Pharmaceutical composition containing dextromethorphan

Abstract

The invention provides a pharmaceutical composition containing dextromethorphan. The pharmaceutical composition further comprises citalopram or escitalopram in the form of free alkali or a pharmaceutically acceptable salt. According to the pharmaceutical composition provided by the invention, the dextromethorphan or the salt thereof and the citalopram or the salt thereof are combined according to a specific proportion, so that the pharmaceutical composition has an excellent synergistic effect. The invention also provides application of the pharmaceutical composition in preparation of drugs for treating cough and psychiatric and neurological disorders, especially depression.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a pharmaceutical composition comprising dextromethorphan and a preparation method thereof, and also relates to the use of the pharmaceutical composition. Background Art

[0002] Dextromethorphan, chemical name is (+)-3-methoxy-17-methyl-(9α, 13α, 14α)-morphinane, and its hydrobromide (CAS: 125-69-9) is often used as a drug in clinical practice. The chemical structure is as follows:

[0003]

[0004] Dextromethorphan (Dex) is a non-competitive NMDA receptor antagonist, sigma-1 receptor agonist and N-type calcium channel blocker with antitussive properties. Dex can interact with NMDA receptor signals and exert its effects through serotonin transporters and sigma-1 receptors. NMDA receptors can activate nitric oxide synthase (NOS) to promote the conversion of L-arginine (L-ARG) to nitric oxide (NO). NO is widely involved in various physiological and pathological processes such as epilepsy, neuroplasticity, pruritus, pain and depression (see Lin Na, Liu Yang, Qi Hui, Zhou Fengling, Zhu Fanhe. Study on the antidepressant effect and mechanism of dextromethorphan [J]. Chinese Journal of Pathophysiology, 2018, Vol. 34 (5): 870-877).

[0005] Dextromethorphan also exhibits significant anti-inflammatory and neuroprotective effects in LPS-mediated central nervous system inflammation. Neuroinflammation is generally considered to be a common feature of a variety of neurodegenerative and psychiatric diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), depression, schizophrenia or bipolar disorder (see Zhou Ran. Anti-inflammatory effect of ultra-low dose dextromethorphan in a mouse sepsis model and brain complement C3 promotes the pathology of chronic neuroinflammation and neurodegeneration [D]. Tianjin Medical University, 2020).

[0006] Zou Yuzhen et al. disclosed in the article "New Progress in Research on the Application of Dextromethorphan in the Nervous System" that dextromethorphan has a good therapeutic effect in excessive crying and laughing syndrome, depression, brain trauma, epilepsy and methotrexate central toxicity.

[0007] Although high-dose dextromethorphan can significantly antagonize central NMDA receptors, dextromethorphan is metabolized quickly in the body, making it difficult to maintain long-term drug concentrations in the body to produce therapeutic effects. AXS-05 is the first oral NMDA receptor antagonist approved for the treatment of depression. It uses the CYP2D6 inhibitory effect of bupropion to increase the exposure of dextromethorphan in subjects by about 80 times at the clinical level and prolong the half-life of dextromethorphan.

[0008] CN112437659A discloses a composition and method comprising bupropion or a related compound and dextromethorphan for use in treating neurological disorders such as depression. Example 2 of the specification and Figure 12 thereof disclose the use of human liver microsomes to examine the ability of various antidepressant compounds to inhibit the metabolism of dextromethorphan. The results show that bupropion can significantly inhibit the metabolism of dextromethorphan (IC50 value 9.1 μM).

[0009] Citalopram, chemically known as 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile, is a widely used selective serotonin reuptake inhibitor (SSRI) antidepressant. Its chemical structure is as follows:

[0010]

[0011] Although dextromethorphan has a unique mechanism of action and has good application prospects in a variety of central nervous system diseases such as depression, Alzheimer's disease, epilepsy, etc., due to its rapid metabolism in the human body, dextromethorphan alone cannot reach a therapeutic blood concentration. Therefore, there is still a need in this field to develop drugs that can reduce the metabolism of dextromethorphan to give full play to the clinical application of dextromethorphan. Summary of the invention

[0012] In order to solve the above problems existing in the prior art, the object of the present invention is to provide a pharmaceutical composition comprising dextromethorphan, so as to solve the shortcomings of dextromethorphan being rapidly metabolized in the body and being difficult to maintain effective blood drug concentration for a long time, and it is expected that the dextromethorphan will exhibit the characteristics of rapid onset of action like the NMDA receptor antagonists already on the market.

[0013] First, the present invention provides a pharmaceutical composition, comprising a first component and a second component, wherein the first component is dextromethorphan in free or pharmaceutically acceptable salt form, and the second component is citalopram in free base or pharmaceutically acceptable salt form, or at least one of escitalopram in free base or pharmaceutically acceptable salt form; further preferably, based on the free base, the mass ratio of dextromethorphan in the first component to citalopram or escitalopram in the second component is (2-5):(1-10), further preferably (3-5):(2-8), and even more preferably (3-4.5):(2-8).

[0014] In the pharmaceutical composition of the present invention, dextromethorphan is an NMDA receptor antagonist, and citalopram and escitalopram are selective serotonin reuptake inhibitors. The present invention creatively combines these two drugs to synergistically enhance the effect, antagonize NMDA receptors, and inhibit 5-HT and / or NE reuptake, and achieves a rapid treatment of depression through multiple targets and multiple mechanisms.

[0015] In a preferred embodiment, the pharmaceutical composition comprises a first component and a second component, wherein the first component is dextromethorphan in the form of a free base or a pharmaceutically acceptable salt, and the second component is citalopram in the form of a free base or a pharmaceutically acceptable salt, or escitalopram in the form of a free base or a pharmaceutically acceptable salt; based on the free base, the mass ratio of dextromethorphan in the first component to citalopram or escitalopram in the second component is (2-5): (1-10), for example (3-5): (1-10), (4-5): (1-10), (3-5): (2-8), (4-5): (2-8), (4-5): (3-8), (4-5): (4-8), (4-5): (4-6), (3-4.5): (2-8), (3-4.5): (4-8), (3-4.5): (4-6), 4.5: (2-10), 4.5: (2-8), 4.5: (3-8), 4.5: (4-8), 4.5: (4-6), 4.5:10.5, 4.5:10, 4.5:9.5, 4.5:9, 4.5:8.5, 4.5:8, 4.5:7.5, 4.5:7, 4.5:6.5, 4.5:6, 4.5:5.5, 4.5:5, 4.5:4.5, 4.5:4, 4.5:3.5, 4.5:3, 4.5:2.5 or 4.5:2, etc. and any value in between.

[0016] In one embodiment, the pharmaceutical composition, wherein the mass ratio of dextromethorphan in the first component to citalopram or escitalopram in the second component, calculated as free base, is (3-5):(2-8), preferably (3-4.5):(2-8), further preferably 4.5:(2-8), and even more preferably 4.5:(3-8).

[0017] In one embodiment, in the pharmaceutical composition, the mass ratio of dextromethorphan to citalopram or escitalopram, calculated as free base, is 4.5:(4-8), preferably 4.5:(4-6).

[0018] In one embodiment, the pharmaceutical composition, wherein the mass ratio of dextromethorphan in the first component to citalopram or escitalopram in the second component, calculated as free base, is 4.5:10.5, 4.5:10, 4.5:9.5, 4.5:9, 4.5:8.5, 4.5:8, 4.5:7.5, 4.5:7, 4.5:6.5, 4.5:6, 4.5:5.5, 4.5:5, 4.5:4.5 (1:1), 4.5:4, 4.5:3.5, 4.5:3, 4.5:2.5, or 4.5:2 and any value therebetween.

[0019] In one embodiment, the pharmaceutical composition, wherein the mass ratio of dextromethorphan in the first component to citalopram or escitalopram in the second component, calculated as free base, is 3:8, 3:7, 3:6, 3:5, 3:4.5, 4:8, 4:7, 4:6, 4:5, 4:4.5, 4:4 (1:1), 4:3, 4:2, 4:1, 4.5:10, 4.5:9.5, 4.5:9, 4.5:8.5, 4.5:8, 4.5:7.5, 4.5:7, 4.5:6.5, 4.5:6, 4.5:5.5, 4.5:5, 4.5:4.5, 4.5:4, 4.5:3.5, 4.5:3, 4.5:2.5, 4.5:2, or 4.5:1 and any value therebetween.

[0020] In one embodiment, the pharmaceutical composition, wherein the pharmaceutically acceptable salt form of dextromethorphan, citalopram or escitalopram includes salts of inorganic acids or organic acids with dextromethorphan, citalopram or escitalopram; the inorganic acids, such as hydrosulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid; the organic acids, such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartrate, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid; and related inorganic and organic acids.

[0021] In a preferred embodiment, the pharmaceutically acceptable salt form of dextromethorphan is a salt formed by hydrobromic acid and dextromethorphan, i.e., dextromethorphan hydrobromide (also referred to as dextromethorphan in the form of hydrobromide, or dextromethorphan hydrobromide). The pharmaceutically acceptable salt form of citalopram is a salt formed by hydrobromic acid and citalopram, i.e., citalopram hydrobromide (also referred to as citalopram in the form of hydrobromide, or citalopram hydrobromide); the pharmaceutically acceptable salt form of escitalopram is preferably a salt formed by oxalic acid and citalopram, i.e., escitalopram oxalate (also referred to as escitalopram in the form of oxalate, or escitalopram oxalate).

[0022] In one embodiment, the pharmaceutical composition of the present invention, wherein the first component is dextromethorphan in the form of a free base or a pharmaceutically acceptable salt, and the second component is citalopram in the form of a free base or a pharmaceutically acceptable salt; further preferably, the first component is dextromethorphan or dextromethorphan hydrobromide, and the second component is citalopram or citalopram hydrobromide; further preferably, the first component is dextromethorphan hydrobromide, and the second component is citalopram hydrobromide.

[0023] In one embodiment, the pharmaceutical composition of the present invention, wherein the first component is dextromethorphan in the form of a free base or a pharmaceutically acceptable salt, and the second component is escitalopram in the form of a free base or a pharmaceutically acceptable salt; further preferably, the first component is dextromethorphan or dextromethorphan hydrobromide, and the second component is escitalopram or escitalopram oxalate; further preferably, the first component is dextromethorphan hydrobromide, and the second component is escitalopram oxalate.

[0024] In one embodiment, the present invention provides a pharmaceutical composition, comprising a first component and a second component, wherein the first component is dextromethorphan in the form of a free base or a pharmaceutically acceptable salt, and the second component is citalopram in the form of a free base or a pharmaceutically acceptable salt; based on the free base of dextromethorphan and citalopram, the mass ratio of the first component to the second component is (2-5): (1-10), for example (3-5): (1-10), (4-5): (1-10), (3-5): (2-8), (4-5): (2-8), (4-5): (3-8), (4-5): (4-8), (4-5): (4-6), (3-5): (1-10). 2~8), (3~4.5): (4~8), (3~4.5): (4~6), 4.5: (2~12), 4.5: (2~10), 4.5: (2~8), 4.5: (3~8), 4.5: (4~8), 4.5: (4~6), 4.5:10.5, 4.5:10, 4.5:9.5, 4.5:9, 4.5:8.5, 4.5:8, 4.5:7.5, 4.5:7, 4.5:6.5, 4.5:6, 4.5:5.5, 4.5:5, 4.5:4.5, 4.5:4, 4.5:3.5, 4.5:3, 4.5:2.5 or 4.5:2 and any value in between.

[0025] Further preferably, the pharmaceutically acceptable salt form of dextromethorphan is dextromethorphan in the form of hydrobromide, and the pharmaceutically acceptable salt form of citalopram is citalopram in the form of hydrobromide;

[0026] Further preferably, based on the free base of dextromethorphan and citalopram, the mass ratio of the first component to the second component is (3-5):(2-8), more preferably (4-5):(4-8), further preferably 4.5:(4-8), especially 4.5:(4-6), for example 4.5:4, 4.5:5, 4.5:6, 4.5:7, 4.5:8, etc. and any value therebetween.

[0027] In one embodiment, the present invention provides a pharmaceutical composition, comprising a first component and a second component, wherein the first component is dextromethorphan in the form of a free base or a pharmaceutically acceptable salt, and the second component is escitalopram in the form of a free base or a pharmaceutically acceptable salt; based on the free base of dextromethorphan and escitalopram, the mass ratio of the first component to the second component is (2-5): (1-10), for example (3-5): (1-10), (4-5): (1-10), (3-5): (2-8), (4-5): (2-8), (4-5): (3-8), (4-5): (4-8), (4-5): (4-6), ( 3~4.5):(2~8), (3~4.5):(4~8), (3~4.5):(4~6), 4.5:(2~10), 4.5:(2~8), 4.5:(3~8), 4.5:(4~8), 4.5:(4~6), 4.5:10.5, 4.5:10, 4.5:9.5, 4.5:9, 4.5:8.5, 4.5:8, 4.5:7.5, 4.5:7, 4.5:6.5, 4.5:6, 4.5:5.5, 4.5:5, 4.5:4.5, 4.5:4, 4.5:3.5, 4.5:3, 4.5:2.5 or 4.5:2, etc. and any value in between.

[0028] Further preferably, the pharmaceutically acceptable salt form of dextromethorphan is dextromethorphan hydrobromide, and the pharmaceutically acceptable salt form of escitalopram is escitalopram oxalate;

[0029] Further preferably, based on the free base of dextromethorphan and escitalopram, the mass ratio of the first component to the second component is (3-5): (2-8), more preferably (4-5): (4-8), further preferably 4.5: (4-8), especially 4.5: (4-6), for example 4.5:4, 4.5:5, 4.5:6, 4.5:7, 4.5:8, etc. and any value therebetween.

[0030] In a preferred embodiment, in any of the above pharmaceutical compositions of the present invention, calculated as free base, the unit dosage form of the pharmaceutical composition contains 5 to 200 mg of dextromethorphan, for example, 50 to 200 mg, 150 to 200 mg, 50 to 150 mg, 50 to 100 mg, 50 to 90 mg, 50 to 80 mg, 50 to 70 mg, 50 to 60 mg, 60 to 65 mg, 60 to 70 mg, 60 to 80 mg, 40 to 65 mg, 40 to 60 mg, 10 to 200 mg, 20 to 100 mg, 25 to 100 mg, 20 to 45 mg, 20 to 50 mg, 30 to 80 mg, 40 to 50 mg, 45 to 50 mg, 30 to 50 mg, 30 to 40 mg, 20mg to 50mg, 20mg to 40mg, 10mg to 50mg, 10mg to 40mg, 10mg to 45mg, 10mg to 35mg, 10mg to 30mg, 10mg to 25mg, 10mg to 20mg, 10mg to 15mg, 5mg to 50mg, 5mg to 45mg, 5mg to 40mg, 5mg to 35mg, 5mg to 30mg, 5mg to 25mg, 5mg to 20mg, 5mg to 15mg, or 5mg to 10mg, and any value therebetween of dextromethorphan; and contains 2mg to 300mg of citalopram or escitalopram, preferably contains 2mg to 100mg of citalopram or escitalopram, for example, contains 4mg to 300mg, 5mg to 250mg, 5mg to 100mg, 10mg to 200mg, 10mg to 80mg Citalopram or escitalopram from 10 mg to 100 mg, 10 mg to 60 mg, 10 mg to 50 mg, 10 mg to 40 mg, 10 mg to 30 mg, 10 mg to 25 mg, 10 mg to 20 mg, 10 mg to 15 mg, 20 mg to 60 mg, 20 mg to 50 mg, 20 mg to 40 mg, 20 mg to 30 mg, 20 mg to 25 mg, 30 mg to 80 mg, 30 mg to 70 mg, 30 mg to 60 mg, 30 mg to 50 mg, 30 mg to 40 mg, 40 mg to 80 mg, 40 mg to 70 mg, 40 mg to 60 mg, 40 mg to 50 mg, 5 mg to 30 mg, 5 mg to 40 mg, 5 mg to 20 mg, 5 mg to 15 mg, or 5 mg to 10 mg, and any value therebetween.Further preferably, the pharmaceutical composition of the present invention, calculated as free base, contains 20 mg to 50 mg of dextromethorphan and 10 mg to 40 mg of citalopram or escitalopram in a unit preparation of the pharmaceutical composition; further preferably, the pharmaceutical composition of the present invention, calculated as free base, contains 10 mg to 50 mg of dextromethorphan and 5 mg to 40 mg of citalopram or escitalopram in a unit preparation of the pharmaceutical composition.

[0031] Further preferably, the pharmaceutical composition of the present invention contains 20 mg to 50 mg of dextromethorphan and 15 mg to 70 mg of citalopram or escitalopram in a unit preparation, calculated as free base. In another preferred embodiment, the pharmaceutical composition of the present invention contains 10 mg to 50 mg of dextromethorphan and 5 mg to 70 mg of citalopram or escitalopram in a unit preparation, calculated as free base.

[0032] The pharmaceutical composition of the present invention further comprises one or more pharmaceutically acceptable excipients, and the pharmaceutically acceptable excipients can be selected according to the dosage form requirements of the drug combination; preferably, the dosage form of the pharmaceutical composition is any one of nasal spray, sublingual tablet, oral tablet, capsule, oral liquid, pill, injection and inhalant.

[0033] In another aspect of the present invention, a method for reducing the metabolic rate of dextromethorphan in the body is provided, the method comprising administering the pharmaceutical composition of the present invention to a patient having a disease in need of treatment with dextromethorphan.

[0034] Further preferably, the patient is a mammal or a human, in particular a human. In some embodiments, the disease to be treated with dextromethorphan includes a neuropsychiatric disorder.

[0035] In another aspect of the present invention, the use of the pharmaceutical composition of the present invention in the preparation of a drug for treating a patient suffering from a disease that can be treated with dextromethorphan is also provided; preferably, the pharmaceutical composition reduces the elimination rate of dextromethorphan in vivo and increases the exposure amount AUC of dextromethorphan in rat plasma. 0-24 The AUC is the plasma exposure achieved by administering the same dose of dextromethorphan alone. 0-24 3 times or more, for example, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times or 30 times or more.

[0036] Further preferably, the diseases treated with dextromethorphan include neuropsychiatric disorders and cough, preferably one or more of depression, Alzheimer's disease, affective disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, seizure disorders or headache; further preferably, the depression includes mild depression, moderate depression, severe depression, refractory depression and refractory bipolar depression.

[0037] In another aspect of the present invention, there is also provided use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating cough and neuropsychiatric disorders.

[0038] Neuropsychiatric disorders in the context of the present invention include one or more of depression, Alzheimer's disease, affective disorders, psychotic disorders, brain dysfunction, movement disorders, dementia, motor neurone disease, neurodegenerative diseases, seizure disorders and headache.

[0039] Further preferably, the neuropsychiatric disorder comprises depression such as mild depression, moderate depression, major depression, refractory depression and refractory bipolar depression, bipolar disorder of cyclothymia, seasonal affective disorder, mania, anxiety, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH), attention deficit / hyperactivity disorder (AD / HD), obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychogenic sexual dysfunction, pseudobulbar mood and mood lability.

[0040] Depression of the present invention can be manifested as mood changes, strong sadness, despair, slow thinking, lack of concentration, pessimistic anxiety, agitation and self-depreciation. The physical symptoms of depression can also include insomnia, anorexia, weight loss, decreased vitality and libido and abnormal hormone circadian rhythm.

[0041] The anxiety disorders include, but are not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD).

[0042] Such manic disorders include, but are not limited to, manic depression, hypomania, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorders, schizoaffective disorders, schizophrenic traits, aggression, Alzheimer's disease aggression, agitation, and Alzheimer's disease agitation.

[0043] Neuropsychiatric disorders that can be treated by the pharmaceutical compositions described herein include, but are not limited to, mild depression, moderate depression, major depression, refractory depression, refractory bipolar depression, seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH) and attention deficit / hyperactivity disorder (AD / HD), bipolar and manic disorders, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychosexual dysfunction, pseudobulbar influence, and mood lability.

[0044] In a preferred embodiment of the present invention, the use of the pharmaceutical composition of the present invention in the preparation of a drug for preventing and / or treating cough and neuropsychiatric disorders is provided, wherein the neuropsychiatric disorder is preferably depression, and further preferably, the depression includes mild depression, moderate depression, severe depression, refractory depression and refractory bipolar depression. Optionally, the depression is tested with the Montgomery-Sberg Depression Rating Scale (MADRS), extreme depression: MADRS≥35; severe depression: 35>MADRS≥30; moderate depression: 30>MADRS≥22; mild depression: 22>MADRS≥12; remission period: MADRS<12. That is, when MADRS≥22, it is a patient with moderate to severe depression.

[0045] Technical Effects

[0046] (1) The pharmaceutical composition comprising dextromethorphan and citalopram or a pharmaceutically acceptable salt thereof provided in the present application can produce a synergistic effect through a specific ratio between the groups, enhance the mechanism of action or pharmacological properties of dextromethorphan and citalopram, effectively inhibit the over-activation of NMDA receptors, and inhibit the reuptake of 5-HT and / or NE, etc., and can greatly improve the therapeutic effect on patients with major depressive disorder (MDD), especially refractory depression (TRD). At the same time, dextromethorphan reduces the dosage of citalopram and possible side effects, and has the advantages of multiple targets and rapid onset of action.

[0047] (2) The pharmaceutical composition provided by the present invention has a more excellent metabolic effect than the prior art, ensuring the appropriate drug concentration and effect.

[0048] (3) When the mass ratio of dextromethorphan to citalopram in the pharmaceutical composition provided by the present invention is (2-5): (1-10), the exposure of dextromethorphan in rats can be significantly increased compared with the administration of the same dose of dextromethorphan alone (ratio 1:0), which well reflects the synergistic effect of dextromethorphan and citalopram. However, when the ratio of dextromethorphan to citalopram is 4.5:1, the exposure is equivalent to that of dextromethorphan alone (ratio 4.5:0), which fails to reflect the effect of citalopram and no synergistic effect is observed. When the ratio of dextromethorphan to citalopram is less than 0.75 (4.5:6), the increase in the exposure of dextromethorphan is not obvious when the dose of citalopram is further increased, indicating that only within a specific ratio range can citalopram increase the exposure of dextromethorphan in a dose-dependent manner. The specific ratio of the pharmaceutical composition of the present invention has an excellent synergistic effect, and the effect is better than that of the combination of dextromethorphan and bupropion.

[0049] Definition of terms

[0050] The present invention is intended to cover all substitutions, modifications and equivalent technical solutions, which are all included in the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail. All patents and publications to which the present invention relates are incorporated herein by reference in their entirety.

[0051] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0052] The terms "selected from...", "preferably..." and "more preferably..." mean that one or more elements in the group listed later are independently selected and may include a combination of two or more elements. In the present invention, one element in the group listed later is preferred.

[0053] The term “comprise” or “include” is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0054] In the context of the present invention, all the numbers disclosed herein are approximate values, regardless of whether the words "approximately", "about" or "roughly" are used. The value of each number may vary by less than 10% or by a reasonable difference considered by those skilled in the art, such as 1%, 2%, 3%, 4% or 5%.

[0055] In the context of the present invention, in the pharmaceutical composition mentioned, "in terms of free base" means that whether the dextromethorphan in the first component is in the form of free base or in the form of a pharmaceutically acceptable salt (such as hydrobromide), it is converted to the content of dextromethorphan free base when calculating the content; similarly, whether citalopram or escitalopram in the second component is in the form of free base or in the form of a pharmaceutically acceptable salt thereof, it is converted to the content of citalopram or escitalopram free base when calculating the content. For example, when the pharmaceutical composition of the present invention comprises a first component and a second component, the first component is dextromethorphan hydrobromide, the second component is citalopram hydrobromide, and the mass ratio of the first component to the second component is (2-5): (1-10), the "mass ratio is (2-5): (1-10)" refers to the mass ratio of the first component in terms of dextromethorphan free base to the second component in terms of citalopram free base. For another example, the phrase “the first component contains 10 mg to 200 mg of dextromethorphan” in the present invention means that the dextromethorphan in the first component exists in the form of a free base or in the form of a pharmaceutically acceptable salt, wherein 10 mg to 200 mg refers to the amount converted into dextromethorphan free base.

[0056] The term "treatment" includes any activity that diagnoses, cures, mitigates, treats, or prevents disease in humans or other animals, or that otherwise affects the structure or any function of the human or other animal body.

[0057] The "unit preparation" mentioned in the context of the present invention has the conventional meaning in the art, and refers to the smallest dosing unit or the smallest delivery unit or the smallest packaging unit that can be divided in a drug. For example, the unit preparation of a tablet is one tablet, the unit preparation of a capsule is one pill, the unit preparation of a powder is one bottle, the unit preparation of a bag is one box, the unit preparation of an injection is one tube, etc.

[0058] The "escitalopram in the form of oxalate" and "escitalopram oxalate" or "escitalopram oxalate" mentioned in the context of the present invention are interchangeable and all refer to the salt formed by oxalic acid and escitalopram.

[0059] The "citalopram in the form of hydrobromide" and "citalopram hydrobromide" or "citalopram hydrobromide" described in the context of the present invention can be interchanged, and all refer to the salt formed by hydrobromic acid and citalopram.

[0060] The "dextromethorphan in the form of hydrobromide" and "dextromethorphan hydrobromide" or "dextromethorphan hydrobromide" described in the context of the present invention can be interchanged, and all refer to the salt formed by hydrobromic acid and dextromethorphan.

[0061] The dextromethorphan, citalopram or escitalopram in the form of free base or pharmaceutically acceptable salts described in the context of the present invention also include hydrates, solvates, polymorphs, other solid forms, etc. in the form of free base or pharmaceutically acceptable salts thereof. For example, dextromethorphan hydrobromide usually exists in the form of its monohydrate, and the dextromethorphan hydrobromide mentioned in the present invention also includes its monohydrate form.

[0062] Dextromethorphan described in the context of the present invention also includes deuterated forms of dextromethorphan, and examples of deuterium-modified dextromethorphan include, but are not limited to, those shown below:

[0063]

[0064] BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 Shown: Effects of various antidepressants on dextromethorphan exposure in rat plasma;

[0066] Figure 2 Shown: Effect of citalopram on dextromethorphan exposure in rat plasma;

[0067] Figure 3 Shown: The dose relationship of the effect of different doses of citalopram on dextromethorphan exposure;

[0068] Figure 4 Shown: The improvement effects of citalopram, dextromethorphan + bupropion and dextromethorphan + citalopram on the forced swimming model of mice. Specific embodiments

[0069] In order to better understand the technical scheme of the present invention, the present invention is further described below in conjunction with specific embodiments. Unless otherwise specified, in the following embodiments, if specific techniques or conditions are not clearly described, those skilled in the art can proceed according to the common techniques or conditions in the art or according to the product instructions. The drugs, reagents or instruments used without indicating the manufacturer are all commercially available conventional products.

[0070] Dextromethorphan was purchased from Chifeng Pharmaceutical Co., Ltd. (batch number D41-220402); bupropion was purchased from Dijia Pharmaceutical Group Co., Ltd. (batch number BP220913W); paroxetine was purchased from Shanghai Haohong Biotechnology Co., Ltd. (batch number Lg0222204220); sertraline (batch number C14934806), fluvoxamine (batch number C14884172), citalopram (batch number C14276148), venlafaxine (batch number C14410430), and duloxetine (batch number C14967293) were all purchased from Shanghai McLean Biochemical Technology Co., Ltd.

[0071] Example 1: Effects of antidepressants on the pharmacokinetics of dextromethorphan in rats

[0072] First-line antidepressants including bupropion, paroxetine, sertraline, fluvoxamine, citalopram, venlafaxine and duloxetine were selected to investigate their effects on the pharmacokinetics of dextromethorphan in rats.

[0073] Dextromethorphan (Dex) and mixed solutions of dextromethorphan and antidepressants (bupropion, paroxetine, sertraline, fluvoxamine, citalopram, venlafaxine, duloxetine) were prepared with pure water as test solutions. The concentration of dextromethorphan solution was 0.45 mg / ml, which was used as the test solution of experimental group A1; the mixed solution of dextromethorphan and antidepressants contained 0.45 mg of dextromethorphan and 1.05 mg of antidepressants per milliliter, which were used as test solutions of experimental groups A2 to A8.

[0074] 24 male SD rats were randomly divided into 8 groups, 3 rats in each group; purchased from Sibeifu (Beijing) Biotechnology Co., Ltd., the animals were fasted overnight before the experiment, and drinking water was not limited. On the day of the experiment, each group was gavaged with the test substance corresponding to the experimental group A1 to A8 according to Table 1.1 below, the administration volume was 10ml / kg, and the administration time was recorded as 0h.

[0075] Table 1.1: Groups and dosages

[0076]

[0077]

[0078] Note: po refers to oral administration;

[0079] After administration, blood was collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration to detect the concentration of dextromethorphan in plasma and calculate the pharmacokinetic parameters. The results are shown in Table 1.2.

[0080] Table 1.2: Effects of different antidepressants on the metabolism of dextromethorphan in rat plasma

[0081]

[0082] Note: Dex refers to dextromethorphan. AUC 0-last Refers to the area under the blood drug concentration-time curve from 0 time to the last sampling time point.

[0083] The above experimental results (as shown in Table 1.2 and Figure 1 ) showed that bupropion, citalopram, paroxetine, and duloxetine could significantly increase the exposure of dextromethorphan in rats, among which citalopram had the most significant effect at the same dose. None of the drugs had a significant effect on the half-life of dextromethorphan in the experiment. The experimental results also showed that citalopram had a greater effect on the exposure of dextromethorphan in rats than paroxetine, a strong CYP2D6 inhibitor.

[0084] Example 2: Effect of Citalopram Dose on the Pharmacokinetics of Dextromethorphan in Rats after Oral Administration of Dextromethorphan and Different Doses of Citalopram

[0085] Sample configuration:

[0086] Dextromethorphan solution was prepared with pure water as solvent at a concentration of 0.45 mg / ml as the test substance of experimental group B1;

[0087] Mixed solutions of dextromethorphan and citalopram of different concentrations were prepared with pure water as solvent, wherein each milliliter of the solution contained 0.45 mg of dextromethorphan and 0.1 mg, 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg and 1.05 mg of citalopram, respectively, which were used as the test substances of experimental groups B2 to B7;

[0088] Experimental methods:

[0089] 28 male SD rats, weighing 240-300g, were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd. and randomly divided into 7 groups; the animals were fasted overnight before the experiment, and drinking water was not limited. On the day of the experiment, each group was gavaged with the corresponding test substance (10ml / kg) according to Table 2.1, and the administration time was recorded as 0h.

[0090] Table 2.1 Groups and doses

[0091]

[0092] After the administration, blood was collected at 15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h after administration to detect the concentrations of dextromethorphan and citalopram in plasma and calculate the pharmacokinetic parameters. The results of the effects of each drug on the pharmacokinetics of dextromethorphan in rats after oral administration of the test substance are shown in Table 2.2.

[0093] Table 2.2 Pharmacokinetic parameters of dextromethorphan in each group of animals

[0094]

[0095] The above experimental results show that the fixed dose of dextromethorphan is 4.5 mg / kg, and the addition of 2-10.5 mg / kg of citalopram can significantly increase the exposure of dextromethorphan in rats (as shown in Table 2.2 and Figure 2 shown); Figure 3 It was shown that at doses of 4 mg / kg and above, the increase in dextromethorphan exposure by citalopram was gradually reduced compared to the increase in citalopram dose.

[0096] Table 2.3 Concentration and pharmacokinetic parameters of citalopram in each group of animals

[0097]

[0098] As shown in the experimental results in Table 2.3, the exposure to citalopram increases with increasing dose, and the amplitude is higher than linear.

[0099] According to the above pharmacokinetic experimental results, it can be seen that in the pharmaceutical composition provided by the present invention, when the dose ratio of dextromethorphan to citalopram is 4.5:(4-8), especially 4.5:(4-6), citalopram has the highest potency in promoting the exposure of dextromethorphan in plasma.

[0100] Example 3: Mouse forced swimming test

[0101] The purpose of this experiment was to explore the effective dose of the combination of citalopram and dextromethorphan and the combination of dextromethorphan and bupropion in the mouse forced swimming model, and to conduct a preliminary investigation on the efficacy of the combination of citalopram and dextromethorphan.

[0102] Sample configuration:

[0103] (1) Pure water was used as the test solution for experimental group C1;

[0104] (2) Citalopram solutions with concentrations of 1 mg / ml, 2 mg / ml, and 4 mg / ml were prepared using pure water as the test solutions for experimental groups C2 to C4;

[0105] (3) Using pure water to prepare mixed solutions of dextromethorphan and bupropion of different concentrations, wherein:

[0106] The test solution of experimental group C5 contained 0.45 mg dextromethorphan and 1.05 mg bupropion per ml of solution;

[0107] The test solution of experimental group C6 contained 0.9 mg dextromethorphan and 2.1 mg bupropion per ml of solution;

[0108] The test solution of experimental group C7 contained 1.8 mg of dextromethorphan and 4.2 mg of bupropion per ml of solution;

[0109] (4) Using pure water to prepare mixed solutions of dextromethorphan and citalopram of different concentrations, wherein:

[0110] The test solution of experimental group C8 contained 0.45 mg dextromethorphan and 1 mg citalopram per ml of solution;

[0111] The test solution of experimental group C9 contained 0.9 mg dextromethorphan and 1 mg citalopram per ml of solution;

[0112] Experimental method: ICR mice were randomly divided into 9 groups, 8 mice in each group. The groups and doses are shown in Table 3.1.

[0113] Each group of animals was gavaged with the corresponding test drug of experimental group C1-C9 (different components were administered at the same time), and a proper amount of water (about 15 cm deep, about 22-25°C) was added to a straight glass cup. The mice were placed in the cup for 6 minutes after 1 hour of administration, and the video was recorded. After the experiment, the video was exported, and then the behavioral analysis software was used to analyze the cumulative immobility time of the mice in the last 4 minutes.

[0114] Table 3.1: Animal groups, dosage and immobility time (s) in the mouse forced swimming test

[0115]

[0116]

[0117] The experimental results are shown in Table 3.1 and Figure 4 The experimental results show that:

[0118] There were no significant differences between groups C2 to C6 and C8 and the vehicle control group, indicating that (1) citalopram alone did not show significant improvement in the model at doses of 10, 20, and 40 mg / kg; (2) dextromethorphan + bupropion (AXS05) did not show significant improvement in the model at doses of 4.5 mg / kg (dextromethorphan) + 10.5 mg / kg (bupropion) and 9 mg / kg (dextromethorphan) + 21 mg / kg (bupropion); (3) 4.5 mg / kg dextromethorphan + 10 mg / kg citalopram did not show significant improvement.

[0119] Although there was no significant difference between group C7 and the vehicle control group, it showed a certain improvement trend at the dose of 18 mg / kg (dextromethorphan) + 42 mg / kg (bupropion);

[0120] In the experiment, the immobility time of animals in the 9mg / kg dextromethorphan + 10mg / kg citalopram group was significantly reduced, and group C9 had significant differences compared with the vehicle control group, while 10mg / kg and higher doses (20mg / kg, 40mg / kg) of citalopram alone did not show improvement, indicating that the efficacy of 9mg / kg dextromethorphan + 10mg / kg citalopram was superior to that of citalopram alone;

[0121] In the experiment, dextromethorphan + bupropion showed an improvement trend at a dose of 18 mg / kg (dextromethorphan) + 42 mg / kg (bupropion), while dextromethorphan + citalopram showed significant improvement at a dose of 9 mg / kg (dextromethorphan) + 10 mg / kg (citalopram), indicating that the dextromethorphan + citalopram combination has the advantage of requiring less drug to achieve the same or similar efficacy compared to the dextromethorphan + bupropion combination, which can reduce the amount of dextromethorphan used in the compound.

Claims

1. A pharmaceutical composition, characterized in that The composition comprises a first component and a second component, wherein the first component is dextromethorphan in the form of a free base or a pharmaceutically acceptable salt, and the second component is citalopram in the form of a free base or a pharmaceutically acceptable salt, or at least one of escitalopram in the form of a free base or a pharmaceutically acceptable salt; and the mass ratio of dextromethorphan in the first component to citalopram or escitalopram in the second component, calculated as free base, is (2-5):(1-10), more preferably (3-5):(2-8), and even more preferably (3-4.5):(2-8).

2. A pharmaceutical composition according to claim 1, characterized in that: The mass ratio of dextromethorphan in the first component to citalopram or escitalopram in the second component is 4.5:(2-8), preferably 4.5:(3-8), and more preferably 4.5:(4-6), calculated as free base.

3. The composition according to claim 1, characterized in that The mass ratio of dextromethorphan in the first component to citalopram or escitalopram in the second component is 3:8, 3:6, 3:5, 4:7, 4:6, 4:5, 4:3, 4:2, 4:1, 4.5:10, 4.5:9.5, 4.5:9, 4.5:8.5, 4.5:8, 4.5:7.5, 4.5:7, 4.5:6.5, 4.5:6, 4.5:5.5, 4.5:5, 4.5:4.5, 4.5:4, 4.5:3.5, 4.5:3, 4.5:2.5, 4.5:2, or 4.5:

1.

4. The composition according to claim 1, characterized in that The mass ratio of dextromethorphan in the first component to citalopram or escitalopram in the second component is 4.5:10.5, 4.5:10, 4.5:9.5, 4.5:9, 4.5:8.5, 4.5:8, 4.5:7.5, 4.5:7, 4.5:6.5, 4.5:6, 4.5:5.5, 4.5:5, 4.5:4.5, 4.5:4, 4.5:3.5, 4.5:3, 4.5:2.5, or 4.5:

2.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The second component is citalopram in the form of a free base or a pharmaceutically acceptable salt; more preferably, the pharmaceutically acceptable salt form of citalopram is citalopram hydrobromide.

6. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The first component is dextromethorphan in the form of a free base or a pharmaceutically acceptable salt, and the second component is citalopram in the form of a free base or a pharmaceutically acceptable salt; further preferably, the first component is dextromethorphan in the form of a free base or a hydrobromide salt, and the second component is citalopram in the form of a free base or a hydrobromide salt; or, The first component is dextromethorphan in the form of a free base or a pharmaceutically acceptable salt, and the second component is escitalopram in the form of a free base or a pharmaceutically acceptable salt; further preferably, the first component is dextromethorphan in the form of a free base or a hydrobromide salt, and the second component is escitalopram in the form of a free base or an oxalate salt.

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that Calculated as free base, the pharmaceutical composition unit preparation contains 5 mg to 200 mg of dextromethorphan and 2 mg to 100 mg of citalopram or escitalopram; preferably, the pharmaceutical composition unit preparation contains 20 mg to 50 mg of dextromethorphan and 10 mg to 40 mg of citalopram or escitalopram.

8. A pharmaceutical composition according to claim 7, characterized in that: After the pharmaceutical composition is orally administered to rats, the AUC of dextromethorphan in the plasma of rats is 0-24 The value is the plasma exposure AUC achieved by administering the same dose of dextromethorphan alone. 0-24 3 times or more of the value.

9. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that The pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. It is further preferred that the pharmaceutical composition is in the form of any one of nasal spray, sublingual tablet, oral tablet, capsule, oral liquid, pill, injection and inhalant.

10. Use of the pharmaceutical composition according to any one of claims 1 to 9 in the preparation of a medicament for treating a patient suffering from a disease that can be treated with dextromethorphan; Preferably, the AUC of dextromethorphan exposure in rat plasma achieved by the pharmaceutical composition treatment is 0-24 The value is the plasma exposure AUC achieved by administering the same dose of dextromethorphan alone. 0-24 3 times or more of the value; Further preferably, the diseases treated with dextromethorphan include neuropsychiatric disorders and cough, preferably depression, Alzheimer's disease, affective disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, paroxysmal disorders and headache; More preferably, the depression is mild depression, moderate depression, severe depression, refractory depression and refractory bipolar depression.

11. Use of the pharmaceutical composition according to any one of claims 1 to 9 in the preparation of a medicament for preventing and / or treating cough and psychiatric disorders; preferably, the psychiatric disorder is depression, and more preferably, the depression is mild depression, moderate depression, severe depression, refractory depression and refractory bipolar depression.

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