 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 ⁇ mol, more preferably 10-20 ⁇ mol.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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 compounds, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its polymorphs, or its pharmaceutically acceptable co-crystals, or both, are administered orally.
  • 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 compounds, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its polymorphs, or its pharmaceutically acceptable co-crystals are administered orally.
  • 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 .
  • 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.
  • 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.
  • cytotoxic chemotherapeutic agents including 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.
  • 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.
  • the additional agent is a binding agent or inhibitor of a kinase (eg, a tyrosine kinase).
  • the additional agent is an antibody or fragment thereof (eg, a monoclonal antibody).
  • the additional treatment is immunotherapy (eg, immunotherapeutic monoclonal antibodies).
  • 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.
  • CTLA-4 cytotoxic T lymphocyte-associated protein 4
  • 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.
  • TIM3 T cell immunoglobulin and mucin domain 3
  • LAG3 lymphocyte activation gene-3
  • the additional agent is metformin.
  • 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.
  • FDA US Food and Drug Administration
  • EMA European Medicines Agency
  • 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).
  • 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.
  • the subject is a companion animal, such as a dog or cat.
  • the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal, eg, a rodent (eg, mouse, rat), dog, pig, or non-human primate.
  • the subject is a genetically engineered animal.
  • 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.
  • 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.
  • range 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.
  • administering refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or a pharmaceutical composition thereof.
  • compound of the present invention includes 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.
  • 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 .
  • 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.
  • 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.
  • 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.
  • inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids
  • organic acids such as acetic, oxalic, maleic, tartaric, lemon acid, succinic acid or malonic acid
  • salts formed by other methods used in the art such as ion exchange.
  • 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, Persulf
  • 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.
  • 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.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • 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.
  • Solids include solution-phase and isolatable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • 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.
  • hydrate refers to a compound that is associated with water.
  • 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.
  • 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)).
  • monohydrate x is 1
  • low hydrate x is a number greater than 0 and less than 1, such as hemihydrate (R 0.5H2O )
  • polyhydrates x is a number greater than 1, such as dihydrate (R ⁇ 2H2O) and hexahydrate (R ⁇ 6H2O)).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • this disclosure also discloses each subgroup of the elements, and any element may be removed from that group.
  • 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.
  • 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
  • Example 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.
  • 6-OHDA neurotoxin 6-hydroxydopamine
  • 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.
  • dextromethorphan quinidine suspension (po, 5 mL/kg) was administered to the rats in the treatment group.
  • 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.
  • EMG in vivo electromyography
  • 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.
  • Example 5 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 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 abnormal opening of the hind limbs
  • NS 2 paralytic attack: partial or complete collapse of the hind limbs without much extension
  • NS 3 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.
  • 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.
  • the treatment group was given dextromethorphan quinidine suspension according to the administration mode in Example 1.
  • the licking rate of the test rats was tested, and the results are shown in FIG. 6 .
  • 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.

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Abstract

一种右美沙芬或其药学上可接受的盐和奎尼丁或其药学上可接受的盐联合用于治疗或缓解神经系统疾病中吞咽困难和/或流涎的用途。该用途可有效治疗或缓解神经系统疾病患者的吞咽困难和/或流涎，避免或减少了相应并发症的发生，对患者生活质量的提高具有非常重要的意义。

Description

一种组合物的医药用途
本申请要求2021年4月27日向中国国家知识产权局提交的，专利申请号为202110460793.5，发明名称为“一种组合物的医药用途”的在先申请的优先权。所述申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及医药领域，具体涉及一种右美沙芬或其药学上可接受的盐和奎尼丁或其药学上可接受的盐的联合用药的新用途。更具体的，涉及右美沙芬或其药学上可接受的盐和奎尼丁或其药学上可接受的盐联合用于治疗或缓解疾病中的吞咽困难和流涎。
背景技术
吞咽障碍和流涎是神经系统疾病伴随的常见胃肠道问题之一，发生比例较高。有研究表明，帕金森病患者吞咽困难的发生率是11-87％。超过50％的急性脑梗死患者伴有不同程度的吞咽障碍。脑卒中患者中吞咽困难的发病率约为51～73％。约三分之一的多发性硬化症患者存在吞咽困难的症状。吞咽困难常导致严重的并发症，如脱水、营养不良、气道阻塞和吸入性肺炎等，严重的甚至会危及生命。另外，由于上述疾病的患者流涎的主要原因是吞咽唾液困难，而不是唾液分泌过多，所以流涎常伴随吞咽困难，是神经系统疾病患者常见的症状。吞咽困难和流涎不仅对身体产生影响，还会产生生活和社会活动上的不便，影响患者的情绪，导致抑郁，从而使患者生活质量下降。
目前，由于尚未有药物被批准用于治疗或缓解吞咽困难和流涎，常通过饮食调整、口腔康复练习、针灸、鼻胃管、深部脑刺激等手段来治疗或改善吞咽困难。但这些手段存在患者顺应性差，有效性不确定、使用范围局限等问题，均无法满足临床需求。
综上所述，对吞咽困难和/或流涎相关药物的研究具有非常重要的临床意义，亟需开发一种能够治疗或缓解神经系统疾病中吞咽困难和/或流涎的药物。
发明内容
本发明的目的在于解决现有技术中的问题，提供一种治疗或缓解神经系统疾病中吞咽困难和/或流涎症状的方法。
本发明的目的可通过以下技术方案实现：
本发明提供一种治疗或缓解疾病中吞咽困难和/或流涎症状的方法，包括给予有效量的：
右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶；以及
奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶；
其中，所述疾病不为肌萎缩侧索硬化。
在某些实施方案中，给予受试者右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶与给予受试者奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶基本上同时进行。在某些实施方案中，给予受试者右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶在给予受试者奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶之前(例如，1至10分钟、10至60分钟、1至6小时或6至24小时之前)。在某些实施方案中，给予受试者右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶在给予受试者奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶之后(例如，1至10分钟、10至60分钟、1至6小时或6至24小时之后)。
在某些实施方案中，所述疾病为神经系统疾病。
在某些实施方案中，该疾病是神经退行性疾病。在某些实施方案中，该疾病是帕金森综合症、阿尔茨海默病、延髓空洞症、沃尔弗拉姆综合征或亨廷顿氏病。
在某些实施方案中，该疾病是脑血管疾病。在某些实施方案中，该疾病是脑卒中或脑梗死。
在某些实施方案中，该疾病是炎性疾病。在某些实施方案中，该疾病是多发性硬化、格林巴利综合征、脊髓灰质炎或莱姆病。
在某些实施方案中，该疾病是神经肌肉接头疾病。在某些实施方案中，该疾病是重症肌无力或神经白塞病。
在某些实施方案中，该疾病是感染性疾病。
在某些实施方案中，该疾病是肿瘤性疾病。在某些实施方案中，该疾病是癌症。在某些实施方案中，该疾病是中枢神经系统癌症。在某些实施方案中，该疾病是脑癌。在某些实施方案中，该疾病是脑干胶质瘤。在某些实施方案中，该疾病是恶性脑膜炎。在某些实施方案中，该疾病是高脑干肿瘤。
在某些实施方案中，该疾病是遗传疾病。在某些实施方案中，该疾病是肯尼迪氏病。在某些实施方案中，该疾病是急性间歇性卟啉病。
在某些实施方案中，该疾病是精神疾病。在某些实施方案中，该疾病是孤独症。在某些实施方案中，该疾病是重度抑郁症。
在某些实施方案中，该疾病是代谢疾病。在某些实施方案中，该疾病是渗透性脱髓鞘综合征。
在某些实施方案中，该疾病选自帕金森综合症、阿尔茨海默症、多发性硬化、脑卒中、脑梗死、亨廷顿舞蹈病、重症肌无力或脑膜炎。优选帕金森综合症、多发性硬化、脑卒中或脑梗死。
在某些实施方案中，右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶与奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的摩尔比为1:1至10:1。在某些实施方案中，右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶与奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的摩尔比为2:1至8:1。在某些实施方案中，右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶与奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的摩尔比为3:1至6:1。在某些实施方案中，右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶与奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的摩尔比为约4:1。
在某些实施方案中，右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶与奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的质量比为1:2至10:1，例如为1:2，1:1，2:1，3:1，4:1，5:1，6:1，7:1，8:1，9:1，10:1。在某些实施方案中，右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶与奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的质量比为1:1至5:1。在某些 实施方案中，右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶与奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的质量比为1:1至2:1。
根据本发明，所述右美沙芬(DM)是下式的化合物：
Figure PCTCN2022088904-appb-000001
其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或其互变异构体。在某些实施方案中，右美沙芬由基本上处于其天然丰度的同位素组成。在某些实施方案中，右美沙芬同位素标记化合物是氘代右美沙芬(例如，单氘代右美沙芬、多氘代右美沙芬或全氘代右美沙芬)。在某些实施方案中，右美沙芬同位素标记化合物是用一个或多个 3H、一个或多个 14C、一个或多个 15N和/或一个或多个 18O标记的右美沙芬。
在某些实施方案中，右美沙芬的药学上可接受的盐是右美沙芬氢溴酸盐，优选的，右美沙芬的药学上可接受的盐是右美沙芬一氢溴酸盐。在某些实施方案中，右美沙芬的药学上可接受的溶剂化物是右美沙芬水合物(例如，右美沙芬一水合物)。在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶是右美沙芬的药学上可接受的盐的水合物。在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶是右美沙芬一氢溴酸盐一水合物。
在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为15至150μmol。
在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为30至100μmol。在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为40至70μmol。在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为约54μmol。
在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的质量为5至150mg。
在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的质量为5至80mg。
在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的质量为10至100mg。在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为10至40mg。在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为10至30mg。在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的质量为20至60mg。在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为约20mg。奎尼丁是下式的化合物：
Figure PCTCN2022088904-appb-000002
其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或其互变异构体或其互变异构体。在某些实施方案中，奎尼丁由基本上处于其天然丰度的同位素组成。在某些实施方案中，奎尼丁同位素标记化合物是氘代奎尼丁(例如，单氘代奎尼丁、多氘代奎尼丁或全氘代奎尼丁)。在某些实施方案中，奎尼丁同位素标记化合物是用一个或多个 3H、一个或多个 14C、一个或多个 15N和/或一个或多个 18O标记的奎尼丁。在某些实施方案中，奎尼丁的药学上可接受的盐是奎尼丁硫酸盐，优选的，奎尼丁的药学上可接受的盐是奎尼丁半硫酸盐。在某些实施方案中，奎尼丁的药学上可接受的溶剂化物是奎尼丁水合物(例如，奎尼丁一水合物)。在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶是奎尼丁的药学上可接受的盐的水合物。在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶是奎尼丁半硫酸盐一水合物。
在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为4至40μmol。
在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为7至25μmol。在某些实施方案中，奎尼丁或其同位素标记化合物奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为10至20μmol。在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为约13μmol。
在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为2.5至150mg。
在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为10至150mg。
在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为10至100mg。
在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为10至60mg。
在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为2.5至40mg。
在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为5至30mg。在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为7至20mg。在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为10至15mg。在某些实施方案中，奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶的量为约10mg。
在优选的实施方式中，所述右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶，以及奎尼丁、其同位素标记化合物、药学上可接受的盐、药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶经口服、注射或胃肠外给药。
在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶和奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶为 两种单独的剂型。在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶和奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶为单一剂型。
本发明还提供一种药物组合物，所述药物组合物包括：
(i)右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶体；
(ii)奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶体。
在一些方面，本发明提供所述药物组合物在制备用于治疗或缓解疾病中吞咽困难和/或流涎症状的药物中的用途。
在另一方面，本发明提供右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶在制备用于治疗或缓解疾病中吞咽困难和/或流涎症状的药物中的用途。
在另一方面，本发明提供奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶在制备用于治疗或缓解疾病中吞咽困难和/或流涎症状的药物中的用途。
根据本发明的实施方案，所述疾病同前文所定义。
根据本发明的实施方案，所述药物组合物含有约15-150μmol右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶。
根据本发明的实施方案，所述药物组合物含有10-150mg右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶。
根据本发明的实施方案，所述药物组合物含有约4-40μmol奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶。
根据本发明的实施方案，所述药物组合物含有10-150mg奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶。
在某些实施方案中，本发明所述药物组合物，进一步包括一种或多种药学上可接受的赋形剂。
在一些实施方案中，所述药物组合物以单位剂量形式。
根据本发明的实施方案，所述单位剂量包含：(1)约15-150μmol右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶；(2)约4-40μmol奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶。
根据本发明的实施方案，所述单位剂量中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶优选为30-100μmol，更优选为40-70μmol；奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶优选为7-25μmol，更优选为10-20μmol。
根据本发明的实施方案，所述单位剂量包含：(1)15-150mg右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶；(2)约10-150mg奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶。
根据本发明的实施方案，所述单位剂量中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶优选为10-100mg，更优选为20-60mg；奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶优选为10-100mg，更优选为10-60mg。
根据本发明的实施方案，所述单位剂量适于口服或胃肠外给药。
本发明的化合物和药物组合物可以通过任何途径给药，包括肠内(例如，口服)、肠胃外、静脉内、肌内、动脉内、髓内、鞘内、皮下、心室内、透皮、真皮间、直肠、阴道内、腹膜内、局部(如通过粉剂、膏剂、霜剂和/或滴剂)、粘膜、鼻、颊、舌下；通过气管内滴注、支气管滴注和/或吸入；和/或作为口腔喷雾剂、鼻腔喷雾剂和/或气雾剂。特别考虑的途径是口服给药、静脉内给药(例如全身静脉内注射)、通过血液和/或淋巴供应的局部给药和/或直接给药至受影响的部位。在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶体和奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶中的一者或两者经口服给药。在某些实施方案中，右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶和奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶中的两者均经口服给药。在某些实施方案中，右美沙芬、 其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶和奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶中的一者或两者不经口服给药。
在某些实施方案中，本发明的方法还包括给予有需要的受试者手术、放射疗法和/或移植或额外的药剂治疗。额外的药剂可在给予本发明的化合物或药物组合物的同时、之前或之后给药。
在某些实施方案中，额外的药剂是额外的治疗活性或预防活性剂，包括但不限于细胞毒性化学治疗剂、表观遗传修饰剂、糖皮质激素、免疫治疗剂、抗增殖剂、抗癌剂、抗血管生成剂、抗炎剂、免疫抑制剂、抗菌剂、抗病毒剂、心血管药物、降胆固醇剂、抗糖尿病剂、抗过敏剂、避孕药、疼痛缓解剂及其组合。在一些实施方案中，额外的药剂是拓扑异构酶抑制剂、MCL1抑制剂、BCL-2抑制剂、BCL-xL抑制剂、BRD4抑制剂、BRCA1抑制剂、BRCA2抑制剂、HER1抑制剂、HER2抑制剂、CDK9抑制剂、Jummonji组蛋白脱甲基酶抑制剂或DNA损伤诱导剂。在某些实施方案中，额外的药剂是激酶(例如酪氨酸激酶)的结合剂或抑制剂。在某些实施方案中，额外的药剂是抗体或其片段(例如，单克隆抗体)。在某些实施方案中，额外的治疗是免疫治疗(例如，免疫治疗单克隆抗体)。在某些实施方案中，额外的药剂是免疫抑制剂。在某些实施方案中，额外的药剂是免疫激活剂。在某些实施方案中，额外的药剂是免疫检查点抑制剂。在某些实施方案中，额外的药剂是程序性细胞死亡1蛋白(PD-1)抑制剂。在某些实施方案中，额外的药剂是程序性细胞死亡1蛋白配体1(PD-L1)抑制剂。在某些实施方案中，额外的药物是细胞毒性T淋巴细胞相关蛋白4(CTLA-4)抑制剂。在某些实施方案中，额外的药剂是T细胞免疫球蛋白结构域和粘蛋白结构域3(TIM3)抑制剂、淋巴细胞活化基因-3(LAG3)抑制剂、含V-SET结构域的T细胞活化抑制剂1(VTCN1或B7-H4)抑制剂、分化抗原簇276(CD276或B7-H3)抑制剂、B和T淋巴细胞衰减因子(BTLA)抑制剂、半乳凝素-9(GAL9)抑制剂、检查点激酶1(Chk1)抑制剂、腺苷A2A受体(A2AR)抑制剂、吲哚胺2,3-双加氧酶(IDO)抑制剂、杀伤细胞免疫球蛋白样受体(KIR)抑制剂或T细胞活化的IgV-结构域抑制剂(VISTA)抑制剂。在某些实施方案中，额外的药剂是二甲双胍。在某些实施方案中，额外的药剂由管理机构(例如美国食品药品监督管理局(FDA)或欧洲药品管理局(EMA))批准用于人和/或兽用。在某些实施方案中，本发明的化合物或药物组合物可以与手术、放射疗法和/或移植(例如，干细胞移植、骨髓移植)组合给药。
在某些实施方案中，受试者是哺乳动物。在某些实施方案中，受试者是人。在某些实施方案中，受试者是18岁或以上的人。在某些实施方案中，受试者是21岁或以上的人。在某些 实施方案中，受试者是12至18岁的人。在某些实施方案中，受试者是2至12岁的人。在某些实施方案中，受试者是29天至小于2岁的人。在某些实施方案中，受试者是小于29天的人。在某些实施方案中，受试者是非人哺乳动物。在某些实施方案中，受试者是驯化动物，例如狗、猫、牛、猪、马、绵羊或山羊。在某些实施方案中，受试者是陪伴动物，例如狗或猫。在某些实施方案中，受试者是家畜动物，例如牛、猪、马、绵羊或山羊。在某些实施方案中，受试者是动物园动物。在另一个实施方案中，受试者是研究动物，例如啮齿动物(例如小鼠、大鼠)、狗、猪或非人灵长类动物。在某些实施方案中，受试者是基因工程动物。在某些实施方案中，受试者是转基因动物(例如，转基因小鼠、转基因猪)。
本发明提供了一种右美沙芬或其药学上可接受的盐和奎尼丁或其药学上可接受的盐的组合的新用途。该用途可治疗或缓解疾病中的吞咽障碍和流涎。并且，本发明提供的右美沙芬或其药学上可接受的盐和奎尼丁或其药学上可接受的盐的组合安全性高，可满足患者用药要求，可显著提高患者的生活质量。
术语和范围等相关解释
当列出了值的范围(“范围”)时，其旨在包括该范围内的每个值和子范围。除非另有说明，否则范围包括该范围两端值。
术语“给予”、“施用”或“给药”是指植入、吸收、摄取、注射、吸入或以其它方式引入化合物或其药物组合物。
术语“病症”、“疾病”和“障碍”可互换使用。
“本发明的化合物”、“本发明所述化合物”、“本发明活性成分”、“活性组成化合物”等术语表述包括组成本发明药物组合物/本发明联合治疗方案的任意药用活性成分，且涵盖这些活性成分的各种变形、存在形式，例如包括右美沙芬、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶；和/或奎尼丁、其同位素标记化合物、其药学上可接受的盐、其药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶。
术语“同位素标记化合物”是指除了在一个或多个位置的同位素组成与本发明化合物有区别之外(如氢相对于氘)，其所具有的化学结构与化学式和本发明的化合物相同的结构，所述同位素标记化合物的至少一个原子包括至少一个富集在其天然丰度以上(例如，富集3倍、10倍、30倍、100倍、300倍、1000倍、3000倍或10000倍以上)的同位素，其中化合物由基本上处于其天然丰度的同位素组成。所述“同位素标记物”包括但不限于氢，碳，氮，氧，氟，硫和氯的同位素(例如 2H， 3H， 13C， 14C， 15N， 18O， 17O， 18F， 35S和 36Cl)标记的本发明化合物。 同位素标记的本发明化合物可用于化合物及其前药和代谢物的组织分布的测定；用于此类测定的优选同位素包括 3H和 14C。此外，在某些情况下，用较重的同位素(例如氘(2H或D))取代化合物可以提供更多的治疗优势效果，例如增加的代谢稳定性，增加的体内半衰期或减少的剂量需求等。本发明的同位素标记的化合物通常可以根据本文所述的方法通过用同位素标记的试剂取代非同位素标记的试剂来制备。
术语“药学上可接受的盐”是指在合理的医学判断范围内，适用于与受试者(例如人)的组织接触而没有过度的毒性、刺激、过敏反应等，并且与合理的获益/风险比相称的盐。药学上可接受的盐是本领域所熟知的。例如，Berge等在J.Pharmaceutical Sciences(1977)66:1-19中详细描述了药学上可接受的盐。本文描述的化合物的药学上可接受的盐包括衍生自合适的无机和有机酸和碱的盐。药学上可接受的无毒酸盐的示例为氨基基团与无机酸(例如盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(例如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)、或通过本领域使用的其它方法(例如离子交换)形成的盐。其它药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂烷硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。衍生自合适的碱的盐包括碱金属盐、碱土金属盐、铵盐和N +(C 1-4烷基) 4盐。代表性的碱金属盐或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。其它药学上可接受的盐包括，如合适，季盐。
术语“溶剂化物”是指通常通过溶剂分解反应与溶剂缔合的化合物形式。这种物理缔合可以包括氢键键合。常规溶剂包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本发明的化合物可以例如以晶型制备，并且可以是溶剂化的。合适的溶剂化物包括药学上可接受的溶剂化物，并且还包括化学计量的溶剂化物和非化学计量的溶剂化物。在某些情况下，例如将一种或多种溶剂分子结合到结晶固体的晶格中时，溶剂化物将能够分离。“溶剂化物”包括溶液相的和可分离的溶剂化物。代表性溶剂化物包括水合物、乙醇化物和甲醇化物。术语“药学上可接受的溶剂化物”是指在合理的医学判断范围内，适用于与受试者(例如人)的组织接触而没有过度的毒性、刺激、过敏反应等，并且与合理的获益/风险比相称的溶剂化物。
术语“水合物”是指与水缔合的化合物。通常，化合物的水合物中所含的水分子的数目与水合物中的化合物分子的数目成特定的比率。因此，化合物的水合物可以由例如通式R·x H 2O表示，其中R为化合物，x为大于0的数。给定化合物可形成一种以上类型的水合物，包括例如一水合物(x为1)、低水合物(x为大于0且小于1的数，例如半水合物(R·0.5H 2O))和多水合物(x为大于1的数，例如二水合物(R·2H 2O)和六水合物(R·6H 2O))。
术语“互变异构体”是指为特定化合物结构的可互换形式的化合物，以及氢原子和电子分布不同的化合物。因此，通过π电子和原子(通常为H)的运动，两种结构可达到平衡。例如，烯醇和酮为互变异构体，因为它们通过用酸或碱处理而快速相互转化。
术语“多晶型物”是指化合物(或其盐、水合物或溶剂化物)在特定晶体堆叠排布中的晶型。所有多晶型物具有相同的元素组成。不同的晶型通常具有不同的X-射线衍射图谱、红外光谱、熔点、密度、硬度、晶体形状、光学和电学性质、稳定性和溶解度。重结晶溶剂、结晶速率、储存温度和其它因素可导致一种晶型占多数。化合物的各种多晶型物可以通过在不同条件下结晶来制备。
术语“病症”、“疾病”和“障碍”可互换使用。
本发明的化合物/药物组合物的“有效量”是指足以引起期望的生物学反应，即缓解症状的量。有效量可根据诸如所需生物终点、给药方式和/或受试者年龄和健康等因素而变化。
此外，本发明涵盖了所有变型、组合和排列，其中来自一项或多项所列权利要求的一个或多个限制、要素、条款和描述性术语被引入另一项权利要求。例如，任何从属于另一项权利要求的权利要求都可以被修改成包括在从属于同一基础权利要求的任何其他权利要求中发现的一个或多个限制。如各要素以列举形式呈现，则本发明也公开了要素的每一子组，且任何要素均可从该组中移除。还应注意，术语“包括”和“含有”意为开放式的，并且允许包括额外的要素或步骤。在给出范围的情况下，包括端点。此外，除非另外指明或根据上下文和本领域普通技术人员的理解中显而易见，否则表示为范围的值可在本发明的不同实施方案中采用范围内的任何具体值或子范围，直至范围下限单位的十分之一，除非上下文另有明确说明。
附图说明
图1为本发明实施例1 6-OHDA诱导的帕金森疾病模型中，诱导造模后第16天的大鼠24小时内水摄入量和舔舐率图；
图2为本发明实施例1 6-OHDA诱导的大鼠帕金森疾病模型中，给药第7天唤起吞咽反射的最小电流图；
图3为本发明实施例1 6-OHDA诱导的大鼠帕金森疾病模型中，给药后左侧和右侧黑质中平均TH阳性核数量图；
图4为本发明实施例1 6-OHDA诱导的大鼠帕金森疾病模型中，给药后左侧和右侧纹状体的总DAB阳性光密度图；
图5为本发明实施例2 MACO诱导的大鼠中风模型中，给药第6天和第14天各组的舔舐率图；
图6为本发明实施例3 SOD1转基因诱导的大鼠ALS模型中，给药第8天和第14天各组舔舐率图；
图7为本发明实施例3 SOD1转基因诱导的大鼠ALS模型中，给药第14天唤起各组吞咽反射的最小电流图；
图8为本发明实施例3 SOD1转基因诱导的大鼠ALS模型中，给药第14天各组60s内吞咽次数图。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1 6-羟基多巴胺(6-OHDA)诱导的大鼠帕金森综合症模型
准确称取100mg氢溴酸右美沙芬和100mg硫酸奎尼丁，加入10mL甲基纤维素溶液(1％w/v)，超声30分钟形成右美沙芬奎尼丁悬浮液。
将6-OHDA-HCl溶解在含有0.02％抗坏血酸的盐水中，配备4.4mg/mL(对应3.0mg/ml游离碱6-OHDA)的溶液，0℃下避光保存。
将雄性SD大鼠(n＝30,220-250g)饲养7天以适应环境，记录基线舔舐率。根据体重和舔舐率将大鼠随机分为空白组、模型组和治疗组，每组10只。向模型组和治疗组大鼠右侧内侧前脑束缓慢注入神经毒素6-羟基多巴胺(6-OHDA)(最大速率：1μL/min，18μg/只)。诱导后第6天至第16天，每天测量各组大鼠24小时水摄入量。在诱导后2周，给予大鼠0.1mg/kg的阿扑吗啡，检测其阿扑吗啡诱导的旋转行为。根据旋转测试结果，将模型组和治疗组重新分组为6-OHDA group-1和6-OHDA group-2。group-1为新的模型组，group-2为新的治疗组。在第16 天测量各大鼠的舔舐率。第16天各大鼠的24小时水摄入量和舔舐率检测结果见图1，其中POD指术后当天。
结果表明，诱导后第16天，大鼠的24小时水摄入量和舔舐率与空白组相比均显著降低，表明大鼠出现吞咽困难。
诱导后第20天，给予治疗组大鼠右美沙芬奎尼丁悬浮液(po，5mL/kg)。在给药后第六天，测试受试大鼠的舔舐率以确定吞咽功能是否有改善。若出现吞咽功能改善，则在给药第7天用体内肌电图(EMG)测量各大鼠上喉神经的生物电信号，记录唤起吞咽反射的最小电流。结果如图2所示。由于是向右侧内侧前脑束注入6-OHDA，左侧躯体运动功能会受损，且对右侧躯体功能有一定的补偿作用。图2结果表明，模型组大鼠唤起吞咽反射的最小电流较空白组高，使用右美沙芬奎尼丁治疗后，唤起大鼠吞咽反射的最小电流显著降低，表明右美沙芬奎尼丁可显著改善吞咽困难症状。
将大鼠处死，对大鼠黑质和纹状体进行酪氨酸羟化酶阳性染色(免疫组化，DAB染色)；检测黒质中平均TH阳性核团数量及纹状体的总DAB阳性光密度，考察给药处理后对PD大鼠黑质和纹状体内多巴胺神经元形态水平的改善。结果见图3和图4。结果表明，经右美沙芬奎尼丁治疗后，大鼠黑质和纹状体的多巴胺能神经元水平均显著提高。由于帕金森疾病的运动障碍与纹状体区和黑质区多巴胺的耗竭相关，该结果表明右美沙芬奎尼丁可显著改善帕金森疾病伴随的运动障碍。
实施例2大脑中动脉闭塞(MCAO)诱导的大鼠中风模型
将雄性SD大鼠(n＝30,220-240g)饲养7天以适应环境，记录基线舔舐率。根据体重和舔舐率将大鼠随机分为空白组、模型组和治疗组，每组10只。将一根经过消毒的细丝插入模型组和治疗组颈外动脉(ECA)，将其向前穿入颈内动脉(ICA)18±0.5mm，直到尖端阻塞大脑中动脉的起点，导致血流停止和大脑动脉的梗塞。1.5小时后将缝合线收回到ECA的残端，实现再灌注。使用激光多普勒血流仪在基线、闭塞后和再灌注时测量脑血流(CBF)。CBF持续降低(rCBF≥70％)被认为是MCAO模型构建成功的标志。
按照与实施例1类似的方式，规律测量各大鼠24小时水摄入量和舔舐率以确认模型组和治疗组大鼠出现吞咽困难。诱导后第17天，治疗组按照实施例1中的给药方式给予右美沙芬奎尼丁悬浮液。在给药后的第6天和第14天，测试受试大鼠的舔舐率以确定吞咽功能是否有改善。结果如图5所示。
结果表明，在给药后的第6天和第14天，治疗组大鼠舔舐率显著提高，表明DMQ治疗组大鼠的吞咽功能均得到显著改善。
实施例3ALS模型
将雄性SOD1转基因大鼠(疾病大鼠，n＝20)和野生型大鼠(n＝10)饲养7天以适应环境，并记录基线舔舐率。按照后肢功能每日对转基因大鼠进行神经评分(NeuroScore，NS)，评分标准为：
NS 0(症状前)：后肢呈现正常张开；
NS 1(第一个症状)：后肢呈现异常张开；
NS 2(麻痹发作)：后肢部分或完全塌陷，没有延伸太多；
NS 3(麻痹)：后肢僵硬麻痹或关节运动最小；
NS 4(人为终点)：后肢僵硬麻痹。
排除NS为0和4的大鼠。按照与实施例1类似的方式，规律测量各大鼠24小时水摄入量和舔舐率以确认模型组和治疗组大鼠出现吞咽困难。出现吞咽困难后，治疗组按照实施例1中的给药方式给予右美沙芬奎尼丁悬浮液。在给药第14天，测试受试大鼠的舔舐率，结果如图6所示。在给药第15天用体内肌电图(EMG)测量上喉神经的生物电信号，记录唤起吞咽反射的最小电流和60s内的吞咽次数，结果分别如图7和图8所示。
图6结果表明，使用右美沙芬奎尼丁治疗后的第14天，治疗组与模型组大鼠的舔舐率无显著差异。
图7和图8结果表明，唤起模型组大鼠吞咽反射的最小电流及60s内大鼠的吞咽次数与健康组相比无显著差异，使用右美沙芬奎尼丁治疗后，唤起大鼠吞咽反射的最小电流与模型组相比也无显著差异。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。本领域技术人员将认识到或能够确定使用不超过常规实验的许多本文的具体实施方案的同等形式。本发明实施方案的范围不旨在受限于以上具体实施方式，而是如所附权利要求书中所陈述。本领域的普通技术人员将理解，在不脱离如所附权利要求中限定的本发明的精神或范围的情况下，可以对本说明书进行各种改变和修改，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (14)

  1. 一种药物组合物在制备用于治疗或缓解疾病中吞咽困难和/或流涎症状的药物中的用途，其特征在于，所述药物组合物包括：
    (i)右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶；以及
    (ii)奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶；
    其中，所述疾病不为肌萎缩侧索硬化。
  2. 如权利要求1所述的用途，其特征在于：所述疾病为神经系统疾病。
  3. 如权利要求1或2所述的用途，其特征在于：所述神经系统疾病选自帕金森综合症、阿尔茨海默症、多发性硬化、脑卒中、脑梗死、亨廷顿舞蹈病、重症肌无力或脑膜炎，优选帕金森综合症、多发性硬化、脑卒中或脑梗死。
  4. 如权利要求1-3任一项所述的用途，其特征在于：所述右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶与奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的摩尔比为1:1至10:1，优选2:1至8:1，更优选3:1至6:1。
  5. 如权利要求1-3任一项所述的用途，其特征在于：所述右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶与奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的质量比为1:2至10:1，优选1:1至5:1，更优选1:1至2:1。
  6. 如权利要求1-5任一项所述的用途，其特征在于：所述右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶是右美沙芬一氢溴酸盐一水合物。
  7. 如权利要求1-6任一项所述的用途，其特征在于：所述奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶是奎尼丁半硫酸盐一水合物。
  8. 如权利要求1-7任一项所述的用途，其特征在于：所述右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的量为15-150μmol，优选30-100μmol，更优选40-70μmol。
  9. 如权利要求1-7任一项所述的用途，其特征在于：所述右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的质量为10-150mg，优 选10-100mg，更优选20-60mg。
  10. 如权利要求1-7任一项所述的用途，其特征在于：所述奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的量为约4-40μmol，优选7-25μmol，更优选10-20μmol。
  11. 如权利要求1-7任一项所述的用途，其特征在于：所述奎尼丁、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶的质量为10-150mg，优选10-100mg，更优选10-60mg。
  12. 如权利要求1-11中任一项所述的用途，其特征在于：所述右美沙芬、其同位素标记化合物、药学上可接受的盐、溶剂化物、多晶型物或药学上可接受的共晶，以及奎尼丁、其同位素标记化合物、药学上可接受的盐、药学上可接受的溶剂化物、多晶型物、或其药学上可接受的共晶中的一者或两者经口服或胃肠外给药。
  13. 如权利要求1-11任一项所述的用途，其特征在于：所述方法额外包括手术、放射疗法和/或移植或额外的药剂治疗。
  14. 如权利要求1-12任一项所述的用途，其特征在于：所述额外的药剂包括细胞毒性化学治疗剂、表观遗传修饰剂、糖皮质激素、免疫治疗剂、抗增殖剂、抗癌剂、抗血管生成剂、抗炎剂、免疫抑制剂、抗菌剂、抗病毒剂、心血管药物、降胆固醇剂、抗糖尿病剂、抗过敏剂、避孕药、疼痛缓解剂及其组合；优选拓扑异构酶抑制剂、MCL1抑制剂、BCL-2抑制剂、BCL-xL抑制剂、BRD4抑制剂、BRCA1抑制剂、BRCA2抑制剂、HER1抑制剂、HER2抑制剂、CDK9抑制剂、Jummonji组蛋白脱甲基酶抑制剂或DNA损伤诱导剂、抗体或其片段、免疫抑制剂、免疫激活剂、免疫检查点抑制剂、程序性细胞死亡1蛋白抑制剂、程序性细胞死亡1蛋白配体1抑制剂、细胞毒性T淋巴细胞相关蛋白4抑制剂、T细胞免疫球蛋白结构域和粘蛋白结构域3抑制剂、淋巴细胞活化基因-3抑制剂、含V-SET结构域的T细胞活化抑制剂1抑制剂、分化抗原簇276抑制剂、B和T淋巴细胞衰减因子抑制剂、半乳凝素-9抑制剂、检查点激酶1抑制剂、腺苷A2A受体抑制剂、吲哚胺2,3-双加氧酶抑制剂、杀伤细胞免疫球蛋白样受体抑制剂或T细胞活化的IgV-结构域抑制剂或二甲双胍。
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