Pharmaceutical composition containing dextromethorphan and application thereof

Abstract

The present invention provides a pharmaceutical composition comprising dextromethorphan, the composition comprising dextromethorphan or a pharmaceutically acceptable salt thereof, and fluoxetine or a pharmaceutically acceptable salt thereof. According to the pharmaceutical composition provided by the invention, the dextromethorphan or the pharmaceutically acceptable salt of the dextromethorphan and the fluoxetine or the pharmaceutically acceptable salt of the fluoxetine are combined according to a specific proportion, so that the pharmaceutical composition not only has an excellent synergistic effect, but also reduces the dosage of the dextromethorphan and the fluoxetine which are independently used. The invention also provides application of the pharmaceutical composition in preparation of drugs for preventing and / or treating cough and neuropsychiatric disorders, especially depression.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a pharmaceutical composition containing dextromethorphan and its uses. Background Technology

[0002] Dextromethorphan, chemically named (+)-3-methoxy-17-methyl-(9α,13α,14α)-morphine, is clinically used primarily as its hydrobromide salt. The chemical structure of dextromethorphan is as follows:

[0003]

[0004] Dextromethorphan (Dex) is a non-competitive NMDA receptor antagonist, a sigma-1 receptor agonist, and an N-type calcium channel blocker with antitussive properties. Dex interacts with NMDA receptor signaling and exerts its effects through serotonin transporters and sigma-1 receptors. NMDA receptors can activate nitric oxide synthase (NOS), thereby promoting 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 widely considered a common feature of various neurodegenerative and mental illnesses, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), depression, schizophrenia, or bipolar disorder (see Zhou Ran. Anti-inflammatory effects of ultra-low dose dextromethorphan in a mouse sepsis model and the pathology of brain complement C3 driving chronic neuroinflammation and neurodegeneration [D]. Tianjin Medical University, 2020).

[0006] In their article "New Advances in the Research of Dextromethorphan in the Nervous System," Zou Yuzhen et al. disclosed that dextromethorphan has good therapeutic effects on involuntary crying and laughing syndrome, depression, traumatic brain injury, epilepsy, and methotrexate central toxicity.

[0007] Although high doses of dextromethorphan can significantly antagonize central NMDA receptors, it is metabolized rapidly in the body, making it difficult to maintain a long-term drug concentration for therapeutic effect. AXS-05 is the first approved oral NMDA receptor antagonist for the treatment of depression. Utilizing the CYP2D6 inhibition of bupropion, it increased dextromethorphan exposure in subjects by approximately 80 times in clinical settings, thereby prolonging the half-life of dextromethorphan.

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

[0009] Fluoxetine is a widely used selective serotonin reuptake inhibitor (SSRI) in clinical practice. It selectively inhibits serotonin transporters, blocks the reuptake of serotonin by the presynaptic membrane, prolongs and increases the effects of serotonin, thereby producing an antidepressant effect. Its chemical structure is as follows:

[0010]

[0011] Dextromethorphan has a unique mechanism of action and shows promising application prospects in various central nervous system diseases such as depression, Alzheimer's disease, and epilepsy. However, due to the rapid metabolism of dextromethorphan in the human body, it is impossible to achieve therapeutic blood drug concentrations when used alone. Therefore, there is still a need in the field to develop drugs that can reduce the metabolism of dextromethorphan in order to fully realize its clinical application effects. Summary of the Invention

[0012] To address the aforementioned problems in the prior art, the present invention aims to provide a pharmaceutical composition containing dextromethorphan, thereby resolving the issue of dextromethorphan's rapid metabolism in vivo and difficulty in maintaining effective blood drug concentrations, and also to achieve lower dosage and higher safety.

[0013] First, the present invention provides a pharmaceutical composition comprising dextromethorphan or a pharmaceutically acceptable salt thereof, and fluoxetine or a pharmaceutically acceptable salt thereof; the mass ratio of dextromethorphan to fluoxetine, based on free base, is (1-4):(1-4), preferably (1-2):1, more preferably 2:1.

[0014] In the pharmaceutical composition described in this invention, dextromethorphan is an NMDA receptor antagonist, and fluoxetine is a selective serotonin reuptake inhibitor. Combining these two drugs synergistically enhances their effects, antagonizing NMDA receptors and inhibiting serotonin reuptake. Through multi-target and multi-mechanism combined action, a rapid therapeutic effect on depression is achieved. In particular, this invention, by selecting specific doses of dextromethorphan and fluoxetine, can increase the exposure of dextromethorphan in plasma, especially in brain tissue, while reducing the dosage of both dextromethorphan and fluoxetine, thus minimizing adverse drug reactions.

[0015] In a preferred embodiment, the pharmaceutical composition comprises dextromethorphan or a pharmaceutically acceptable salt thereof, and fluoxetine or a pharmaceutically acceptable salt thereof, wherein the mass ratio of dextromethorphan or a pharmaceutically acceptable salt thereof and fluoxetine or a pharmaceutically acceptable salt thereof, respectively, in the form of free bases, is (1-4):(1-4), for example, any two values ​​between 1:1, 1:2, 1:3, 1:4, 2:1, 2:3, 3:1, 3:2, 3:4, 4:1, or 4:3; preferably (1-4):1, more preferably (1-2):1, and particularly preferably 2:1.

[0016] In one embodiment, the pharmaceutical composition wherein, based on free base, the mass ratio of dextromethorphan to fluoxetine is (1-4):1, preferably (1-2):1.

[0017] In one embodiment, the pharmaceutical composition wherein, based on free base, the mass ratio of dextromethorphan to fluoxetine is 2:1.

[0018] In one embodiment, the pharmaceutical composition wherein the pharmaceutically acceptable salt comprises a salt of an inorganic acid or an organic acid formed with dextromethorphan and fluoxetine, respectively; the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid; and the organic acid includes 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.

[0019] In a preferred embodiment, the pharmaceutically acceptable salt of dextromethorphan is dextromethorphan hydrobromide (also known as: dextromethorphan hydrobromide), which is typically present in hydrate form. Dextromethorphan hydrobromide as described in the context of this invention also comprises its hydrate, with the structure shown below:

[0020]

[0021] In a preferred embodiment, the pharmaceutically acceptable salt of fluoxetine is fluoxetine hydrochloride (also known as: fluoxetine hydrochloride), and fluoxetine hydrochloride as used in the context of this invention also includes its hydrate, the structure of which is as follows:

[0022]

[0023] In one embodiment, the pharmaceutical composition of the present invention comprises dextromethorphan or dextromethorphan hydrobromide, and fluoxetine or fluoxetine hydrochloride.

[0024] In one embodiment, the present invention provides a pharmaceutical composition comprising dextromethorphan or dextromethorphan hydrobromide, and fluoxetine or fluoxetine hydrochloride, wherein the mass ratio of dextromethorphan or dextromethorphan hydrobromide to fluoxetine or fluoxetine hydrochloride, respectively, in the free base form, is (1-4):(1-4), for example, 1:1, 1:2, 1:3, 1:4, 2:1, 2:3, 3:1, 3:2, 3:4, 4:1 or 4:3, and any value between any two numbers; preferably (1-4):1, more preferably (1-2):1, and particularly preferably 2:1.

[0025] In a preferred embodiment, in any of the above-described pharmaceutical compositions, the unit dose of the pharmaceutical composition, calculated as free base, comprises 5 mg to 100 mg of dextromethorphan, for example, 5 mg to 50 mg, 5 mg to 40 mg, 5 mg to 30 mg, 5 mg to 20 mg, 5 mg to 10 mg, 10 mg to 60 mg, 10 mg to 50 mg, 10 mg to 40 mg, 10 mg to 30 mg, 10 mg to 20 mg, 10 mg to 15 mg, 15 mg to 60 mg, 15 mg to 50 mg, 15 mg to 40 mg, 15 mg to 30 mg, 15 mg to 20 mg, 20 ... Dextromethorphan in doses of 1 mg to 25 mg, 20 mg to 30 mg, 20 mg to 40 mg, 20 mg to 50 mg, 20 mg to 60 mg, 20 mg to 70 mg, or 20 mg to 80 mg, or any value between thereof; and containing 1 mg to 30 mg of fluoxetine, such as fluoxetine in doses of 1 mg to 30 mg, 5 mg to 30 mg, 5 mg to 20 mg, 5 mg to 10 mg, 5 mg to 15 mg, 10 mg to 20 mg, 10 mg to 15 mg, 15 mg to 20 mg, 15 mg to 25 mg, or 15 mg to 30 mg, or any value between thereof.

[0026] More preferably, the pharmaceutical composition of the present invention contains, per unit dose, 10 mg to 60 mg of dextromethorphan and 5 mg to 30 mg of fluoxetine, based on free base.

[0027] More preferably, the pharmaceutical composition of the present invention contains, per unit dose, 20 mg to 60 mg of dextromethorphan and 10 mg to 30 mg of fluoxetine, calculated as free base.

[0028] More preferably, the pharmaceutical composition of the present invention, calculated as free base, contains 20 mg to 40 mg of dextromethorphan and 10 mg to 20 mg of fluoxetine per unit dose. More preferably, the pharmaceutical composition of the present invention, calculated as free base, contains 10 mg to 40 mg of dextromethorphan and 5 mg to 20 mg of fluoxetine per unit dose. More preferably, the pharmaceutical composition of the present invention, calculated as free base, contains 10 mg to 20 mg of dextromethorphan and 5 mg to 10 mg of fluoxetine per unit dose.

[0029] More preferably, the pharmaceutical composition of the present invention, calculated as free base, contains 40 mg of dextromethorphan and 20 mg of fluoxetine per unit dose. More preferably, the pharmaceutical composition of the present invention, calculated as free base, contains 20 mg of dextromethorphan and 10 mg of fluoxetine per unit dose.

[0030] More preferably, the pharmaceutical composition of the present invention contains 10 mg of dextromethorphan and 5 mg of fluoxetine per unit dose, calculated as free base.

[0031] In a preferred embodiment, the present invention provides a pharmaceutical composition comprising dextromethorphan hydrobromide and fluoxetine hydrochloride, wherein, based on free base, the pharmaceutical composition contains 20 mg to 60 mg of dextromethorphan and 10 mg to 30 mg of fluoxetine per unit dose, and more preferably, the mass ratio of dextromethorphan to fluoxetine is 2:1.

[0032] In another preferred embodiment, the pharmaceutical composition of the present invention comprises dextromethorphan hydrobromide and fluoxetine hydrochloride, wherein, based on free base, the pharmaceutical composition contains 20 mg to 40 mg of dextromethorphan and 10 mg to 20 mg of fluoxetine per unit dose, and more preferably, the mass ratio of dextromethorphan to fluoxetine is 2:1.

[0033] In another preferred embodiment, the pharmaceutical composition of the present invention comprises dextromethorphan hydrobromide and fluoxetine hydrochloride, wherein, based on free base, each unit dose of the pharmaceutical composition contains 40 mg of dextromethorphan and 20 mg of fluoxetine.

[0034] In another preferred embodiment, the pharmaceutical composition of the present invention comprises dextromethorphan hydrobromide and fluoxetine hydrochloride, wherein, based on free base, each unit dose of the pharmaceutical composition contains 20 mg of dextromethorphan and 10 mg of fluoxetine.

[0035] In another preferred embodiment, the pharmaceutical composition of the present invention comprises dextromethorphan hydrobromide and fluoxetine hydrochloride, wherein, based on free base, each unit dose of the pharmaceutical composition contains 10 mg of dextromethorphan and 5 mg of fluoxetine.

[0036] In a preferred embodiment of the present invention, the total daily dose of the pharmaceutical composition administered to a human comprises about 40-80 mg of dextromethorphan and about 20-40 mg of fluoxetine, more preferably about 80 mg of dextromethorphan and about 40 mg of fluoxetine, or equimolar amounts of pharmaceutically acceptable salts of dextromethorphan (such as hydrobromide) and pharmaceutically acceptable salts of fluoxetine (such as hydrochloride). The pharmaceutical composition is preferably administered twice daily when administered to a human. Therefore, the unit dose of the pharmaceutical composition of the present invention comprises 20-40 mg of dextromethorphan and 10-20 mg of fluoxetine, and most preferably 40 mg of dextromethorphan and 20 mg of fluoxetine.

[0037] The pharmaceutical composition of the present invention further includes one or more pharmaceutically acceptable excipients, which can be selected according to the dosage form requirements of the pharmaceutical composition; preferably, the pharmaceutical composition of the present invention is any one of oral preparations, injections, granules, nasal sprays, and inhalers; the oral preparations include, but are not limited to, sublingual tablets, oral tablets, capsules, oral liquids, oral microcapsules, etc.; the injections include, but are not limited to, intramuscular injections, subcutaneous injections, intravenous injections, subcutaneous embeddings, intraperitoneal injections, etc.

[0038] More preferably, the pharmaceutical composition is an oral formulation or an injection.

[0039] When the pharmaceutical composition described in this invention is administered to a patient, it can be administered as a separate composition or dosage form, or as a single composition or dosage form comprising both.

[0040] In one specific embodiment, the pharmaceutical composition is an oral formulation. When administered to a patient, it is preferred that fluoxetine or a pharmaceutically acceptable salt thereof be administered orally first, and dextromethorphan or a pharmaceutically acceptable salt thereof be administered when the concentration of fluoxetine in plasma or brain tissue reaches or approaches its maximum. When fluoxetine or a pharmaceutically acceptable salt thereof is administered to a patient orally, the maximum drug concentration of fluoxetine in plasma or brain tissue is typically reached 1 to 3 hours after administration, preferably 2 hours, at which point dextromethorphan or a pharmaceutically acceptable salt thereof is administered. More preferably, when fluoxetine or a pharmaceutically acceptable salt thereof is administered to a patient orally, dextromethorphan or a pharmaceutically acceptable salt thereof is typically administered 1 to 3 hours after administration, for example, 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours, or any two of these numbers, and particularly preferably at an interval of 1.5 to 2.5 hours.

[0041] In one specific embodiment, the pharmaceutical composition is an injection, wherein when the pharmaceutical composition is administered to a patient, fluoxetine or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially with dextromethorphan or a pharmaceutically acceptable salt thereof, wherein the time interval between the sequential administrations does not exceed 1 hour, for example, not more than 0.5 hours, or not more than 20 minutes, or not more than 10 minutes, or not more than 5 minutes.

[0042] In another aspect of the invention, a method for reducing the rate of metabolism of dextromethorphan in the body is also provided, the method comprising administering the pharmaceutical composition of the invention to a patient with a disease requiring prevention and / or treatment with dextromethorphan;

[0043] More preferably, when the pharmaceutical composition is administered to a patient, fluoxetine or a pharmaceutically acceptable salt thereof is first administered, and dextromethorphan or a pharmaceutically acceptable salt thereof is then administered when the concentration of fluoxetine in the plasma or brain tissue reaches or approaches its maximum value.

[0044] For example, when a patient orally administers the pharmaceutical composition of the present invention, it is preferred to first administer fluoxetine or a pharmaceutically acceptable salt thereof orally, and then administer dextromethorphan or a pharmaceutically acceptable salt thereof when the concentration of fluoxetine in plasma or brain tissue reaches or approaches its maximum value; more preferably, when fluoxetine or a pharmaceutically acceptable salt thereof is administered to a patient orally, dextromethorphan or a pharmaceutically acceptable salt thereof is usually administered 1 to 3 hours after administration, for example, 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours, or any two of these numbers, and particularly preferably 1.5 to 2.5 hours after administration.

[0045] In another embodiment, when a patient is given the pharmaceutical composition of the present invention by injection, the fluoxetine or a pharmaceutically acceptable salt thereof and dextromethorphan or a pharmaceutically acceptable salt thereof may be administered to the patient simultaneously or sequentially. When administered sequentially, the time interval is preferably no more than 1 hour, particularly no more than 0.5 hours, or no more than about 20 minutes, or no more than about 10 minutes, or no more than about 5 minutes.

[0046] When the pharmaceutical composition is administered to rats via oral gavage or intraperitoneal injection, the resulting plasma and brain tissue exposures of dextromethorphan are both increased compared to those achieved by administering the same dose of dextromethorphan alone.

[0047] More preferably, the patient is a mammal or a human, particularly a human; in some embodiments, the disease prevented and / or treated with dextromethorphan includes neuropsychiatric disorders.

[0048] In another aspect of the invention, the use of the pharmaceutical composition of the invention in the preparation of a medicament for the prevention and / or treatment of patients suffering from diseases that can be prevented and / or treated with dextromethorphan is also provided; preferably, the pharmaceutical composition prevents and / or treats by reducing the rate of elimination of dextromethorphan in vivo and increasing the AUC of dextromethorphan in rat plasma. 0-24 The plasma exposure AUC is the result of administering the same dose of dextromethorphan alone. 0-24 Three 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.

[0049] Further preferably, the diseases prevented and / or treated with dextromethorphan include neuropsychiatric disorders and cough; preferably, the neuropsychiatric disorders are selected from one or more of depression, Alzheimer's disease, mood disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, episodic disorders, and headache; further preferably, the depression includes mild depression, moderate depression, severe depression, treatment-resistant depression, and treatment-resistant bipolar depression.

[0050] In another aspect of the invention, a method for preventing and / or treating cough and / or neuropsychiatric disorders is also provided, the method comprising oral administration of the pharmaceutical composition of the invention, wherein the interval between oral administration of fluoxetine or a pharmaceutically acceptable salt thereof and dextromethorphan or a pharmaceutically acceptable salt thereof is 1 to 3 hours, preferably 1.5 to 2.5 hours, for example, about 2 hours; or,

[0051] The method includes administering the pharmaceutical composition of the present invention via injection, wherein the fluoxetine or a pharmaceutically acceptable salt thereof and dextromethorphan or a pharmaceutically acceptable salt thereof are administered simultaneously by injection, wherein simultaneous administration means that the time interval between administrations is no more than 0.5 h, preferably no more than about 20 min, or no more than about 10 min, or no more than about 5 min;

[0052] More preferably, in the method, the single-dose dose, calculated as free base, comprises 40 mg of dextromethorphan and 20 mg of fluoxetine, or 20 mg of dextromethorphan and 10 mg of fluoxetine. More preferably, the method comprises administering the drug composition twice or more daily, such that the total daily dose of dextromethorphan and the total daily dose of fluoxetine administered to a human is about 80 mg.

[0053] The inventors have discovered that when the pharmaceutical composition of the present invention is administered to a patient, taking dextromethorphan or a pharmaceutically acceptable salt thereof when the plasma concentration of fluoxetine is at or near its maximum is beneficial to increasing the synergistic effect and significantly increasing the exposure to dextromethorphan. In another aspect of the invention, the use of the pharmaceutical composition of the present invention in the preparation of medicaments for the prevention and / or treatment of cough and neuropsychiatric disorders is also provided.

[0054] The neuropsychiatric disorders described in the context of this invention include one or more of the following: depression, Alzheimer's disease, mood disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, episodic disorders, and headache.

[0055] Further preferably, the neuropsychiatric disorders include depression such as mild depression, moderate depression, severe depression, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorder of cyclic affective disorder, seasonal affective disorder, mania, anxiety disorder, 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 instability.

[0056] The depression described in this invention can manifest as mood swings, intense sadness, despair, slowed thinking, loss of concentration, pessimistic anxiety, agitation, and self-deprecation. Physical symptoms of depression may also include insomnia, anorexia, weight loss, decreased energy and libido, and abnormal circadian rhythms of hormones.

[0057] The anxiety disorders mentioned 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).

[0058] The manic disorders mentioned include, but are not limited to, bipolar disorder, hypomania, stress disorder, somatic symptom disorder, personality disorder, psychosis, schizophrenia, delusional disorder, schizophrenic disorder, schizophrenic traits, aggressive behavior, Alzheimer's disease aggressive behavior, agitation, and Alzheimer's disease agitation.

[0059] Neuropsychiatric disorders that can be treated with the pharmaceutical compositions described in this invention include, but are not limited to, mild depression, moderate depression, severe depression, treatment-resistant depression, treatment-resistant bipolar disorder, seasonal affective disorder, mood disorders, chronic depression (psychotic depression), psychotic depression, postpartum depression, premenstrual anxiety disorder (PMDD), situational depression, atypical depression, mania, anxiety disorder, attention deficit disorder (ADD), attention deficit disorder with hyperactivity disorder (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, psychogenic dysfunction, pseudobulbar effects, and mood instability.

[0060] In a preferred embodiment of the present invention, the use of the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention and / or treatment of cough and neuropsychiatric disorders is provided. The neuropsychiatric disorders are preferably depression, and more preferably, the depression includes mild depression, moderate depression, severe depression, treatment-resistant depression, and treatment-resistant bipolar depression. Optionally, the depression is tested using the Montgomery-Sberg Depression Rating Scale (MADRS), with extreme depression: MADRS ≥ 35; severe depression: 35 > MADRS ≥ 30; moderate depression: 30 > MADRS ≥ 22; mild depression: 22 > MADRS ≥ 12; remission: MADRS < 12. That is, a MADRS ≥ 22 indicates moderate to severe depression.

[0061] In another aspect of the invention, a product kit is also provided, the product kit comprising a combination of dextromethorphan or a pharmaceutically acceptable salt thereof and fluoxetine or a pharmaceutically acceptable salt thereof; more preferably, the product kit comprises 20 mg to 60 mg of dextromethorphan and 10 mg to 30 mg of fluoxetine, based on free base, and wherein once or twice daily administration of the dosage form produces greater efficacy in the human body than dextromethorphan alone, wherein the mass ratio of dextromethorphan to fluoxetine is (1-2):1.

[0062] In some embodiments, the product kit contains a combination of dextromethorphan or a pharmaceutically acceptable salt thereof, and fluoxetine or a pharmaceutically acceptable salt thereof; preferably, the unit dose of the product kit, based on free base, contains 20 mg to 40 mg of dextromethorphan and 10 mg to 20 mg of fluoxetine, and that administration of the unit dose of the combination of dextromethorphan and fluoxetine once or twice daily produces a greater effect in the human body than administration of dextromethorphan alone, wherein the mass ratio of dextromethorphan to fluoxetine is (1-2):1.

[0063] In some embodiments, the product kit contains a combination of dextromethorphan or a pharmaceutically acceptable salt thereof, and fluoxetine or a pharmaceutically acceptable salt thereof; preferably, the unit dose of the product kit contains 40 mg of dextromethorphan and 20 mg of fluoxetine, based on free base, and that once or twice daily administration of the dosage form produces greater efficacy in the human body than dextromethorphan alone.

[0064] In some embodiments, the product kit contains a combination of dextromethorphan or a pharmaceutically acceptable salt thereof, and fluoxetine or a pharmaceutically acceptable salt thereof; preferably, the unit dose of the product kit contains 20 mg of dextromethorphan and 10 mg of fluoxetine, based on free base, and that once or twice daily administration of the dosage form produces greater efficacy in the human body than dextromethorphan alone.

[0065] Technical effect

[0066] (1) The pharmaceutical composition provided by this invention, comprising dextromethorphan or a pharmaceutically acceptable salt thereof and fluoxetine or a pharmaceutically acceptable salt thereof, can produce a synergistic effect through specific ratios between the components, enhancing the mechanism of action or pharmacological properties of dextromethorphan and fluoxetine. It can effectively inhibit the overactivation of NMDA receptors and inhibit 5-HT reuptake, significantly improving the therapeutic effect on patients with major depressive disorder (MDD), especially treatment-resistant depression (TRD). Simultaneously, the combination of dextromethorphan and fluoxetine reduces the dosage and potential side effects of using dextromethorphan and fluoxetine alone, and has the advantage of rapid onset of action. Furthermore, fluoxetine's effect on increasing dextromethorphan exposure in rats is stronger than that of the strong CYP2D6 inhibitor paroxetine.

[0067] (2) The drug composition provided by the present invention has a better metabolic effect than the prior art, provides a suitable drug concentration and effect. In particular, in the C57 mouse forced swimming model, the combination of 20 mg / kg dextromethorphan and 10 mg / kg fluoxetine showed a significant advantage in increasing the exposure of dextromethorphan in the brain compared with the low-dose group and the high-dose group, and significantly reduced the immobility time of the animals.

[0068] (3) The combination of dextromethorphan and fluoxetine provided by the present invention has a lower dosage of fluoxetine and a more significant increase in plasma exposure of dextromethorphan compared to the combination of dextromethorphan and bupropion.

[0069] Terminology Definition

[0070] This invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials described herein can be used to practice this invention. This invention is by no means limited to the methods and materials described herein. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0071] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0072] The terms “selected from…”, “preferred…” and “more preferred…” refer to one or more elements from the group listed below, selected independently, and may include a combination of two or more elements. In this invention, one element from the group listed below is preferred.

[0073] The terms “comprising” or “including” are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0074] In the context of this invention, all figures disclosed herein are approximate, regardless of whether the words “about,” “approximately,” or “roughly” are used. Each figure may vary by less than 10% or by a difference that is considered reasonable by those skilled in the art, such as 1%, 2%, 3%, 4%, or 5%.

[0075] In the context of this invention, the term "based on free base" in the pharmaceutical composition refers to the content of dextromethorphan free base when calculating its content, regardless of whether dextromethorphan exists in the pharmaceutical composition as a free base or as a pharmaceutically acceptable salt (such as hydrobromide); similarly, the content of fluoxetine is calculated as the content of fluoxetine free base when calculating its content, regardless of whether fluoxetine exists in the pharmaceutical composition as a free base or as a pharmaceutically acceptable salt. For example, when the pharmaceutical composition of this invention contains dextromethorphan hydrobromide and fluoxetine hydrochloride, and the mass ratio of dextromethorphan to fluoxetine is (1-2):1 based on free base, the term "mass ratio of (1-2):1" means that after converting dextromethorphan hydrobromide to dextromethorphan free base and fluoxetine hydrochloride to fluoxetine free base, the mass ratio of the two is (1-2):1. For example, the phrase "the pharmaceutical composition contains 20 mg to 60 mg of dextromethorphan" in this invention means that regardless of whether the dextromethorphan in the pharmaceutical composition exists in the form of a free base or a pharmaceutically acceptable salt, the 20 mg to 60 mg refers to the content after conversion to the free base of dextromethorphan.

[0076] The term “treatment” includes any activity that diagnoses, cures, alleviates, treats, or prevents disease in a person or other animal, or otherwise affects the structure or any function of the body in a person or other animal.

[0077] In the context of this invention, "unit dose" and "single dose" have the conventional meaning in the art, referring to the smallest unit of administration, the smallest unit of payment, or the smallest unit of packaging that can be divided in a drug, such as a tablet being a single tablet, a capsule being a single capsule, or an injection being an ampoule.

[0078] The term "person" refers to adults and children around 12 years of age and older.

[0079] AUC 0-last The area under the blood drug concentration-time curve from 0:00 to the last sampling time; AUC 0-inf The area under the blood drug concentration-time curve from 0 to infinity; MRT 0-last This refers to the average retention time.

[0080] In the context of this invention, "fluoxetine hydrochloride" and "fluoxetine hydrochloride" are interchangeable and both refer to the salt formed by hydrochloric acid and fluoxetine.

[0081] In the context of this invention, "dextromethorphan in hydrobromic acid form" and "dextromethorphan hydrobromide" or "dextromethorphan hydrobromide" are interchangeable and all refer to the salt formed by hydrobromic acid and dextromethorphan.

[0082] The free bases or pharmaceutically acceptable salts of dextromethorphan and fluoxetine described in the context of this invention also include their hydrates, solvates, polymorphs, and other solid forms.

[0083] The dextromethorphan described in the context of this invention can also be a deuterated form of dextromethorphan, examples of which include, but are not limited to, those shown below:

[0084] Attached Figure Description

[0085] Figure 1 The effect of oral administration of fluoxetine, bupropion, paroxetine and other drugs on dextromethorphan exposure in SD rats was shown.

[0086] Figure 2 The effect of gavage administration of fluoxetine at different time points on dextromethorphan exposure in SD rats was shown.

[0087] Figure 3 The effect of gavage administration of fluoxetine and dextromethorphan on immobility time in an ICR mouse forced swimming model was shown.

[0088] Figure 4 The effect of intraperitoneal injection of fluoxetine followed by gavage administration of dextromethorphan on immobility time in a forced swimming model of C57 mice was shown.

[0089] Figure 5 Display: Dextromethorphan concentrations in plasma, cerebrospinal fluid, and brain tissue; among which... Figure 5 (A), 5(B), and 5(C) show the concentrations of dextromethorphan in plasma, cerebrospinal fluid, and brain tissue, respectively.

[0090] Figure 6 This study demonstrates the effects of intraperitoneal injection of fluoxetine and bupropion on dextromethorphan exposure in C57 mice. Specific Implementation

[0091] To better understand the technical solution of the present invention, the present invention will be further described below with reference to specific embodiments. Unless otherwise specified, if specific techniques or conditions are not explicitly described in the following embodiments, those skilled in the art can perform them according to common techniques or conditions in the art or according to the product instructions. Drugs, reagents, or instruments used without a specified manufacturer are all commercially available conventional products.

[0092] Example 1: Effect of oral fluoxetine on dextromethorphan exposure in SD rats

[0093] To investigate the effect of fluoxetine combined with dextromethorphan administered by gavage on dextromethorphan exposure in SD rats, and to compare it with the same dose of bupropion, paroxetine, etc.

[0094] Experimental protocol: Thirty-three male SD rats were randomly divided into 11 groups. Purchased from Beijing Spaford, the animals were fasted overnight before the experiment but had unlimited water intake. On the day of the experiment, each group was administered the corresponding test substance by gavage according to Table 1.1, and the time of administration was recorded as 0h.

[0095] Table 1.1 Groups and Dosages

[0096]

[0097]

[0098] After administration, blood samples were collected at 15 min, 30 min and 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.

[0099] The experimental results are shown in Table 1.2 and Figure 1 The results showed that fluoxetine significantly increased the exposure of dextromethorphan in rats. None of the drugs had a significant effect on the half-life of dextromethorphan, but the mean retention time (MRT) in the fluoxetine group tended to be prolonged. These results indicate that fluoxetine's effect on increasing dextromethorphan exposure in rats was stronger than that of the strong CYP2D6 inhibitor paroxetine and also stronger than bupropion.

[0100] Table 1.2 Pharmacokinetic parameters of dextromethorphan in each group of animals

[0101]

[0102] Note: In Table 1.2, "right" refers to dextromethorphan.

[0103] Example 2: Effect of different gavage times of fluoxetine on dextromethorphan exposure in rats

[0104] The inventors further explored the effect of pre-administration of fluoxetine on the exposure of dextromethorphan in rats.

[0105] Experimental protocol: Sixteen male SD rats were randomly divided into four groups. Purchased from Beijing Spaford, the animals were fasted overnight before the experiment but had unlimited water intake. On the day of the experiment, each group was administered the corresponding test substance by gavage at the time points specified in Table 2.1 (fluoxetine was administered 1 hour and 2 hours earlier in groups 3 and 4, respectively), and the administration time of dextromethorphan was recorded as 0 h.

[0106] Table 2.1 Groups and Dosages

[0107]

[0108] After administration, blood samples were collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration to measure plasma dextromethorphan concentration and calculate pharmacokinetic parameters.

[0109] The experimental results are shown in Table 2.2 and Figure 2 As shown, gavage administration of fluoxetine 1 h and 2 h in advance can further increase the exposure of dextromethorphan in rats, with the effect of administration 2 h in advance being better than that of administration 1 h in advance.

[0110] Table 2.2 Pharmacokinetic parameters of dextromethorphan in each group of animals

[0111] Dextromethorphan Dextromethorphan + Fluoxetine 0h Dextromethorphan + Fluoxetine 1 hour Dextromethorphan + Fluoxetine 2h <![CDATA[AUC 0-last (mg / mL)]]> 20.91 131.03 199.46 229.81 <![CDATA[AUC 0-inf (mg / mL)]]> 29.19 147.43 218.46 299.52

[0112] Example 3: Effects of gavage administration of fluoxetine and dextromethorphan on immobility time in an ICR mouse forced swimming model

[0113] Experimental protocol: Forty-eight male ICR mice were randomly divided into 6 groups; purchased from Beijing Spaford. On the day of the experiment, the animals were administered the corresponding test drug by gavage according to Table 3.1 (fluoxetine was administered by gavage 2 hours before dextromethorphan administration, and fluoxetine was administered 2.5 hours before the test). A suitable amount of water (approximately 15 cm deep, approximately 22-25℃) was added to a straight-sided glass. Thirty minutes after dextromethorphan administration, the mice were placed in the glass for 6 minutes, and the experiment was recorded. After the experiment, the videos were exported, and behavioral analysis software was used to analyze the cumulative immobility time of the mice in the last 4 minutes (120-360 s). The effects of each group on the immobility time of the ICR mouse forced swimming model are shown below. Figure 3 As shown.

[0114] Table 3.1: Groups and Dosages

[0115] Group Dosage (mg / kg) Remark solvent / / Dextromethorphan 36 / Fluoxetine 20 Fluoxetine was administered 2.5 hours before the test. Dextromethorphan + Fluoxetine 9+20 Fluoxetine is administered 2 hours before dextromethorphan. Dextromethorphan + Fluoxetine 18+20 Fluoxetine is administered 2 hours before dextromethorphan. Dextromethorphan + Fluoxetine 36+20 Fluoxetine is administered 2 hours before dextromethorphan.

[0116] The experimental results are shown in Table 3.2 and Figure 3 As shown, dextromethorphan at 36 mg / kg and fluoxetine at 20 mg / kg alone had no significant effect on immobility time in mice; however, dextromethorphan plus fluoxetine at doses of 18+20 mg / kg and 36+20 mg / kg significantly reduced immobility time in mice, indicating that the combination of fluoxetine and dextromethorphan has a synergistic effect.

[0117] Table 3.2: Immobility time of mice from 120 to 360 seconds

[0118]

[0119] A p-value less than 0.05 indicates a significant difference.

[0120] Example 4: Effect of intraperitoneal injection of fluoxetine followed by gavage administration of dextromethorphan on immobility time in a forced swimming model of C57 mice;

[0121] In Example 3, although the combined use of fluoxetine and dextromethorphan showed a synergistic effect, no obvious dose relationship was found; the inventors further investigated the pharmacological effects of fluoxetine combined with dextromethorphan.

[0122] Experimental protocol: Seventy-two male C57BL / 6 mice were randomly divided into six groups. Purchased from Jiangsu Jicui Pharmaceutical Co., Ltd., the mice were administered the corresponding drugs via the routes specified in Table 4.1. A suitable amount of water (approximately 15 cm deep, 22-25℃) was added to a cylindrical glass. Thirty minutes after drug administration, the mice were placed in the glass for six minutes, and the experiment was recorded. After the experiment, the videos were exported, and behavioral analysis software was used to analyze the cumulative immobility time of the mice in the last four minutes (120-360 seconds). After the tests, four animals from each group were sampled to collect plasma, cerebrospinal fluid, and brain tissue. The concentrations of dextromethorphan and fluoxetine were measured. The results are as follows: Figure 5 As shown.

[0123] Table 4.1 Groups and Dosages

[0124]

[0125] The experimental results showed that the dextromethorphan 20 mg / kg gavage group (dextromethorphan 20), the dextromethorphan 20 mg / kg intraperitoneal injection group (fluoxetine 20), the fluoxetine + dextromethorphan at doses of 10 + 10 mg / kg (fluoxetine 10 + dextromethorphan 10), and the fluoxetine + dextromethorphan at doses of 20 + 20 mg / kg (fluoxetine 20 + dextromethorphan 20) did not significantly reduce the immobility time of animals compared with the solvent group (P values ​​were 0.1757, 0.1, and 0.1, respectively). The concentrations of fluoxetine and dextromethorphan (0.32, 0.1197, and 0.9972) in the 10+20 mg / kg dose group (fluoxetine 10 + dextromethorphan 20) showed a significant difference in reducing immobility time in animals compared to the solvent group (P = 0.0055). This indicates that the 1:2 mass ratio of fluoxetine to dextromethorphan significantly reduces immobility time in animals, and its effect is stronger than that of dextromethorphan or fluoxetine alone, and also stronger than the 1:1 dose combination of fluoxetine and dextromethorphan. Figure 4 The results show the effect of different dosage groups on immobility time in a forced swimming model of C57 mice.

[0126] Figure 5 (A) shows that the effect of dextromethorphan + fluoxetine on dextromethorphan exposure at doses of 10+10 mg / kg, 20+10 mg / kg and 20+20 mg / kg increases with increasing fluoxetine dose; Figure 5(B) and 5(C) show that at a dose of 20 ± 10 mg / kg, the exposure of dextromethorphan in brain tissue and cerebrospinal fluid was higher than that in the low-dose group (dextromethorphan + fluoxetine at 10 ± 10 mg / kg) and the high-dose group (dextromethorphan + fluoxetine at 20 ± 20 mg / kg). This indicates that a 1:2 mass ratio of fluoxetine to dextromethorphan is beneficial in increasing the concentration of dextromethorphan in brain tissue and brain homogenate, and reducing the immobility time of animals. Its effect is stronger than that of dextromethorphan or fluoxetine alone, and also stronger than the dose combination of fluoxetine and dextromethorphan at a 1:1 mass ratio.

[0127] Example 5: Effect of intraperitoneal injection of fluoxetine on dextromethorphan exposure in C57 mice

[0128] Based on the opposite efficacy-dose relationship between fluoxetine (intraperitoneal injection) and dextromethorphan (gavage) at different doses in Example 4, a pharmacokinetic (PK) study was conducted to verify the exposure of dextromethorphan in animals at these two doses, and compared with intraperitoneal injection of bupropion plus gavage of dextromethorphan.

[0129] Experimental protocol: Forty-eight male C57BL / 6 mice were randomly divided into four groups of 12 each. Purchased from Beijing Spaford, the mice were fasted overnight but allowed free access to water. On the day of the experiment, bupropion or fluoxetine was administered intraperitoneally according to Table 5.1, followed immediately by gavage administration of dextromethorphan. Plasma concentrations of dextromethorphan, bupropion, and fluoxetine were collected and measured at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after gavage administration (blood was collected from four animals at each time point), and pharmacokinetic (PK) parameters were calculated.

[0130] Table 5.1 Groups and Dosages

[0131] Group Dextromethorphan (mg / kg) Bupropion (mg / kg) Fluoxetine (mg / kg) Dextromethorphan 20 20 0 0 Dextromethorphan + Bupropion 20 + 46.7 20 46.7 0 Dextromethorphan + Fluoxetine 20+10 20 0 10 Dextromethorphan + Fluoxetine 20+20 20 0 20

[0132] The experimental results are shown in Table 5.2 and Figure 6 As shown, intraperitoneal injection of fluoxetine 20 mg / kg or bupropion 46.7 mg / kg both increased dextromethorphan exposure in C57BL / 6 mice, and the effect of fluoxetine was stronger than that of bupropion; the effect of dextromethorphan + fluoxetine on dextromethorphan exposure at doses of 20+10 mg / kg and 20+20 mg / kg increased with increasing fluoxetine dose.

[0133] Table 5.2: Pharmacokinetic parameters of dextromethorphan in mouse plasma

[0134]

[0135] The aforementioned pharmaceutical composition, particularly the combination of dextromethorphan 20 mg / kg and fluoxetine 10 mg / kg, exhibits significant advantages in pharmacokinetics and efficacy in mice. Based on the conversion of drug dosage relationships between mice and humans, it can be inferred that when this pharmaceutical composition is administered to humans, the daily dose converted to a clinical dose of approximately 81 mg of dextromethorphan and approximately 40.6 mg of fluoxetine will also have similar efficacy and pharmacokinetic properties. For ease of clinical use, in a preferred embodiment of the present invention, the daily dosage of the pharmaceutical composition comprises approximately 80 mg of dextromethorphan and approximately 40 mg of fluoxetine, or equimolar amounts of pharmaceutically acceptable dextromethorphan salts (such as hydrobromide) and pharmaceutically acceptable fluoxetine salts (such as hydrochloride). The pharmaceutical composition is preferably administered twice daily to patients.

[0136] Example 6: Product Medicine Box

[0137] In some embodiments, the product kit contains a combination of dextromethorphan hydrobromide and fluoxetine hydrochloride, and the product kit contains a dosage form of about 20 mg to about 60 mg of dextromethorphan and about 10 mg to about 30 mg of fluoxetine, based on free base, and the mass ratio of dextromethorphan to fluoxetine is 2:1.

[0138] In some implementations, the product kit contains 40 mg of dextromethorphan and 20 mg of fluoxetine, calculated as free base.

Claims

1. A pharmaceutical composition, characterized in that, It contains dextromethorphan or a pharmaceutically acceptable salt thereof, and fluoxetine or a pharmaceutically acceptable salt thereof; the mass ratio of dextromethorphan to fluoxetine, based on free base, is (1-4):(1-4), preferably (1-2):1, more preferably 2:

1.

2. The pharmaceutical composition according to claim 1, characterized in that, Based on free base, the mass ratio of dextromethorphan to fluoxetine is 1:1, 1:2, 1:3, 1:4, 2:1, 2:3, 3:1, 3:2, 3:4, 4:1 or 4:3, or any value between two such ratios.

3. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that, The pharmaceutical composition contains 20 mg to 60 mg of dextromethorphan per unit dose, calculated as free base. Preferably, the pharmaceutical composition contains 20 mg to 40 mg of dextromethorphan per unit dose; More preferably, the pharmaceutical composition contains 10 mg to 20 mg of dextromethorphan per unit dose.

4. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that, The pharmaceutical composition contains 10 mg to 30 mg of fluoxetine per unit dose, based on free base. Preferably, the pharmaceutical composition contains 10 mg to 20 mg of fluoxetine per unit dose.

5. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that, Based on free base, the pharmaceutical composition comprises 20 mg to 40 mg of dextromethorphan and 10 mg to 20 mg of fluoxetine per unit dose, wherein the mass ratio of dextromethorphan to fluoxetine is 2:

1. Preferably, the total daily dose of the pharmaceutical composition administered to a human comprises 40-80 mg of dextromethorphan and 20-40 mg of fluoxetine, or equimolar amounts of pharmaceutically acceptable salts of dextromethorphan and fluoxetine.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that, The dextromethorphan or a pharmaceutically acceptable salt thereof is selected from dextromethorphan hydrobromide; the fluoxetine or a pharmaceutically acceptable salt thereof is selected from fluoxetine hydrochloride.

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that, The pharmaceutical composition is any one of oral preparations, injections, granules, nasal sprays, and inhalers; Preferably, the pharmaceutical composition is an oral formulation or an injection; More preferably, the dextromethorphan or a pharmaceutically acceptable salt thereof and fluoxetine or a pharmaceutically acceptable salt thereof are administered in separate compositions or dosage forms, or in a single composition or dosage form comprising both.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that, When the pharmaceutical composition is administered to rats via oral gavage or intraperitoneal injection, the resulting plasma and brain tissue exposures of dextromethorphan are both increased compared to those achieved by administering the same dose of dextromethorphan alone.

9. A medicine box comprising the pharmaceutical composition according to any one of claims 1 to 8; The kit contains dextromethorphan or a pharmaceutically acceptable salt thereof, and fluoxetine or a pharmaceutically acceptable salt thereof, wherein the unit dose of dextromethorphan is 20 mg to 60 mg based on free base, the unit dose of fluoxetine is 10 mg to 30 mg, and the mass ratio of dextromethorphan to fluoxetine is (1 to 2):

1. Further preferably, the dextromethorphan or a pharmaceutically acceptable salt thereof and fluoxetine or a pharmaceutically acceptable salt thereof are administered separately in separate dosage forms.

10. Use of the pharmaceutical composition according to any one of claims 1 to 8 or the medicament according to claim 9 in the preparation of a medicament for the prevention and / or treatment of patients suffering from diseases that can be prevented and / or treated with dextromethorphan; Preferably, the diseases treated with dextromethorphan include neuropsychiatric disorders or cough; Further preferably, the neuropsychiatric condition is one or more of the following: depression, Alzheimer's disease, mood disorder, mental disorder, brain dysfunction, motor disorder, dementia, motor neuron disease, neurodegenerative disease, episodic symptoms, or headache. Further preferably, the depression is one or more of the following: mild depression, moderate depression, severe depression, treatment-resistant depression, or treatment-resistant bipolar depression.

11. Use of a combination of dextromethorphan or a pharmaceutically acceptable salt thereof and fluoxetine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of neuropsychiatric disorders, wherein the mass ratio of dextromethorphan or a pharmaceutically acceptable salt thereof, calculated as dextromethorphan and fluoxetine or a pharmaceutically acceptable salt thereof, calculated as fluoxetine, is (1-2):

1. Further preferably, the dextromethorphan or its pharmaceutically acceptable salt, calculated as dextromethorphan, has a unit dose of 20 mg to 40 mg, preferably 40 mg; and the fluoxetine or its pharmaceutically acceptable salt, calculated as fluoxetine, has a unit dose of 10 mg to 20 mg, preferably 20 mg. More preferably, the total daily dose of dextromethorphan and the total daily dose of fluoxetine administered to humans are 80 mg and 40 mg, respectively. Further preferably, the neuropsychiatric disorders are selected from one or more of the following: depression, Alzheimer's disease, mood disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, episodic disorders, and headache; preferably, the depression is one or more of the following: mild depression, moderate depression, severe depression, treatment-resistant depression, and treatment-resistant bipolar depression. Further preferably, the dextromethorphan or its pharmaceutically acceptable salt and fluoxetine or its pharmaceutically acceptable salt are administered to the patient in separate dosage forms, and the dextromethorphan or its pharmaceutically acceptable salt is administered 1 to 3 hours, preferably 2 hours, after oral administration of the fluoxetine or its pharmaceutically acceptable salt formulation; or the dextromethorphan or its pharmaceutically acceptable salt and fluoxetine or its pharmaceutically acceptable salt formulation are administered to the patient simultaneously by injection.

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