Use of pharmaceutical composition

Abstract

The present disclosure relates to use of a pharmaceutical composition. Specifically, the pharmaceutical composition provided by the present disclosure is used for treating inflammatory depression, wherein the pharmaceutical composition comprises: (i) dextromethorphan or a salt of dextromethorphan and (ii) celecoxib or a salt of celecoxib. The pharmaceutical composition of the present disclosure is directed to inflammatory depression (especially inflammatory treatment-resistant depression and anhedonia depression).

Description

Use of a pharmaceutical composition

[0001] Cross-reference to related applications

[0002] The present disclosure claims priority to the Chinese patent application with the application number 2024112476192, the title of “Use of a pharmaceutical composition”, and the filing date of 2024 / 09 / 06. The present disclosure incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0003] The present disclosure relates to the field of biological medicine, in particular to the use of a pharmaceutical composition. BACKGROUND

[0004] Inflammatory depression is a new subtype of depression. Patients with inflammatory depression have abnormal inflammatory markers (such as IL-6, TNF-α, IL-2β, CRP, etc.) in peripheral blood and cerebrospinal fluid. Studies have found that the inflammatory biomarkers such as inflammatory cytokines (such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and C-reactive protein (CRP)) in the peripheral blood and cerebrospinal fluid of patients with refractory depression and anhedonic depression are significantly increased. The abnormality of inflammatory markers is related to the poor clinical effect of depression treatment drugs. Therefore, refractory depression and anhedonic depression are associated with inflammation.

[0005] Treatment-resistant depression (TRD) is a common disease state in clinical practice, which usually refers to depression that has not been relieved (usually refers to Hamilton Depression Scale-17 items ≤7 points) after sufficient and full-course treatment of two or more different mechanism of action antidepressants. Individuals who do not achieve remission not only have adverse outcomes due to residual symptoms, but also have an increased risk of recurrence of depression. In addition, there are more somatic symptoms, and their social functioning is also impaired.

[0006] Anhedonic depression: The definition of anhedonia in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (abbreviated: DSM-5) established by the American Psychiatric Association is the loss of interest in all or almost all activities, the loss of response to ordinary pleasurable stimuli. Studies show that about 50-80% of patients with depression have anhedonia, and patients with anhedonia have more severe depression and higher suicide rates. As the core symptom of this subtype of depression, anhedonia also predicts poor clinical outcomes, including adolescents. At the same time, anhedonia may be a risk factor for patients with previous use of monoamine antidepressants developing treatment-resistant depression (TRD).

[0007] In 2022, the first oral NMDA receptor antagonist for the treatment of depression, Auvelity, was approved by the FDA. Auvelity is a combination of two approved drugs, but it only shows some effect in the treatment of general depression (such as major depressive disorder (MDD)), and performs poorly in the treatment of treatment-resistant depression and anhedonic depression. The results of the current phase III clinical trial for treatment-resistant depression show that Auvelity has limited efficacy and high side effects. Therefore, there is still a need to find effective drugs for the treatment of treatment-resistant depression or anhedonic depression and other inflammation-related depression. SUMMARY

[0008] The purpose of the present disclosure is to provide a use of a pharmaceutical composition.

[0009] Another purpose of the present disclosure is a method for treating inflammatory depression.

[0010] According to an aspect of the present disclosure, a use of a pharmaceutical composition for (i) treating inflammatory depression; and / or (ii) preparing a drug for treating inflammatory depression; is provided, wherein the pharmaceutical composition comprises: (i) dextromethorphan or a salt of dextromethorphan; and (ii) celecoxib or a salt of celecoxib.

[0011] In one embodiment, the inflammatory depression is at least one selected from treatment-resistant depression and anhedonic depression.

[0012] In one embodiment, the treatment-resistant depression is inflammatory treatment-resistant depression, and the patient with inflammatory treatment-resistant depression exhibits symptoms of inflammatory cytokine imbalance.

[0013] In one embodiment, the pharmaceutical composition consists of (i) dextromethorphan or a salt of dextromethorphan; and (ii) celecoxib.

[0014] In one embodiment, the mass ratio of the dextromethorphan and the celecoxib in the pharmaceutical composition is 1 : (0.5-10) on a free base basis.

[0015] In one embodiment, the mass ratio of the dextromethorphan and the celecoxib in the pharmaceutical composition is 1 : (0.5-6) on a free base basis.

[0016] In one embodiment, the mass ratio of the dextromethorphan and the celecoxib in the pharmaceutical composition is 1 : (1-6) on a free base basis.

[0017] In one embodiment, the mass ratio of the dextromethorphan and the celecoxib in the pharmaceutical composition is 1 : (1-5) on a free base basis.

[0018] In one embodiment, the mass ratio of the dextromethorphan and the celecoxib in the pharmaceutical composition is 1 : (1-4) on a free base basis.

[0019] In one embodiment, the mass ratio of the dextromethorphan and the celecoxib in the pharmaceutical composition is 1 : (1.5-3) on a free base basis.

[0020] In one embodiment, the mass ratio of the dextromethorphan and the celecoxib in the pharmaceutical composition is 1 : (2-3) on a free base basis.

[0021] In one embodiment, the mass ratio of the dextromethorphan and the celecoxib in the pharmaceutical composition is 1 : (1.5-2.5) on a free base basis.

[0022] In one embodiment, the mass ratio of the dextromethorphan and the celecoxib in the pharmaceutical composition is 1 : (1.1-2.0) on a free base basis.

[0023] In one embodiment, the mass ratio of the dextromethorphan and the celecoxib in the pharmaceutical composition is 1 :2 on a free base basis.

[0024] In one embodiment, the mass ratio of the dextromethorphan and the celecoxib in the pharmaceutical composition is 1 :3 on a free base basis.

[0025] In one embodiment, the salt of the dextromethorphan is dextromethorphan hydrobromide.

[0026] In one embodiment, the salt of the dextromethorphan is a salt containing water of crystallization, such as dextromethorphan hydrobromide monohydrate.

[0027] In one embodiment, the dextromethorphan hydrobromide monohydrate is represented by the following formula (I):

[0028] In one embodiment, the celecoxib has the structure shown below as formula (II):

[0029] In one embodiment, the amount of celecoxib in the pharmaceutical composition is 10-500 mg as free base; more preferably 30-400 mg; more preferably 30-300 mg; more preferably 40-200 mg, for example 120 mg.

[0030] In one embodiment, the amount of dextromethorphan in the pharmaceutical composition is 10-500 mg as free base; more preferably 20-300 mg; more preferably 25-100 mg; more preferably 20-80 mg, for example 60 mg.

[0031] In one embodiment, the amount of dextromethorphan in the pharmaceutical composition is 10-500 mg as free base and the amount of celecoxib is 10-500 mg; and the mass ratio of the dextromethorphan to the celecoxib is 1 : (1-5).

[0032] In one embodiment, the amount of dextromethorphan in the pharmaceutical composition is 20-300 mg as free base and the amount of celecoxib is 30-400 mg; and the mass ratio of the dextromethorphan to the celecoxib is 1 : (1-5).

[0033] In one embodiment, the amount of dextromethorphan in the pharmaceutical composition is 20-300 mg as free base and the amount of celecoxib is 30-400 mg; and the mass ratio of the dextromethorphan to the celecoxib is 1 : (1.5-3).

[0034] In one embodiment, the amount of dextromethorphan in the pharmaceutical composition is 20-300 mg as free base and the amount of celecoxib is 30-400 mg; and the mass ratio of the dextromethorphan to the celecoxib is 1 : (1.5-2.5).

[0035] In one embodiment, the amount of dextromethorphan in the pharmaceutical composition is 20-300 mg as free base and the amount of celecoxib is 30-400 mg; and the mass ratio of the dextromethorphan to the celecoxib is 1 : (2-3).

[0036] In one embodiment, the amount of dextromethorphan in the pharmaceutical composition is 20-300 mg as free base and the amount of celecoxib is 30-300 mg; and the mass ratio of the dextromethorphan to the celecoxib is 1 : (1.5-2.5).

[0037] In one embodiment, the content of dextromethorphan in the pharmaceutical composition is 20-300 mg, and the content of celecoxib is 30-400 mg, in terms of free base; and the mass ratio of the dextromethorphan to the celecoxib is 1:2.

[0038] In one embodiment, the content of dextromethorphan in the pharmaceutical composition is 20-300 mg, and the content of celecoxib is 30-400 mg, in terms of free base; and the mass ratio of the dextromethorphan to the celecoxib is 1:3.

[0039] In one embodiment, the content of dextromethorphan in the pharmaceutical composition is 20-300 mg, and the content of celecoxib is 30-300 mg, in terms of free base; and the mass ratio of the dextromethorphan to the celecoxib is 1:2.

[0040] In one embodiment, the content of dextromethorphan in the pharmaceutical composition is 20-60 mg, and the content of celecoxib is 40-120 mg, in terms of free base; and the mass ratio of the dextromethorphan to the celecoxib is 1:(1-5).

[0041] In one embodiment, the content of dextromethorphan in the pharmaceutical composition is 20-60 mg, and the content of celecoxib is 40-120 mg, in terms of free base; and the mass ratio of the dextromethorphan to the celecoxib is 1:(1.5-2.5).

[0042] In one embodiment, the content of dextromethorphan in the pharmaceutical composition is 20-60 mg, and the content of celecoxib is 40-120 mg, in terms of free base; and the mass ratio of the dextromethorphan to the celecoxib is 1:2.

[0043] In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0044] In one embodiment, the pharmaceutical composition is a tablet or a capsule.

[0045] In one embodiment, the pharmaceutical composition is a controlled release or sustained release formulation.

[0046] In one embodiment, (i) dextromethorphan or a salt of dextromethorphan and (ii) celecoxib or a salt of celecoxib in the pharmaceutical composition are packaged separately.

[0047] In one embodiment, (i) dextromethorphan or a salt of dextromethorphan and (ii) celecoxib or a salt of celecoxib in the pharmaceutical composition are packaged together.

[0048] In one embodiment, (i) dextromethorphan or a salt of dextromethorphan and (ii) celecoxib or a salt of celecoxib in the pharmaceutical composition are used simultaneously.

[0049] In one embodiment, (i) dextromethorphan or a salt of dextromethorphan and (ii) celecoxib or a salt of celecoxib in the pharmaceutical composition are used sequentially.

[0050] According to another aspect of the present disclosure, there is provided a method of treating inflammatory depression, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises: (i) dextromethorphan or a salt of dextromethorphan; and (ii) celecoxib or a salt of celecoxib.

[0051] In one embodiment, the salt of dextromethorphan and the salt of celecoxib are pharmaceutically acceptable salts.

[0052] In one embodiment, the subject in need is a human, and the method of preventing and / or treating inflammatory depression comprises the step of administering to the subject in need a combination of dextromethorphan (or a salt of dextromethorphan) and celecoxib (or a salt of celecoxib) in a single administration; wherein the administration dosage of dextromethorphan is 0.5-1.0 mg / kg (e.g. 0.81 mg / kg), and the administration dosage of celecoxib is 1.0-2.0 mg / kg (e.g. 1.63 mg / kg).

[0053] In one embodiment, the subject in need has been previously treated with a monoamine antidepressant drug.

[0054] The present disclosure has at least the following advantages over the prior art:

[0055] (1) The pharmaceutical composition provided by the present disclosure exhibits a significantly better efficacy than that of a pharmaceutical composition of dextromethorphan and bupropion in the treatment of inflammatory depression (especially refractory depression and anhedonic depression).

[0056] (2) The half-life of the pharmaceutical composition provided by the present disclosure is longer, and the PK performance is significantly better than that of a pharmaceutical composition of dextromethorphan and bupropion. BRIEF DESCRIPTION OF DRAWINGS

[0057] Figure 1 shows the effect of the pharmaceutical composition of the present disclosure on the expression of inflammatory cytokines and corticosterone in vivo. Note: D represents dextromethorphan; B represents bupropion; and C represents celecoxib.

[0058] Figure 2 shows the results of toxicity studies of the pharmaceutical composition of the present disclosure. DETAILED DESCRIPTION

[0059] This disclosure provides novel uses of pharmaceutical compositions comprising dextromethorphan or a salt thereof, and celecoxib or a salt thereof, which exhibit excellent therapeutic efficacy against inflammatory depression. This disclosure also provides methods for treating inflammatory depression.

[0060] Specific implementation schemes are provided below to illustrate the technical content of this disclosure. Those skilled in the art can easily understand other advantages and effects of this disclosure through the content disclosed in the specification. This disclosure can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of this disclosure.

[0061] I. Definition

[0062] Unless otherwise defined, throughout the specification and claims, the term “comprising” or its variations such as “including” or “comprising” shall be understood to include the stated elements or components without excluding other elements or other components.

[0063] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In this specification, the singular form also includes the plural form unless the context clearly specifies otherwise; for example, the terms “a” or “an” are understood as singular or plural, and the term “or” is understood as inclusive. For example, “an element” refers to one or more elements. Throughout this specification, the word “comprising” or variations thereof are to be understood as implying inclusion of the specified element, integer, or step, or a group of elements, integers, or steps, but not excluding any other element, integer, or step, or a group of elements, integers, or steps. “Approximately” can be understood as within 10%, 9%, or indicating values ​​of 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%. Unless the context clearly specifies otherwise, all numerical values ​​provided herein are modified by the term “about”.

[0064] As used herein, the terms “optional” or “optionally” mean that an event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0065] Pharmaceutical Composition

[0066] As used in the text, the term "pharmaceutical composition" includes combinations of active ingredients, combinations of active ingredients with other non-active ingredients (such as pharmaceutically acceptable carriers or excipients), and combinations of one active ingredient with other non-active ingredients (such as pharmaceutically acceptable carriers or excipients). The aforementioned non-active ingredients should all be pharmaceutically acceptable ingredients, depending on the nature of the mode of administration and the nature of the dosage form. Examples of non-active ingredients include, but are not limited to, carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, flavorants, lubricants, dispersants, temperature-sensitive materials, temperature-regulating agents, adhesion agents, stabilizers, suspending agents, and the like.

[0067] In one example, the pharmaceutical composition contains only one active ingredient, which is combined with other non-active ingredients (such as pharmaceutically acceptable carriers or excipients) to form the pharmaceutical composition. In one example, the pharmaceutical composition contains multiple active ingredients, which are combined to form the pharmaceutical composition. In one example, the pharmaceutical composition consists of multiple active ingredients without containing other non-active ingredients, which are combined to form the pharmaceutical composition. In one example, the pharmaceutical composition contains multiple active ingredients, each of which is separately combined with other non-active ingredients to form the pharmaceutical composition. In one example, the pharmaceutical composition contains multiple active ingredients, which are combined with other non-active ingredients to form the pharmaceutical composition. The scope of the pharmaceutical composition herein includes combinations of active ingredients, single formulations, fixed-dose combination finished pharmaceutical products, combination drugs, and combination packaged pharmaceutical products.

[0068] As used in the text, the term "single formulation" refers to a finished product of a preparation containing one active substance.

[0069] As used in the text, the term "fixed-dose combination finished pharmaceutical product (FDC-FPP)" refers to a finished product of a preparation in which two or more active substances are combined in a fixed-dose ratio.

[0070] As used in the text, the term "compounding drug" refers to a preparation in which multiple drugs are mixed and formulated in any ratio, mainly for meeting the individualized medication needs of patients. Generally, the ratio of various drugs in a compounding drug is determined according to a prescription issued by a doctor.

[0071] As used herein, the term "co-packaged medicines" refers to the final formulation of two or more independent medicines into one medicine package, packaged together, to provide the medicines to the patient in a co-packaged form.

[0072] As used herein, the term "dextromethorphan" is a non-selective NMDA receptor antagonist, CAS: 125-71-3, with the English name: Dextromethorphan, and the chemical name: (+)-3-methoxy-17-methyl-(9a, 13a, 14a)-morphinane. Dextromethorphan is clinically used as its hydrobromide salt (CAS: 125-69-9) as a drug, more specifically as dextromethorphan hydrobromide monohydrate, CAS: 6700-34-1, with the chemical structure as shown below. Dextromethorphan is a non-selective NMDA receptor antagonist with NMDA, sigma-1, serotonin reuptake (SET), norepinephrine reuptake (NET) activity, which is mainly metabolized by CYP2D6 (cytochrome P450 superfamily enzyme) into dextrorphan with pharmacological activity.

[0073] As used herein, the term "celecoxib" is a COX-2 inhibitor, CAS: 169590-42-5, with the English name: Celecoxib, and the chemical name: 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide, which is clinically used as celecoxib (CAS: 169590-42-5) as a drug, with the chemical structure as shown below.

[0074] As used herein, the term "pharmaceutically acceptable" means those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0075] As used herein, the term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each component must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenecity, or other problems or complications commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy 21st Ed.; Lippincott Williams and Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Ed.; Rowe et al. Eds., The Pharmaceutical Press and American Pharmaceutical Association: 2005; J. Am. Chem. Soc, 2005, 11: 1959, and Handbook of Pharmaceutical Additives, 3rd Ed.; Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Formulation and Dosage, Gibson Ed., CRC Press, Boca Raton, FL.

[0076] As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and non-biological properties of the free acids and bases of the specified compound and do not impart undesired toxicological effects. For example, acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases). Examples of organic acids herein include, without limitation, hydrobromic and benzoic acids. Examples of pharmaceutically acceptable salts include, without limitation, hydrobromide and benzoate salts. Pharmaceutically acceptable salts herein also include those that contain water or other solvents.

[0077] As used herein, the term "hydrate" refers to a compound that contains water of hydration, the water molecules in the hydrate participating in the crystal structure as neutral water molecules in a defined amount of water occupying defined positions in the crystal lattice.

[0078] Pharmaceutically acceptable salts as used herein can be synthesized from the parent compound that contains a sufficiently basic or acidic moiety by conventional chemical methods. Generally, such salt forms will be prepared by reacting the free acid or base forms of the compound with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0079] The pharmaceutical or pharmaceutical composition of the present disclosure can be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers.

[0080] The pharmaceutical or pharmaceutical composition of the present disclosure can be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, e.g., bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical composition of the present disclosure can take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0081] The pharmaceutical or pharmaceutical composition of the present disclosure can also be formulated for rectal administration, e.g., as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0082] As used herein, the term "modified release formulation" refers to a formulation that modifies the rate, location or time of release of a drug by technical means, such as sustained release, controlled release, delayed release, and the like. The term "sustained release" refers to a formulation that releases a drug at a desired, non-constant rate in a defined release medium, and that reduces the frequency of dosing by half or by some amount compared to conventional formulations, which helps to increase the medication adherence of a subject in need thereof. The term "controlled release" refers to a formulation that releases a drug at a desired, constant rate in a defined release medium, and that reduces the frequency of dosing by half or by some amount compared to conventional formulations, which helps to increase the medication adherence of a subject in need thereof. The term "delayed release" refers to a formulation that does not release a drug immediately after administration, such as enteric delayed release, colon- targeted delayed release, and pulse delayed release, and the like.

[0083] In some embodiments, the pharmaceutical composition is prepared as a modified release formulation and is administered orally. Pharmaceutical compositions suitable for oral administration can be presented as discrete units such as capsules (including gelatin capsules and hard and soft shell gelatin capsules), cachets or tablets; preferably tablets, e.g., ordinary tablets, dispersible tablets, coated tablets, sublingual tablets, and the like; as two-layered tablets having different release mechanisms for immediate release layer and sustained release layer; as a powder or granule; as a solution or suspension in an aqueous or non-aqueous liquid; as an oil-in-water liquid emulsion; as a water-in-oil liquid emulsion; filled in a liposome; filled in a nanomicrosphere; or as a bolus, and the like. Soft gelatin capsules can be suitable for containing a suspension, which can advantageously increase the rate of absorption of the drug.

[0084] In the case of oral tablets, common carriers include lactose, corn starch and microcrystalline cellulose and the like, and usually a lubricant such as magnesium stearate, stearic acid, sodium dodecyl sulfate and the like is also added. For oral administration in a double layer tablet form, a double layer tablet press is used to first compress the sustained release tablet layer, and the active ingredient of the immediate release tablet layer is granulated using direct granulation or nanocrystal grinding, and then the immediate release tablet layer is compressed, and finally coated. Hydrophobic polymers such as polyacrylic acid polymers, ethyl cellulose, hydroxypropyl methyl cellulose are often used for the sustained release layer to control the release rate of the drug, and disintegrants such as sodium starch glycolate (SSG), cross-linked sodium carboxymethyl cellulose (CCS), cross-linked polyvinyl pyrrolidone (crospovidone) and the like are used to promote rapid disintegration of the tablet in water to achieve immediate release effect. For oral administration in the form of capsules, suitable diluents include lactose and dried corn starch. When aqueous suspensions are orally administered, the active ingredient is combined with an emulsifying and suspending agent. If necessary, certain sweetening and / or flavoring and / or coloring agents can be added.

[0085] In some embodiments, the pharmaceutical composition is prepared as a modified release formulation and administered by parenteral administration. Suitable pharmaceutical compositions for parenteral administration include aqueous and non-aqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets. Injection solutions can be in the form of, for example, sterile injectable aqueous or oleaginous suspensions.

[0086] As used herein, the term "on a free base basis" means that the amount of the salted drug is represented by the amount of the free base and the amount of the counterion in the medium, with the amount of the free base as the standard of measurement. For example, the mass concentration of the salted drug on a free base basis is the mass of the free base per mass of the solution; the mass ratio of two salted drugs on a free base basis is the ratio of the mass of the free base. The free base basis is usually used when the active ingredient is acidic. For example, the mass of dextromethorphan hydrobromide monohydrate herein is equal to the mass of dextromethorphan on a free base basis; the mass of celecoxib salt is equal to the mass of celecoxib on a free base basis.

[0087] Unless otherwise specified, the proportions of the components herein are mass ratios.

[0088] Therapeutic methods

[0089] As used herein, the terms "subject," "organism," "animal," "subject of treatment," "subject in need thereof," or "patient" include humans, wild animals and domestic animals. Wild animals are animals in a natural state and have not been artificially domesticated. Domestic animals are animals artificially raised to provide a food source, such as, but not limited to, dogs, cats, mice, rats, hamsters, pigs, rabbits, cattle, water buffalo, oxen, sheep, goats, geese, chickens, and the like. The "patient" or "organism" to be treated is preferably a mammal, especially a human.

[0090] As used herein, the term "prevention" refers to the use of various means or measures to prevent the occurrence or development of a disease, including medical, physical or chemical means, to prevent and reduce the occurrence or development of various symptoms of the disease before the disease. Clinical standards are not recognized.

[0091] As used herein, the term "treatment" includes inhibition, alleviation, prevention or elimination of one or more symptoms or side effects associated with the disease, disorder or disorder being treated. The term "effective amount" or "therapeutically effective amount" means a dose sufficient to treat, inhibit or alleviate one or more symptoms of the disease state being treated or otherwise provide the desired pharmacologic and / or physiologic effect. The precise dose will vary according to a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), disease or illness, and treatment administered. The effect of an effective amount can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the subject's condition prior to administration of the drug or drug combination or without administration, or in the case of a drug combination, the effect of the combination can be compared to the effect of administering only one drug.

[0092] As used herein, the term "administration" refers to the process by which a pharmaceutical product is made to act on a subject in need thereof. The route of administration is not limited. Exemplary oral or parenteral administration can be performed. The route of parenteral administration is, for example, intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transdermal, sublingual and buccal, etc. The route of administration can also be topical administration, including eye, skin, eye, rectum, and by insufflation, nasal inhalation of aerosol, etc. In some embodiments, various forms of administration can also be combined.

[0093] There is growing evidence that a subset of patients with depression have increased levels of inflammatory markers (e.g., IL-6, IL-10, IL-1β, TNF-α, CRP, Cortisol, etc.) in blood and cerebrospinal fluid, and inflammation is an important pathogenesis of this subtype of depression. Patients with depression with abnormal (e.g., elevated, fluctuated, or decreased) inflammatory markers may represent a relatively refractory population of patients with depression. The term “inflammatory depression” as used herein refers to patients with depression with abnormal levels of inflammatory markers (e.g., IL-6, IL-10, TNF-α, IL-1β, CRP, Cortisol, etc.) in peripheral blood and cerebrospinal fluid. The term “inflammatory marker” refers to a substance that can reflect the degree and development of inflammation. Exemplary inflammatory markers include, but are not limited to, IL-6, IL-10, TNF-α, IL-1β, CRP, Cortisol, etc. See Beurel E, Toups M, Nemeroff CB. The Bidirectional Relationship of Depression and Inflammation: Double Trouble [J]. Neuron. 2020 Jul 22; 107(2): 234-256.

[0094] The term “inflammatory cytokines” refers to a class of proteins or polypeptides secreted by immune system cells, which have the function of regulating immune responses and promoting inflammatory processes. They are produced when the body is infected, tissue is damaged, or other stimuli, and can interact with other immune cells or tissue cells, initiating and regulating inflammatory responses. Exemplary inflammatory cytokines include interleukins (e.g., IL-1, IL-6, IL-8, IL-1β, IL-1RA, IL-2, IL-4, IL-5, IL-7, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17A, IL-18, etc.), tumor necrosis factor (e.g., TNF-α), interferon (e.g., IFN-γ), chemokines (CCL2, CCL3, CCL4, CCL5, CCL11, CCL2, CXCL4, CXCL7, and CXCL10, etc.), cell colony stimulating factor (G-CSF), GM-CSF, slL-2 receptor, TGFβ1, STNFR2, etc. In some embodiments, the inflammatory marker is an inflammatory cytokine.

[0095] As used in the text, the term "treatment-resistant depression" refers to depression that has not been alleviated (usually refers to Hamilton Depression Scale-17 items ≤7 points) after sufficient dose and course of treatment with two or more antidepressants of different mechanisms of action; a part of treatment-resistant depression patients have abnormal inflammatory markers (or inflammatory cytokines) in peripheral blood and cerebrospinal fluid, and the term "inflammatory treatment-resistant depression" refers to treatment-resistant depression with this specific symptom.

[0096] As used in the text, the term "anhedonia" refers to loss of interest in all or almost all activities, and loss of response to ordinary pleasurable stimuli, according to the definition of DSM-5. The term "anhedonic depression" refers to depression patients whose clinical manifestations are characterized by specific symptoms of loss of interest or pleasure. Anhedonic depression subtypes of patients are usually distinguished by anhedonia scale (DARS). See "Clinical Assessment and Treatment Guidance for Melancholic / Anhedonic Depression" Journal of Clinical Psychiatry 2021, Vol. 31, No. 1.

[0097] As used in the text, the term "lipopolysaccharide (LPS)-induced depression model" is the most commonly used animal model for evaluating inflammatory cytokines-induced depression behavior. Lipopolysaccharide is a component of the cell wall of gram-negative bacteria, which can not only induce peripheral inflammatory processes, but also cause central nervous system inflammation, manifested by activation of brain microglia cells and production of more pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, etc. Intraperitoneal injection of LPS can cause an increase in the above neuroinflammatory response in the central nervous system, causing changes in depression-like behavior and cognition in mice. LPS-induced depression model is commonly used to establish an animal model of immune activation-induced depression-like behavior, or an animal model of inflammatory depression.

[0098] As used in the text, the term "learned helplessness (LH)" model is one of the most commonly used acute stress models to explain depression, which involves placing animals in unpredictable and uncontrollable stress conditions, such as unavoidable electric shock. After being subjected to a series of stress events that cannot be escaped, animals usually exhibit a lack of ability to respond to escapable aversive situations, as well as a loss of pleasure, a decrease in sugar water preference, a decrease in activity, and a decrease in social behavior, and other behaviors of despair, such as decreased cognitive ability and attention. Learned helplessness is considered to be part of the pathogenesis of depression, and the behaviors exhibited by rodents in the LH model are similar to depression symptoms in many ways, including response to antidepressants. LH model is commonly used for preliminary screening of antidepressants.

[0099] As used in the text, the term "sucrose preference test" refers to a depression accompanied by a variety of behavioral phenotypes, one of which is anhedonia, i.e., an individual's inability to experience pleasure from rewards or enjoyable activities. In animal model experiments, the sucrose preference test (SPT) is often used to test anhedonia symptoms.

[0100] As used in the text, the term "forced swimming test (FST)" was first established by Porsolt RD in 1977 to detect the effects of antidepressants. Later, the forced swimming test became an animal model for evaluating the antidepressant effects of drugs. This test method is a behavioral despair test method, and is a commonly used detection experiment for screening antidepressants and detecting whether model animals exhibit "depression-like" behavior.

[0101] As used in the text, the term "tail suspension test" was first proposed by Steru et al. in 1985 to assess the depression-like state of behavioral despair in mice. This experiment is based on research on antidepressants, and measures the emotional state of mice by observing their inability to escape from a suspended state for a period of time, and can be used to screen potential antidepressants and detect whether model animals exhibit "depression-like" behavior.

[0102] One aspect of the present disclosure provides a use of a pharmaceutical composition for preventing and / or treating inflammatory depression.

[0103] In one embodiment, the pharmaceutical composition comprises dextromethorphan or a salt of dextromethorphan; and celecoxib or a salt of celecoxib.

[0104] In one embodiment, the pharmaceutical composition comprises dextromethorphan; and celecoxib.

[0105] In one embodiment, the pharmaceutical composition comprises a salt of dextromethorphan; and celecoxib.

[0106] In one embodiment, the pharmaceutical composition comprises dextromethorphan hydrobromide; and celecoxib.

[0107] In one embodiment, the pharmaceutical composition comprises a salt of dextromethorphan containing crystallization water; and celecoxib.

[0108] In one embodiment, the pharmaceutical composition comprises dextromethorphan hydrobromide monohydrate; and celecoxib.

[0109] In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0110] In one embodiment, the pharmaceutical composition is a fixed-dose combination preparation.

[0111] In one embodiment, the pharmaceutical composition is a combination drug.

[0112] In one embodiment, the pharmaceutical composition is a combination packaged drug.

[0113] In one embodiment, the salt of dextromethorphan or the salt of celecoxib is a pharmaceutically acceptable salt.

[0114] In one embodiment, the salt of dextromethorphan is dextromethorphan hydrobromide.

[0115] In one embodiment, the salt of dextromethorphan is a salt containing crystal water or bound water, more preferably a salt containing crystal water.

[0116] In one embodiment, the salt of dextromethorphan is a hydrobromide salt containing one or more crystal waters, preferably a hydrobromide salt containing one crystal water (dextromethorphan hydrobromide monohydrate).

[0117] In one embodiment, the pharmaceutical composition contains (i) and (ii) as active ingredients, and a pharmaceutically acceptable carrier or excipient; (i) dextromethorphan or a salt of dextromethorphan; (ii) celecoxib or a salt of celecoxib.

[0118] In one embodiment, (i) and (ii) can be dispersed in each other or together in a pharmaceutically acceptable carrier or excipient; (i) dextromethorphan or a salt of dextromethorphan; (ii) celecoxib or a salt of celecoxib.

[0119] In one embodiment, (i) and (ii) are substantially uniformly dispersed in the pharmaceutical composition or dosage form; (i) dextromethorphan or a salt of dextromethorphan; (ii) celecoxib or a salt of celecoxib.

[0120] In one embodiment, (i) and (ii) can be in separate domains or separate phases in the pharmaceutical composition or dosage form; (i) dextromethorphan or a salt of dextromethorphan; (ii) celecoxib or a salt of celecoxib. Illustratively, one drug can be in a coating of the drug, and the other drug can be in the core of the coating.

[0121] In one embodiment, the amount of celecoxib in the pharmaceutical composition is 10-500 mg as a free base; more preferably 30-400 mg; more preferably 30-300 mg; more preferably 40-200 mg. For example, the pharmaceutical composition contains 30, 35, 40, 45, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, or 200 mg of celecoxib.

[0122] In one embodiment, the amount of celecoxib in the pharmaceutical composition is 40-120 mg as a free base.

[0123] In one embodiment, the amount of dextromethorphan in the pharmaceutical composition is 10-500 mg as a free base; more preferably 20-300 mg; more preferably 25-100 mg; more preferably 20-80 mg. For example, the pharmaceutical composition contains 10, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 mg of celecoxib.

[0124] In one embodiment, the amount of dextromethorphan in the pharmaceutical composition is 10-500 mg as a free base; more preferably 20-300 mg; more preferably 25-100 mg; more preferably 20-80 mg. For example, the pharmaceutical composition contains 10, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 mg of celecoxib.

[0125] In one embodiment, the content of dextromethorphan in the pharmaceutical composition is 20-60 mg, and the content of celecoxib is 40-120 mg, in terms of free base.

[0126] In one embodiment, the mass ratio of dextromethorphan and celecoxib in the pharmaceutical composition is 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.8, 1:2.0, 1:2.3, 1:2.6, 1:2.7, 1:2.8, 1:1.29, 1:3, 1:3.3, 1:3.5, 1:3.6, 1:4, 1:5, 1:6, in terms of free base.

[0127] In one embodiment, the mass ratio of dextromethorphan and celecoxib in the pharmaceutical composition is 1:(0.5-10); preferably 1:(0.5-6); preferably 1:(1-5); preferably 1:(1-4); preferably 1:(1.5-2.5); preferably 1:(1.5-3.5); preferably 1:(2-3); preferably 1:2, in terms of free base.

[0128] In one embodiment, the content of dextromethorphan in the pharmaceutical composition is 20-60 mg, and the content of celecoxib is 80-120 mg, in terms of free base; and the mass ratio of dextromethorphan and celecoxib is 1:(2-3).

[0129] In one embodiment, the content of dextromethorphan in the pharmaceutical composition is 20-60 mg, and the content of celecoxib is 40-120 mg, in terms of free base; and the mass ratio of dextromethorphan and celecoxib is 1:(1.5-2.5).

[0130] In one embodiment, the content of dextromethorphan in the pharmaceutical composition is 20-60 mg, and the content of celecoxib is 40-120 mg, in terms of free base; and the mass ratio of dextromethorphan and celecoxib is 1:2.

[0131] In one embodiment, the pharmaceutical composition is a fixed-dose combination. In a more preferred embodiment, the fixed-dose combination is a conventional dosage form (e.g. a powder, a granule, a tablet, a pill, a capsule, an injection, an infusion, a suspension, an inhalant, a transdermal patch, or a microemulsion, etc.) or a modified release formulation (e.g. a sustained release formulation or a controlled release formulation, etc.).

[0132] In one embodiment, the pharmaceutical composition is a fixed-dose combination, and the fixed-dose combination comprises immediate release materials and / or sustained release materials.

[0133] In one embodiment, the pharmaceutical composition is a combination packaged pharmaceutical product comprising a first medicament and a second medicament packaged separately; the first container contains dextromethorphan or a salt thereof; the second container contains celecoxib or a salt thereof.

[0134] In one embodiment, the pharmaceutical composition is a combination packaged pharmaceutical product comprising a first medicament and a second medicament packaged separately; the first medicament contains dextromethorphan or a salt thereof, and a pharmaceutically acceptable carrier or excipient; the second medicament contains celecoxib or a salt thereof, and a pharmaceutically acceptable carrier or excipient; wherein the dosage form of the first medicament and the dosage form of the second medicament are the same or different.

[0135] In one embodiment, the pharmaceutical composition is a combination packaged pharmaceutical product comprising a first medicament and a second medicament packaged separately; the first medicament contains dextromethorphan or a salt thereof, and a pharmaceutically acceptable carrier or excipient; the second medicament contains celecoxib or a salt thereof, and a pharmaceutically acceptable carrier or excipient; wherein the dosage form of the first medicament is a sustained release dosage, such as sustained release pellets, a nasal drop, a sustained release capsule, a mouth dissolving film, a sustained release tablet, a heat sensitive nasal gel.

[0136] In one embodiment, the pharmaceutical composition is a combination packaged pharmaceutical product comprising a first medicament and a second medicament packaged separately; the first medicament contains dextromethorphan or a salt thereof, and a pharmaceutically acceptable carrier or excipient; the second medicament contains celecoxib or a salt thereof, and a pharmaceutically acceptable carrier or excipient; wherein the dosage form of the first medicament is an oral formulation (such as tablets, capsules, syrups, granules, etc.) or an injection, and the dosage form of the second medicament is an oral formulation (such as tablets, capsules, syrups, granules, etc.).

[0137] Another aspect of the present disclosure also provides a method for preventing and / or treating inflammatory depression.

[0138] In one embodiment, the inflammatory depression is depression in which patients show symptoms of inflammatory cytokine imbalance.

[0139] In one embodiment, the inflammatory depression is refractory depression; more preferably, the inflammatory refractory depression in which patients show symptoms of inflammatory cytokine imbalance, or one of the causes of the inflammatory refractory depression in patients is inflammation.

[0140] In one embodiment, the inflammatory depression is anhedonic depression.

[0141] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein.

[0142] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the mass ratio of dextromethorphan and celecoxib, on a free base basis, is 1 :2.

[0143] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the mass ratio of dextromethorphan and celecoxib, on a free base basis, is 1 :2.

[0144] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the content of dextromethorphan is 20-40 mg and the content of celecoxib is 10-20 mg.

[0145] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the content of dextromethorphan is 20-40 mg and the content of celecoxib is 20-40 mg.

[0146] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the content of dextromethorphan is 20-40 mg and the content of celecoxib is 40-80 mg.

[0147] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the content of dextromethorphan is 40-60 mg and the content of celecoxib is 80-120 mg.

[0148] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the content of dextromethorphan is 20-60 mg and the content of celecoxib is 80-200 mg.

[0149] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the amount of dextromethorphan is 20-40 mg and the amount of celecoxib is 100-200 mg.

[0150] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the amount of dextromethorphan is 20-40 mg and the amount of celecoxib is 100-200 mg.

[0151] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the amount of dextromethorphan is 20-40 mg and the amount of celecoxib is 100-200 mg.

[0152] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the amount of dextromethorphan is 20-40 mg and the amount of celecoxib is 100-200 mg.

[0153] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the amount of dextromethorphan is 20-40 mg and the amount of celecoxib is 100-200 mg.

[0154] In one embodiment, the method for preventing and / or treating inflammatory depression comprises the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition herein, wherein the pharmaceutical composition is a fixed-dose combination formulation, wherein the amount of dextromethorphan is 20-40 mg and the amount of celecoxib is 100-200 mg.

[0155] In one embodiment, the dose of the pharmaceutical composition administered to a subject in need thereof is the same during a course of treatment.

[0156] In one embodiment, the dose of the pharmaceutical composition administered to a subject in need thereof can be different during different courses of treatment.

[0157] In one embodiment, the pharmaceutical composition herein is administered to a subject in need thereof once a day, twice a day, three times a day, once every two days, three times every two days, once every three days, once every four days, or once a week; preferably twice a day.

[0158] In one embodiment, the pharmaceutical composition herein is administered to a subject for not less than 3 months, not less than 4 months, not less than 5 months, not less than 6 months, not less than 7 months, not less than 8 months, not less than 9 months, not less than 10 months, or not less than 1 year; for example, 3-6 months.

[0159] The pharmaceutical composition of the present disclosure can be used in combination with other antidepressants. In one embodiment, a therapeutically effective amount of the pharmaceutical composition herein is administered to a subject in need thereof, while or sequentially with the administration of a therapeutically effective amount of other antidepressants to the subject.

[0160] II. Examples

[0161] The present disclosure is further illustrated by reference to the following examples. The description of the specific exemplary embodiments of the present disclosure is intended for purposes of illustration and example only. These descriptions are not intended to limit the disclosure in any way and it is clear that various changes and modifications can be made by those skilled in the art without departing from the scope of the present disclosure as set forth in the following claims. The examples are chosen and described in order to explain the principles of the present disclosure and its practical application to thereby enable one skilled in the art to best utilize the present disclosure and various examples with various modifications as are suited to the particular use contemplated.

[0162] The experimental methods used in the following examples are conventional unless otherwise stated.

[0163] The materials, reagents and the like used in the following examples are commercially available unless otherwise stated.

[0164] The raw materials used in the following examples are dextromethorphan hydrobromide monohydrate, bupropion hydrochloride, and celecoxib, and the mass of each substance used in the experiment is calculated in free concentration, i.e. dextromethorphan hydrobromide monohydrate is calculated as dextromethorphan, and bupropion hydrochloride is calculated as bupropion. The molecular weight of dextromethorphan hydrobromide monohydrate is calculated as 370.32, and the molecular weight of dextromethorphan is calculated as 271.40; the molecular weight of bupropion hydrochloride is calculated as 276.20, and the molecular weight of bupropion is calculated as 239.74; the molecular weight of celecoxib is calculated as 381.37.

[0165] Dextromethorphan hydrobromide monohydrate used in the following examples was purchased from Shanghai McLean Biotech Co., Ltd.; Celecoxib was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Bupropion hydrochloride was purchased from Nanjing Kangmanlin Biomedical Technology Co., Ltd.; Human CYP2D6 recombinant enzyme was purchased from Corning Incorporated, USA.

[0166] Example 1: Single oral dextromethorphan + bupropion or celecoxib pharmacokinetic study in C57BL / 6J mice

[0167] 1.1 Experimental animals

[0168] Eighteen male C57BL / 6J mice, weighing 25-30 g, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0169] 1.2 Reagent configuration

[0170] Dextromethorphan group: accurately weigh dextromethorphan hydrobromide monohydrate into a suitable container, add the target volume of normal saline, configure into a 2.8 mg / mL (free base, dextromethorphan concentration is 2.0 mg / mL) drug solution, vortex well before use.

[0171] Dextromethorphan + bupropion group: accurately weigh dextromethorphan hydrobromide monohydrate and bupropion hydrochloride into a suitable container, add the target volume of normal saline, configure into a 2.8+4.6 mg / mL (free base, dextromethorphan + bupropion concentration is 2.0+4.0 mg / mL) drug solution, vortex well before use.

[0172] Dextromethorphan + celecoxib group: accurately weigh dextromethorphan hydrobromide monohydrate and celecoxib into a suitable container, add the target volume of 5% anhydrous ethanol + 5% Cremophor + 90% normal saline, configure into a 2.8+4.0 mg / mL (free base, dextromethorphan + celecoxib concentration is 2.0+4.0 mg / mL) drug solution, vortex well before use.

[0173] 1.3 Experimental method

[0174] Eighteen male C57BL / 6J mice were randomly divided into three groups, namely dextromethorphan group (20 mg / kg, free concentration is 2.0 mg / mL), dextromethorphan + bupropion group (20+40 mg / kg, free concentration is 2.0+4.0 mg / mL), dextromethorphan + celecoxib group (20+40 mg / kg, free concentration is 2.0+4.0 mg / mL), respectively, according to 10 mL / mg, respectively, intragastrically administered with the above drugs.

[0175] Each group of mice numbered 1-6, 3 mice at each time point, 3-4 times of blood sampling for each mouse, 1-3 mice blood sampling time points were 0.25h, 1h and 4h, 4-6 mice blood sampling points were 0.5h, 2h, 8h and 24h, about 120μL of whole blood was collected from the retro-orbital plexus of each mouse, placed in a labeled EDTA-2K anticoagulant tube, centrifuged at 4℃, 2000g(relative centrifugal force) for 10 minutes to separate plasma.

[0176] 1.4 Data statistics: the blood drug concentrations of three animals at the same time point were averaged, and WinNonlin was used to calculate the pharmacokinetic parameters of dextromethorphan.

[0177] 1.5 Experimental results: the results are shown in Table 1 below.

[0178] Table 1 Pharmacokinetic study results

[0179] The experimental results show that the exposure of dextromethorphan monotherapy group is 408h*ng / mL, and the Cmax is 285ng / mL. When dextromethorphan is combined with celecoxib (ratio of 1:2), the exposure of dextromethorphan in mice is 734h*ng / mL, and the Cmax is 367ng / mL. Compared with the monotherapy group, the exposure and Cmax are significantly improved, and the combination of dextromethorphan and celecoxib shows good synergistic effect. Similarly, under the condition of 1:2 ratio of dose, the exposure and Cmax of dextromethorphan combined with celecoxib are significantly higher than those of dextromethorphan combined with bupropion, and the in vivo mouse PK experiment shows that the combination of dextromethorphan and celecoxib is better than that of dextromethorphan and bupropion.

[0180] Example 2: Antidepressant efficacy study in LPS-induced depression mouse model

[0181] 2.1 Reagents and instruments:

[0182] 0.9% sodium chloride injection, Zhejiang Tianrui Pharmaceutical Co., Ltd., batch number: 123100602

[0183] Lipopolysaccharide (LPS, Lipopolysaccharide, E. coli 055:B5), Sigma-Aldrich

[0184] Sucrose, Beijing Solaybao Technology Co., Ltd.

[0185] Polyoxyethylene castor oil EL (Cremophor), Shanghai Aladdin Biochemical Technology Co., Ltd.

[0186] Electronic balance BSA224S model factory number 36490541, Sartorius Scientific Instruments (Beijing) Co., Ltd.; weighing balance, Yongkang Molin Trading Co., Ltd.; tail suspension apparatus, Shenzhen Ruivode Life Science Technology Co., Ltd.; forced swimming tank (tank height 40 cm, diameter 11 cm circular plastic transparent tank).

[0187] 2.2 Experimental animals:

[0188] 50 male C57BL / 6J mice, weighing 20-25 g (8-10 W), purchased from Zhejiang Vantong Lihua Experimental Animal Technology Co., Ltd.

[0189] 2.3 Experimental method:

[0190] 2.3.1 Preparation of preparation:

[0191] Dextromethorphan + bupropion group: accurately weigh dextromethorphan hydrobromide monohydrate and bupropion hydrochloride in a suitable container, add the target volume of normal saline, configure into a 1.4 + 2.3 mg / mL (calculated as free base, the concentration of dextromethorphan + bupropion is 1.0 + 2.0 mg / mL) administration solution, and use after vortex mixing.

[0192] Dextromethorphan + celecoxib group: accurately weigh dextromethorphan hydrobromide monohydrate and celecoxib in a suitable container, add the target volume of solvent 5% anhydrous ethanol + 5% Cremophor + 90% normal saline, respectively configure into 1.4 + 0.5 mg / mL (calculated as free base, the concentration of dextromethorphan + celecoxib is 1.0 + 0.5 mg / mL), 1.4 + 1.0 mg / mL (calculated as free base, the concentration of dextromethorphan + celecoxib is 1.0 + 1.0 mg / mL), 1.4 + 2.0 mg / mL (calculated as free base, the concentration of dextromethorphan + celecoxib is 1.0 + 2.0 mg / mL), 1.4 + 4.0 mg / mL (calculated as free base, the concentration of dextromethorphan + celecoxib is 1.0 + 4.0 mg / mL) administration solution, and use after vortex mixing.

[0193] 2.3.2 Male C57BL / 6J mice were randomly divided into groups of 10 by body weight, namely blank control group, LPS model group, dextromethorphan + bupropion group (10 + 20 mg / kg, free concentration 1.0 + 2.0 mg / mL), dextromethorphan + celecoxib group 1 (10 + 5 mg / kg, free concentration 1.0 + 0.5 mg / mL), dextromethorphan + celecoxib group 2 (10 + 10 mg / kg, free concentration 1.0 + 1.0 mg / mL), dextromethorphan + celecoxib group 3 (10 + 20 mg / kg, free concentration 1.0 + 2.0 mg / mL), dextromethorphan + celecoxib group 4 (10 + 40 mg / kg, free concentration 1.0 + 4.0 mg / mL), then according to body weight, the blank control group was normally fed, intraperitoneally injected with 5% absolute ethanol + 5% Cremophor + 90% normal saline for 3 days; the LPS model group was intraperitoneally injected with LPS (1.0 mg / kg) for 3 days; the remaining groups were all LPS treatment + corresponding drug treatment, intraperitoneally injected with LPS (1.0 mg / kg) and simultaneously given the corresponding dose of drug for 3 days, the drug volume was 10 ml / kg, and the antidepressant effect of the drug on mice was observed by the following behavioral tests.

[0194] 2.3.3 Sugar water preference test: on the first day after modeling, the sugar water preference test was performed to observe the hedonic deficit behavior of the mice. All mice were fasted and watered for 24 h before the experiment, then 2 standard water bottles were placed in each cage, one was tap water and the other was 1% sucrose water, and the water bottle position was exchanged at 12 h, the weight of the water bottle was recorded at 0 h, 12 h and 24 h, the sugar water consumption and pure water consumption were calculated, and the sugar water preference rate of the mice was calculated:

[0195] Sugar water preference percentage (%) = sugar water consumption (g) / sugar water consumption (g) + pure water consumption (g), wherein

[0196] Efficiency (%) = (sugar water preference rate of drug group - sugar water preference rate of LPS model group) / sugar water preference rate of LPS model group * 100%.

[0197] 2.3.4 Tail suspension test: the end of the mouse tail was fixed with medical tape, the tape was clamped with a clamp, the other side of the clamp was hung on the hook at the top of the tail suspension box, so that the mouse was suspended in the air about 10 cm from the plane, the total suspension time was 6 min, during which the time of the mouse suspension was recorded by the instrument, and the time of the mouse suspension in the last 4 min was used for data analysis, wherein the efficiency (%) = (LPS model group mouse tail suspension time drug group - drug group mouse tail suspension time) / LPS model group mouse tail suspension time * 100%.

[0198] 2.3.5 Forced swimming test: Mice were placed in a cylindrical bucket with water depth of 25 cm, water temperature of 20-23℃, and the mice were swimming in the bucket for 6 min, during which the immobility time of the mice was recorded by the instrument, and the immobility time of the last 4 min was used for data analysis, wherein

[0199] Efficiency (%) = (LPS model group of mice forced swimming immobility time drug group - drug group of mice forced swimming immobility time) / LPS model group of mice forced swimming immobility time * 100%.

[0200] 2.4 Data collection and analysis

[0201] All experimental data were expressed as mean. Statistical analysis was performed using Graphad Prism 8 software. The difference between two groups was analyzed by t-test method, and the comparison between animal groups was analyzed by one-way ANOVA with Dunnett multiple comparison test data, P<0.05 indicating statistical significance.

[0202] 2.5 Experimental results:

[0203] The results are shown in Tables 2, 3 and 4.

[0204] Table 2 Antidepressant effect of dextromethorphan + bupropion and dextromethorphan + celecoxib in LPS-induced depression mouse model (sucrose preference test) Note: *P<0.05 compared with LPS model group

[0205] Table 3 Antidepressant effect of dextromethorphan + bupropion and dextromethorphan + celecoxib in LPS-induced depression mouse model (tail suspension test) Note: **P<0.01, ***P<0.001, ****P<0.0001 compared with LPS model group

[0206] Table 4 Antidepressant effect of dextromethorphan + bupropion and dextromethorphan + celecoxib in LPS-induced depression mouse model (forced swimming test) Note: *P<0.05, **P<0.01, ***P<0.001 compared with LPS model group

[0207] 2.6 Experimental conclusion:

[0208] The anti-depression effect of dextromethorphan + celecoxib combination was tested in a LPS-induced depression mouse model. It was found that the dextromethorphan + celecoxib combination group (1:0.5-1:4 according to dextromethorphan: celecoxib) could significantly reduce the immobility time in the tail suspension and the forced swimming of LPS-induced depression mice, indicating that the dextromethorphan + celecoxib combination had good anti-depression effect within the ratio range.

[0209] When the ratio of the dextromethorphan + celecoxib combination group was 1:2 (according to dextromethorphan: celecoxib), it could simultaneously improve the sugar water preference degree of depression mice (effective rate was 18.3%, P<0.05), reduce the immobility time of depression mice in the tail suspension (effective rate was 52.1%, P<0.001) and the forced swimming (effective rate was 48.6%, P<0.001) in the LPS-induced depression mouse model, and had better anti-depression effect.

[0210] The anti-depression effect of the dextromethorphan + celecoxib (10+20 mg / kg) combination group was compared with that of the dextromethorphan + bupropion (10+20 mg / kg) combination group at the same dose by LPS-induced depression mice. It was found that the dextromethorphan + celecoxib combination group was obviously superior to the dextromethorphan + bupropion combination group in improving the sugar water preference degree of depression mice (18.3% & 13.1%), reducing the immobility time of depression mice in the tail suspension (52.1% & 38.6%) and the forced swimming (48.6% & 23.1%), indicating that the anti-depression effect of the dextromethorphan + celecoxib combination was obviously superior to that of the dextromethorphan + bupropion combination.

[0211] Example 3: Anti-depression efficacy research in LPS-induced depression mouse model

[0212] 3.1 Reagents and instruments

[0213] 0.9% sodium chloride injection, Zhejiang Tianrui Pharmaceutical Co., Ltd., batch number: 123100602;

[0214] Lipopolysaccharide (LPS, E. coli 055:B5), Sigma-Aldrich;

[0215] Sucrose, Beijing Solabio Technology Co., Ltd.;

[0216] Polyoxyethylene castor oil EL (Cremophor), Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0217] Electronic balance BSA224S model factory number 36490541, Sartorius Scientific Instruments (Beijing) Co., Ltd.;

[0218] Weighing balance, Yongkang Molin Trading Co., Ltd.

[0219] Tail suspension apparatus, Shenzhen Ruivode Life Science Co., Ltd.

[0220] Forced swimming tank (tank height 40 cm, diameter 11 cm round plastic transparent tank).

[0221] 3.2 Experimental animals:

[0222] 50 male C57BL / 6J mice, weighing 20-25 g (8-10 W), purchased from Zhejiang Vantong Lihua Experimental Animal Technology Co., Ltd.

[0223] 3.3 Preparation of preparation

[0224] Dextromethorphan group: accurately weigh dextromethorphan hydrobromide monohydrate in a suitable container, add the target volume of normal saline, configure into a 1.4 mg / mL (calculated as free base, the concentration of dextromethorphan is 1.0 mg / mL) administration solution, and use after vortex mixing.

[0225] Celecoxib group: accurately weigh celecoxib in a suitable container, add the target volume of solvent 5% anhydrous ethanol + 5% Cremophor + 90% normal saline, configure into a 2.0 mg / mL (calculated as free base, the concentration of celecoxib is 2.0 mg / mL) administration solution, and use after vortex mixing.

[0226] Dextromethorphan + celecoxib group: accurately weigh dextromethorphan hydrobromide monohydrate and celecoxib in a suitable container, add the target volume of solvent 5% anhydrous ethanol + 5% Cremophor + 90% normal saline, configure into a 1.4+2.0 mg / mL (calculated as free base, the concentration of dextromethorphan + celecoxib is 1.0+2.0 mg / mL) administration solution, and use after vortex mixing.

[0227] Dextromethorphan + ibuprofen group: accurately weigh dextromethorphan hydrobromide monohydrate and ibuprofen in a suitable container, add the target volume of solvent 5% anhydrous ethanol + 5% Cremophor + 90% normal saline, configure into a 1.4+2.0 mg / mL (calculated as free base, the concentration of dextromethorphan + ibuprofen is 1.0+2.0 mg / mL) administration solution, and use after vortex mixing.

[0228] 3.4 Experimental method

[0229] Male C57BL / 6J mice were randomly divided into groups of 10 by weight, namely blank control group, LPS model group, dextromethorphan group (10 mg / kg, free concentration 1.0 mg / mL), celecoxib group (20 mg / kg, free concentration 2.0 mg / mL), dextromethorphan + celecoxib group (10+20 mg / kg, free concentration 1.0+2.0 mg / mL), dextromethorphan + ibuprofen group (10+20 mg / kg, free concentration 1.0+2.0 mg / mL), then according to the weight, the blank control group was normally fed, intraperitoneally injected with 5% anhydrous ethanol + 5% Cremophor + 90% normal saline for 3 days; the LPS model group was intraperitoneally injected with LPS (1 mg / kg) for 3 days; the remaining drug groups were all LPS treatment + corresponding drug treatment, intraperitoneally injected with LPS (1.0 mg / kg) and simultaneously given the corresponding dose of drug for 3 days, the drug volume was 10 ml / kg, and the antidepressant effect of the drug on mice was observed by the following behavioral tests.

[0230] 3.4.1 Sugar water preference test: On the first day after modeling, the sugar water preference test was performed to observe the hedonic deficit behavior of the mice. All mice were fasted and watered for 24 h before the experiment, then 2 standard water bottles were placed in each cage, one bottle was tap water and the other bottle was 1% sucrose water, and the water bottle position was exchanged at 12 h, the weight of the water bottle was recorded at 0 h, 12 h and 24 h, the sugar water consumption and pure water consumption were calculated, and the sugar water preference rate of the mice was calculated: sugar water preference percentage (%) = sugar water consumption (g) / sugar water consumption (g) + pure water consumption (g), wherein the effective rate (%) = (sugar water preference rate of drug group - sugar water preference rate of LPS model group) / sugar water preference rate of LPS model group * 100%.

[0231] 3.4.2 Tail suspension test: The tail end of the mouse was fixed with medical tape, the tape was clamped with a clamp, and the other side of the clamp was hung on the hook at the top of the tail suspension box, so that the mouse was suspended in the air about 10 cm from the plane, the total suspension time was 6 min, and the time of the mouse suspended motionless during this period was recorded by the instrument, and the time of motionless in the last 4 min was used for data analysis, wherein the effective rate (%) = (LPS model group mouse tail suspension time drug group - drug group mouse tail suspension time) / LPS model group mouse tail suspension time * 100%.

[0232] 3.4.3 Forced swimming test: Mice were placed in a cylindrical bucket with water depth of 25 cm, water temperature of 20-23℃, and the mice were swimming in the bucket for 6 min, during which the immobility time of the mice was recorded by the instrument, and the immobility time of the last 4 min was used for data analysis, wherein the efficiency (%) = (LPS model group of mice forced swimming immobility time drug group - drug group of mice forced swimming immobility time) / LPS model group of mice forced swimming immobility time * 100%.

[0233] 3.5 Data collection and analysis

[0234] All experimental data were expressed as mean. Statistical analysis was performed using Graphad Prism 8 software. The difference between two groups was analyzed by t-test method, and the comparison between animal groups was analyzed by one-way ANOVA with Dunnett's multiple comparison test, P<0.05 indicating statistical significance.

[0235] 3.5 Experimental results:

[0236] The results are shown in Tables 5, 6 and 7.

[0237] Table 5 Antidepressant effect of dextromethorphan, celecoxib, dextromethorphan + ibuprofen, and dextromethorphan + celecoxib in LPS-induced inflammatory depression mouse model (sugar water preference test) Note: *P<0.05 compared with the LPS model group

[0238] Table 6 Antidepressant effect of dextromethorphan, celecoxib, dextromethorphan + ibuprofen, and dextromethorphan + celecoxib in LPS-induced inflammatory depression mouse model (tail suspension test) Note: *P<0.05, **P<0.01 compared with the LPS model group

[0239] Table 7 Antidepressant effect of dextromethorphan, celecoxib, dextromethorphan + ibuprofen, and dextromethorphan + celecoxib in LPS-induced inflammatory depression mouse model (forced swimming test) Note: *P<0.05, **P<0.01 compared with the LPS model group

[0240] 3.6 Experimental conclusion:

[0241] Compared with dextromethorphan (10 mg / kg) and celecoxib (20 mg / kg) monotherapy, dextromethorphan + celecoxib (10+20 mg / kg) combination therapy group has more obvious effect on improving the sucrose preference of LPS-induced depressive mice (the effective rates of dextromethorphan & celecoxib & dextromethorphan + celecoxib sucrose preference are 9.4% & 7.5% & 18.9% respectively) and reducing the tail suspension immobility time (the effective rates of dextromethorphan & celecoxib & dextromethorphan + celecoxib tail suspension immobility time are 9.1% & 22.3% & 35.6% respectively) and forced swimming immobility time (the effective rates of dextromethorphan & celecoxib & dextromethorphan + celecoxib forced swimming immobility time are 17.1% & 13.7% & 42.9% respectively) of depressive mice, which shows that the combination of the two has better synergistic effect, that is, the compound has better antidepressant effect and synergistic effect on LPS-induced depressive mice at a ratio of 1:2.

[0242] Compared with dextromethorphan + ibuprofen (10+20 mg / kg) combination therapy group, dextromethorphan + celecoxib (10+20 mg / kg) combination therapy group has more obvious effect on improving the sucrose preference of LPS-induced depressive mice (the effective rates of dextromethorphan + ibuprofen & dextromethorphan + celecoxib sucrose preference are 13.6% & 18.9% respectively) and reducing the tail suspension immobility time (the effective rates of dextromethorphan + ibuprofen & dextromethorphan + celecoxib tail suspension immobility time are 4.5% & 35.6% respectively) and forced swimming immobility time (the effective rates of dextromethorphan + ibuprofen & dextromethorphan + celecoxib forced swimming immobility time are 30.1% & 42.9% respectively) of depressive mice. It is proved that under the condition that ibuprofen and celecoxib are both non-steroidal anti-inflammatory drugs, the synergistic effect of dextromethorphan and celecoxib combination therapy group is obviously better than that of dextromethorphan and ibuprofen combination therapy group.

[0243] Example 4: Antidepressant efficacy research in the learned helplessness model of mice

[0244] 4.1 Reagents and instruments

[0245] YLS-9A physiological and pharmacological electronic stimulator, purchased from Jinan Yiyandian Science and Technology Development Co., Ltd.

[0246] 4.2 Experimental animals

[0247] 40 male C57BL / 6J mice, weighing 20-25 g, were purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.

[0248] 4.3 Preparation of formulations

[0249] Dextromethorphan + celecoxib group: accurately weigh dextromethorphan hydrobromide monohydrate and celecoxib in a suitable container, add the target volume of solvent 5% anhydrous ethanol + 5% Cremophor + 90% normal saline, respectively, to prepare 1.0 + 1.0 mg / mL (in free base, the concentration of dextromethorphan + celecoxib is 0.73 + 1.0 mg / mL), 1.0 + 2.0 mg / mL (in free base, the concentration of dextromethorphan + celecoxib is 0.73 + 2.0 mg / mL), 1.0 + 4.0 mg / mL (in free base, the concentration of dextromethorphan + celecoxib is 0.73 + 4.0 mg / mL) administration solutions, and use after vortex mixing.

[0250] 4.4 Experimental method

[0251] Adult male C57BL / 6J mice were randomly divided by weight, 10 in each group, into blank control group, model group, dextromethorphan + celecoxib group 1 (7.3 + 10 mg / kg, free concentration 0.73 + 1.0 mg / mL), dextromethorphan + celecoxib group 2 (7.3 + 20 mg / kg, free concentration 0.73 + 2.0 mg / mL), dextromethorphan + celecoxib group 3 (7.3 + 40 mg / kg, free concentration 0.73 + 4.0 mg / mL). The blank control group of healthy mice was placed in the same electric shock device without electric shock, and at the same time, intraperitoneal injection of solvent (5% anhydrous ethanol + 5% Cremophor + 90% normal saline) was performed for 3 days. The model group and drug group mice were placed in the electric shock device and subjected to continuous three-day electric shock training, and each day's training included 60 unavoidable foot shocks with an intensity of 0.3 mA for 5 seconds, and the interval between two shocks was randomly 5-30 seconds. At the same time of modeling, the model group was given solvent, and the drug group was given corresponding doses of drugs for 3 days, with a dose of 10 ml / kg. The antidepressant effect of the drugs on mice was observed by the following behavioral tests.

[0252] 4.4.1 Sucrose preference test: on the first day after modeling, the sucrose preference test was performed to observe the anhedonia behavior of the mice. All mice were fasted and deprived of water for 24 h before the experiment, then, 2 standard water bottles were placed in each cage, one with tap water and the other with 1% sucrose solution, and the water bottle position was exchanged at 12 h. The weight of the water bottles was recorded at 0 h, 12 h and 24 h, and the sucrose consumption and pure water consumption were calculated. The sucrose preference rate of the mice was calculated as follows: sucrose preference percentage (%) = sucrose consumption (g) / sucrose consumption (g) + pure water consumption (g), and the effective rate (%) = (sucrose preference rate of the drug group - sucrose preference rate of the LPS model group) / sucrose preference rate of the LPS model group * 100%.

[0253] 4.4.2 Forced swimming test: Mice were placed in a cylindrical bucket with water depth of 25 cm, water temperature of 20-23℃, and the mice were swimming in the bucket for 6 min, during which the immobility time of the mice was recorded by the instrument, and the immobility time of the last 4 min was used for data analysis, wherein the efficiency (%) = (LPS model group of mice forced swimming immobility time drug group - drug group of mice forced swimming immobility time) / LPS model group of mice forced swimming immobility time * 100%.

[0254] 4.5 Data collection and analysis:

[0255] All experimental data were expressed as mean. Statistical analysis was performed using Graphad Prism 8 software. The difference between two groups was analyzed by t-test method, and the comparison between animal groups was analyzed by one-way ANOVA with Dunnett's multiple comparison test, P<0.05 indicating statistical significance.

[0256] 4.6 Experimental results: As shown in Tables 8 and 9 below.

[0257] Table 8 Antidepressant effect of dextromethorphan + celecoxib in learned helplessness depression mouse model (sugar water preference test) Note: *P<0.05, **P<0.01 compared with the model group

[0258] Table 9 Antidepressant effect of dextromethorphan + celecoxib in learned helplessness depression mouse model (forced swimming test) Note: *P<0.05, **P<0.01 compared with the model group

[0259] 4.7 Experimental conclusion:

[0260] The antidepressant effect of dextromethorphan + celecoxib combination was tested by learned helplessness depression mouse model, and it was found that the dextromethorphan + celecoxib combination group (1:1.4-1:5.5 according to dextromethorphan: celecoxib) could significantly improve the sugar water preference of learned helplessness depression mice, and reduce the forced swimming immobility time of learned helplessness depression mice, indicating that within the above ratio range, the dextromethorphan + celecoxib combination had good antidepressant effect.

[0261] In summary, the targets of dextromethorphan, celecoxib and dextromethorphan + celecoxib combination include NMDA receptor, Sigma-1 receptor, serotonin (5-HT), norepinephrine (NE), nicotinic acetylcholine (nAch) receptor, cyclooxygenase-2 (Cox-2) and other targets, which are related to the pathogenesis of depression. Moreover, the mechanism of dextromethorphan + celecoxib combination is not the same as that of dextromethorphan + bupropion combination, which belongs to a new type of antidepressant combination with a new mechanism of action. Through two different mouse depression models (LPS-induced depression mouse model and learned helplessness depression mouse model), it is proved that dextromethorphan + celecoxib combination has good antidepressant effect. Through the inflammation (LPS)-induced depression mouse model, it is found that the antidepressant effect of dextromethorphan + celecoxib combination is better than that of dextromethorphan + bupropion combination and dextromethorphan + ibuprofen combination under the same ratio of dose, and dextromethorphan + celecoxib combination has a synergistic effect.

[0262] Example 5: Dextromethorphan and celecoxib combination reduces the expression of inflammatory levels in vivo

[0263] The levels of inflammatory cytokines (TNF-α, IL-6, IL-1β, and corticosterone) in the serum of the four groups (blank control group, LPS model group, dextromethorphan + bupropion group (10+20 mg / kg), and dextromethorphan + celecoxib group (10+20 mg / kg)) in Example 2 were detected by double antibody one-step sandwich enzyme-linked immunosorbent assay: the corresponding inflammatory cytokine antibody-coated microwells were added with samples, standards, and HRP-labeled detection antibodies in sequence, incubated, and thoroughly washed. Color development was performed with substrate TMB, which was converted to blue under the catalysis of peroxidase and to the final yellow under the action of acid. The absorbance (OD value) was measured at 450 nm wavelength by an enzyme marker, and the concentration was calculated.

[0264] The results show that, compared with the LPS model group, the expression of TNF-α, IL-6, IL-1β, and corticosterone in the serum of the dextromethorphan + celecoxib combination group of depressed mice is significantly reduced, indicating that dextromethorphan + celecoxib combination can significantly reduce the inflammatory level in the body of depressed mice, and the results are shown in Figure 1.

[0265] Example 6: Exploration of single-dose acute toxicity of C57BL / 6J mice

[0266] 6.1 Experimental animals

[0267] Forty C57BL / 6 mice, weighing 20-25 g, were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0268] 6.2 Experimental groups and preparation of preparations

[0269] Dosing Groups (Doses): G1-G10 are healthy mice, dextromethorphan + celecoxib (10+20 mg / kg, as free base), dextromethorphan + celecoxib (10+40 mg / kg, as free base), dextromethorphan + celecoxib (10+60 mg / kg, as free base), dextromethorphan + celecoxib (10+100 mg / kg, as free base), dextromethorphan + celecoxib (10+140 mg / kg, as free base), dextromethorphan + celecoxib (10+180 g / kg, as free base), dextromethorphan + bupropion (10+60 mg / kg, as free base), dextromethorphan + bupropion (10+140 mg / kg, as free base), dextromethorphan + bupropion (10+180 mg / kg, as free base).

[0270] Formulation Configuration:

[0271] Accurately weigh dextromethorphan hydrobromide monohydrate and celecoxib in a suitable container, add the target volume of 5% anhydrous ethanol + 5% Cremophor + 90% physiological saline vehicle, and configure into dextromethorphan + celecoxib (1.0+2.0 mg / mL), dextromethorphan + celecoxib (1.0+4.0 mg / mL), dextromethorphan + celecoxib (1.0+6.0 mg / mL), dextromethorphan + celecoxib (1.0+10.0 mg / mL), dextromethorphan + celecoxib (1.0+14.0 mg / mL), dextromethorphan + celecoxib (1.0+18.0 mg / mL) transparent administration solutions, respectively, and use after vortex mixing.

[0272] Accurately weigh dextromethorphan hydrobromide monohydrate and celecoxib in a suitable container, add the target volume of 5% anhydrous ethanol + 5% Cremophor + 90% physiological saline vehicle, and configure into dextromethorphan + celecoxib (1.0+2.0 mg / mL), dextromethorphan + celecoxib (1.0+4.0 mg / mL), dextromethorphan + celecoxib (1.0+6.0 mg / mL), dextromethorphan + celecoxib (1.0+10.0 mg / mL), dextromethorphan + celecoxib (1.0+14.0 mg / mL), dextromethorphan + celecoxib (1.0+18.0 mg / mL) transparent administration solutions, respectively, and use after vortex mixing.

[0273] 6.3 Experimental Methods

[0274] C57BL / 6 mice were randomly divided into 10 groups according to body weight, 4 in each group (2 males and 2 females), namely G1-healthy mice, G2-dextromethorphan+celecoxib (10+20 mg / kg, 1:2 based on free base), G3-dextromethorphan+celecoxib (10+40 mg / kg, 1:4 based on free base), G4-dextromethorphan+celecoxib (10+60 mg / kg, 1:6 based on free base), G5-dextromethorphan+celecoxib (10+100 mg / kg, 1:10 based on free base), G6-dextromethorphan+celecoxib (10+140 mg / kg, 1:14 based on free base), G7-dextromethorphan+celecoxib (10+180 mg / kg, 1:18 based on free base), G8-dextromethorphan+bupropion (10+60 g / kg, 1:6 based on free base), G9-dextromethorphan+bupropion (10+140 mg / kg, 1:14 based on free base), and G10-dextromethorphan+bupropion (10+180 mg / kg, 1:18 based on free base). The mice in each group were given a single intragastrical administration of the corresponding test product at a volume of 10 mL / kg, and the safety of the mice was observed after administration.

[0275] 6.4 Results

[0276] The experimental results are shown in Figure 2. The results show that the dextromethorphan+celecoxib group did not exhibit toxic reactions at a dose ratio of 1:2-1:18, and the body weight of the mice was normal after 6 days of continuous observation. The dextromethorphan+bupropion group exhibited decreased activity in one male mouse at a dose ratio of 1:14 (10+140 mg / kg), and exhibited obvious salivation, decreased activity, and slightly rigid tail in one male mouse at a dose ratio of 1:18 (10+180 mg / kg). In addition, the body weight of the mice exhibited a continuous decrease after 6 days of continuous observation. The above results show that the dextromethorphan+bupropion group exhibited obvious toxic reactions at a dose equal to or greater than 10+140 mg / kg.

Claims

1. Use of a pharmaceutical composition for: (i) treating inflammatory depression; and / or (ii) the manufacture of a medicament for treating inflammatory depression; wherein said pharmaceutical composition comprising: (i) dextromethorphan or a salt of dextromethorphan; and (ii) celecoxib or a salt of celecoxib.

2. Use according to claim 1, characterized in that, said inflammatory depression is selected from at least one of: (i) refractory depression with inflammation; (ii) anhedonic depression.

3. Use according to claim 1 or 2, characterized in that, said salt of dextromethorphan is dextromethorphan hydrobromide, preferably dextromethorphan hydrobromide monohydrate.

4. Use according to claim 1 or 2, characterized in that, the mass ratio of dextromethorphan to celecoxib in said pharmaceutical composition is 1 : (0.5-10) on a free base basis.

5. Use according to any one of claims 1 to 4, characterized in that, the mass of dextromethorphan in said pharmaceutical composition is 10-500 mg on a free base basis.

6. Use according to any one of claims 1 to 4, characterized in that, the mass of celecoxib in said pharmaceutical composition is 10-500 mg on a free base basis.

7. Use according to any one of claims 1 to 6, characterized in that, said pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

8. Use according to claim 7, characterized in that, said pharmaceutical composition is a tablet or a capsule.

9. Use according to claim 7, characterized in that, said pharmaceutical composition is a controlled release or sustained release formulation.

10. Use according to any one of claims 1 to 9, characterized in that, said pharmaceutical composition is a fixed-dose combination, a combination drug or a combination packaged drug product.

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