阅读说明：本技术 一种含有度洛西丁的药物组合物及其应用 (Pharmaceutical composition containing dolocidine and application thereof ) 是由 肖瑛 邢伟 胡雪峰 黄伟鑫 吴俊军 张志新 孙晶超 于 2021-08-02 设计创作，主要内容包括：本发明提供了药物组合应用技术领域,具体涉及一种含有度洛西丁的药物组合物及其应用。所述药物组合物中,氘代右美沙芬或其盐和度洛西汀或其盐的质量比为1-10：1-10。以及药物组合物在制备预防和/或治疗咳嗽及各种神经类病症的药物用途。(The invention provides the technical field of pharmaceutical composition application, and particularly relates to a pharmaceutical composition containing doloxetine and application thereof. In the pharmaceutical composition, the mass ratio of the deuterated dextromethorphan or the salt thereof to the duloxetine or the salt thereof is 1-10: 1-10. And the application of the pharmaceutical composition in preparing medicaments for preventing and/or treating cough and various neurological diseases.)

1. A pharmaceutical composition comprising deuterated dextromethorphan or a salt thereof and duloxetine or a salt thereof.

2. The pharmaceutical composition according to claim 1 or 2, wherein the mass ratio of the deuterated dextromethorphan or the salt thereof to the duloxetine or the salt thereof in the pharmaceutical composition is 1-10: 1-10.

3. A pharmaceutical composition according to any one of claims 1, wherein in said pharmaceutical composition: the deuterated dextromethorphan or the salt thereof is calculated by deuterated dextromethorphan, the duloxetine or the salt thereof is calculated by duloxetine, and the mass ratio of the deuterated dextromethorphan to the duloxetine is 1: 1-10.

4. A pharmaceutical composition according to any one of claims 1, wherein in said pharmaceutical composition: the deuterated dextromethorphan or the salt thereof is calculated by deuterated dextromethorphan, the duloxetine or the salt thereof is calculated by duloxetine, and the mass ratio of the deuterated dextromethorphan to the duloxetine is 1: 4-10.

5. A pharmaceutical composition according to any one of claims 1 to 4, wherein in said composition: the deuterated dextromethorphan or the salt thereof is calculated by deuterated dextromethorphan, the duloxetine or the salt thereof is calculated by duloxetine, and the mass ratio of the deuterated dextromethorphan to the duloxetine is 1: 1. 1: 1.25, 1: 1.5, 1: 1.75, 1: 2. 1: 2.25, 1: 2.5, 1: 2.75, 1: 3. 1: 3.25, 1: 3.5, 1: 3.75, 1: 4. 1: 4.25, 1: 4.5, 1: 4.75, 1: 5. 1: 5.25, 1: 5.5, 1: 5.75, 1: 6. 1: 6.25, 1: 6.5, 1: 6.75, 1: 7. 1: 7.25, 1: 7.5, 1: 7.75, 1: 8. 1: 8.25, 1: 8.5, 1: 8.75, 1: 9. 1: 9.25, 1: 9.5, 1: 9.75, 1: 10.

6. a pharmaceutical composition according to any one of claims 1 to 4, wherein the salt is selected from: sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, bromate, iodate, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, bromate, iodate, acetate, caprate, fumarate, maleate, butyrate, benzoate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, dihydrogenate, dihydrogensulfonate, metaphosphate, or salt of a, Lactate, beta-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate.

7. A pharmaceutical composition according to any one of claims 1 to 4, wherein in the pharmaceutical composition: the structure of the deuterated dextromethorphan is shown as formula I:

8. a pharmaceutical composition according to any one of claims 1 to 4, wherein in the pharmaceutical composition:

the salt of deuterated dextromethorphan is selected from:

the salt of dolocidine is selected from:

9. a pharmaceutical composition according to any one of claims 1 to 4, wherein in the pharmaceutical composition:

the hydrate of the salt of deuterated dextromethorphan is selected from the group consisting of:

10. a pharmaceutical composition according to claim 1, wherein said pharmaceutical composition comprises a pharmaceutical composition suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.

11. Use of a pharmaceutical composition according to any one of claims 1-10 for the preparation of a medicament for the prevention and/or treatment of cough and various neurological disorders.

12. The pharmaceutical use according to claim 10, characterized in that: such neurological disorders include, but are not limited to, depression, major depression, refractory depression, and refractory bipolar depression.

13. The pharmaceutical use according to claim 12, characterized in that: the depression includes bipolar disorders of cyclothymic psychosis, seasonal affective disorders, mania, anxiety disorders, Attention Deficit Disorder (ADD), attention deficit disorder with hyperactivity (ADDH), attention deficit/hyperactivity disorder (AD/HD), bipolar and manic disorders, obsessive compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychological dysfunction, pseudobulbar mood, and mood swings.

Technical Field

The invention provides the technical field of pharmaceutical composition application, and particularly relates to a pharmaceutical composition containing doloxetine and application thereof.

Background

Dextromethorphan (CAS: 125-71-3), with the English name: dextrometorphan, chemically known as (+) -3-methoxy-17-methyl- (9 α, 13 α, 14 α) -morphinan, is clinically used as a medicament with its hydrobromide salt (CAS: 125-69-9), and more specifically as Dextromethorphan hydrobromide monohydrate, and has the following chemical structure:

dextromethorphan deuterated compounds can be obtained by the prior art CN101687868A and the like, for example, one deuterated dextromethorphan has the following chemical structure:

duloxetine (CAS: 116539-59-4), its English name: duloxetine, having the chemical name (3S) -N-methyl-3- (naphthalen-1-yloxy) -3- (thiophen-2-yl) propan-1-amine, is clinically used as a drug in its hydrochloride salt (CAS: 136434-34-9), and Duloxetine has the following chemical structure:

CN106163522A discloses a composition and method containing bupropion or related compounds and dextromethorphan, which are used for treating neurological disorders such as depression, and related drugs are in clinical stage at present. There is also a wide range of unresolved clinical needs in this field.

Disclosure of Invention

In view of the clinical needs of the prior art, the primary object of the present invention is to provide a pharmaceutical composition comprising deuterated dextromethorphan or a salt thereof, and duloxetine or a salt thereof.

In the pharmaceutical composition, deuterated dextromethorphan or a salt thereof and duloxetine or a salt thereof can be combined in any proportion, and particularly, the mass ratio of the deuterated dextromethorphan or a salt thereof to the duloxetine or a salt thereof is 1-10: 1-10, including but not limited to: 1: 1. 2: 1. 3: 1. 4: 1. 5: 1. 6: 1. 7: 1. 8: 1. 9: 1. 10: 1. 2: 1. 3: 1. 4: 1. 5: 1. 6: 1. 7: 1. 8: 1. 9: 1. 10: 1.

as a preferred technical scheme of the present invention, the pharmaceutical composition comprises the following components by mass:

as a preferred technical scheme of the present invention, the pharmaceutical composition comprises the following components by mass:

as a preferred technical scheme of the present invention, the pharmaceutical composition comprises the following components by mass:

as a preferred technical solution of the present invention, in the pharmaceutical composition: the deuterated dextromethorphan or the salt thereof is calculated by deuterated dextromethorphan, the duloxetine or the salt thereof is calculated by duloxetine, and the mass ratio of the deuterated dextromethorphan to the duloxetine is 1: 1-10.

As a preferred technical solution of the present invention, in the pharmaceutical composition: the deuterated dextromethorphan or the salt thereof is calculated by deuterated dextromethorphan, the duloxetine or the salt thereof is calculated by duloxetine, and the mass ratio of the deuterated dextromethorphan to the duloxetine is 1: 4-10.

As a preferred technical solution of the present invention, in the pharmaceutical composition: the deuterated dextromethorphan or the salt thereof is calculated by deuterated dextromethorphan, the duloxetine or the salt thereof is calculated by duloxetine, and the mass ratio of the deuterated dextromethorphan to the duloxetine is 1: 1. 1: 1.25, 1: 1.5, 1: 1.75, 1: 2. 1: 2.25, 1: 2.5, 1: 2.75, 1: 3. 1: 3.25, 1: 3.5, 1: 3.75, 1: 4. 1: 4.25, 1: 4.5, 1: 4.75, 1: 5. 1: 5.25, 1: 5.5, 1: 5.75, 1: 6. 1: 6.25, 1: 6.5, 1: 6.75, 1: 7. 1: 7.25, 1: 7.5, 1: 7.75, 1: 8. 1: 8.25, 1: 8.5, 1: 8.75, 1: 9. 1: 9.25, 1: 9.5, 1: 9.75, 1: 10.

as a preferred technical scheme of the present invention, the pharmaceutical composition comprises the following components by mass:

as a preferred technical scheme of the present invention, the pharmaceutical composition comprises the following components by mass:

as a preferred technical scheme of the present invention, the pharmaceutical composition comprises the following components by mass:

as a preferred technical solution of the present invention, in the pharmaceutical composition: the structure of the deuterated dextromethorphan is shown as formula I:

in one embodiment of the invention, the pharmaceutical composition contains 10mg to 500mg, 20mg to 200mg, 25mg to 100mg, 30mg to 80mg of deuterated dextromethorphan; and the mass ratio of the components is 1: 1. 1: 1.25, 1: 1.5, 1: 1.75, 1: 2. 1: 2.25, 1: 2.5, 1: 2.75, 1: 3. 1: 3.25, 1: 3.5, 1: 3.75, 1: 4. 1: 4.25, 1: 4.5, 1: 4.75, 1: 5. 1: 5.25, 1: 5.5, 1: 5.75, 1: 6. 1: 6.25, 1: 6.5, 1: 6.75, 1: 7. 1: 7.25, 1: 7.5, 1: 7.75, 1: 8. 1: 8.25, 1: 8.5, 1: 8.75, 1: 9. 1: 9.25, 1: 9.5, 1: 9.75, 1:10 in combination with duloxetine or a salt thereof, respectively.

For example: the pharmaceutical composition contains 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, 80mg of deuterated dextromethorphan; and the mass ratio of the components is 1: 1. 1: 1.25, 1: 1.5, 1: 1.75, 1: 2. 1: 2.25, 1: 2.5, 1: 2.75, 1: 3. 1: 3.25, 1: 3.5, 1: 3.75, 1: 4. 1: 4.25, 1: 4.5, 1: 4.75, 1: 5. 1: 5.25, 1: 5.5, 1: 5.75, 1: 6. 1: 6.25, 1: 6.5, 1: 6.75, 1: 7. 1: 7.25, 1: 7.5, 1: 7.75, 1: 8. 1: 8.25, 1: 8.5, 1: 8.75, 1: 9. 1: 9.25, 1: 9.5, 1: 9.75, 1:10 in combination with duloxetine or a salt thereof, respectively.

Wherein, the chemical structures of the duloxetine and the duloxetine hydrochloride are as follows:

the active compound as in the pharmaceutical composition of the present invention also includes any salt, solvate or hydrate thereof.

Salts of the compounds of the invention are formed from an acid and a basic group of the compound (such as an amino functional group) or from a base and an acidic group of the compound (such as a carboxyl functional group). According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt. Various pharmaceutically acceptable salts are generally selected.

The term "pharmaceutically acceptable" as used herein, means that the component is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.

Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrosulfuric acid (hydrosulfide), hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid; and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid (bitartric acid), ascorbic acid, maleic acid, benzenesulfonic acid (besylic acid), fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid; and related inorganic and organic acids.

Thus, the pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, bromate, iodate, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, decanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, dihydrogenphosphate, octanoate, dihydrogenphosphate, decanoate, dihydrogenphosphate, fumarate, and a pharmaceutically acceptable salt, such as a pharmaceutically acceptable salt, a, Xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts.

In one embodiment, pharmaceutically acceptable acid addition salts include salts with inorganic acids such as duloxetine hydrochloride and deuterated dextromethorphan hydrobromide.

As a preferred embodiment of the present invention,

the salt of deuterated dextromethorphan is selected from:

the salt of dolocidine is selected from:

the term "hydrate" as used herein means a compound that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

As a preferred embodiment of the present invention, the hydrate of the deuterated dextromethorphan salt is selected from the group consisting of:

the term "solvate" as used herein means a compound that further includes a stoichiometric or non-stoichiometric amount of a solvent (such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, etc.) that is bound by non-covalent intermolecular forces.

"D" refers to deuterium.

The pharmaceutical compositions of the present invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.

The method of preparation includes the step of combining the molecule to be administered with ingredients, such as a carrier, that constitute one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, liposomes or finely divided solid carriers or both, and then, if necessary, shaping the product.

In certain embodiments, the compound is administered orally. Compositions of the invention suitable for oral administration may be provided as follows: separate units (such as capsules, cachets or tablets) each containing a predetermined amount of the active ingredient; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; an oil-in-water liquid emulsion; a water-in-oil type liquid emulsion; filling in liposome; or bolus (bolus) etc. Soft gelatin capsules may be suitable for containing the suspension, which may advantageously increase the rate of absorption of the compound.

In the case of oral tablets, carriers commonly used include lactose and corn starch. Lubricating agents such as magnesium stearate are also commonly added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may 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 may be prepared from sterile powders, granules and tablets.

The injectable solutions may be in the form of, for example, sterile injectable aqueous or oleaginous suspensions.

In addition, the pharmaceutical compositions of the present invention may be administered with a nasal aerosol or inhalant.

The invention further provides application of the pharmaceutical composition in preparing a medicament for preventing and/or treating neurological diseases.

Such neurological disorders include, but are not limited to, depression, major depression, refractory depression, and refractory bipolar depression.

More particularly, the depression includes bipolar disorders of cyclothymic disorder, seasonal affective disorder, mania, anxiety disorders, Attention Deficit Disorder (ADD), attention deficit disorder with hyperactivity (ADDH), attention deficit/hyperactivity disorder (AD/HD), bipolar and manic disorders, obsessive compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychological dysfunction, pseudobulbar mood, and mood swings.

In addition, the selection of non-deuterated dextromethorphan is not excluded by the person skilled in the art after being aware of the present inventionOr a salt thereof in combination with duloxetine or a salt thereof, specifically, for example:

dextromethorphan or a salt thereof and duloxetine or a salt thereof can be used in combination in any ratio to prepare alternative compositions in which the mass ratio of dextromethorphan or a salt thereof to duloxetine or a salt thereof is 1-10: 1-10, including but not limited to: 1: 1. 2: 1. 3: 1. 4: 1. 5: 1. 6: 1. 7: 1. 8: 1. 9: 1. 10: 1. 2: 1. 3: 1. 4: 1. 5: 1. 6: 1. 7: 1. 8: 1. 9: 1. 10: 1;

specifically, dextromethorphan or a salt thereof is calculated as dextromethorphan, duloxetine or a salt thereof is calculated as duloxetine, and the mass ratio of the dextromethorphan to the duloxetine is 1: 1. 1: 1.25, 1: 1.5, 1: 1.75, 1: 2. 1: 2.25, 1: 2.5, 1: 2.75, 1: 3. 1: 3.25, 1: 3.5, 1: 3.75, 1: 4. 1: 4.25, 1: 4.5, 1: 4.75, 1: 5. 1: 5.25, 1: 5.5, 1: 5.75, 1: 6. 1: 6.25, 1: 6.5, 1: 6.75, 1: 7. 1: 7.25, 1: 7.5, 1: 7.75, 1: 8. 1: 8.25, 1: 8.5, 1: 8.75, 1: 9. 1: 9.25, 1: 9.5, 1: 9.75, 1: 10;

such alternative compositions contain from 10mg to 500mg, from 20mg to 200mg, from 25mg to 100mg, from 30mg to 80mg of dextromethorphan; and the mass ratio of the components is 1: 1. 1: 1.25, 1: 1.5, 1: 1.75, 1: 2. 1: 2.25, 1: 2.5, 1: 2.75, 1: 3. 1: 3.25, 1: 3.5, 1: 3.75, 1: 4. 1: 4.25, 1: 4.5, 1: 4.75, 1: 5. 1: 5.25, 1: 5.5, 1: 5.75, 1: 6. 1: 6.25, 1: 6.5, 1: 6.75, 1: 7. 1: 7.25, 1: 7.5, 1: 7.75, 1: 8. 1: 8.25, 1: 8.5, 1: 8.75, 1: 9. 1: 9.25, 1: 9.5, 1: 9.75, 1:10 in combination with duloxetine or a salt thereof, respectively;

for example: the pharmaceutical composition contains 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, 80mg of dextromethorphan; and the mass ratio of the components is 1: 1. 1: 1.25, 1: 1.5, 1: 1.75, 1: 2. 1: 2.25, 1: 2.5, 1: 2.75, 1: 3. 1: 3.25, 1: 3.5, 1: 3.75, 1: 4. 1: 4.25, 1: 4.5, 1: 4.75, 1: 5. 1: 5.25, 1: 5.5, 1: 5.75, 1: 6. 1: 6.25, 1: 6.5, 1: 6.75, 1: 7. 1: 7.25, 1: 7.5, 1: 7.75, 1: 8. 1: 8.25, 1: 8.5, 1: 8.75, 1: 9. 1: 9.25, 1: 9.5, 1: 9.75, 1:10 in combination with duloxetine or a salt thereof, respectively.

The beneficial effects of the invention compared with the prior art comprise:

(1) compared with the prior art, the pharmaceutical composition has more excellent metabolic effect, and ensures the appropriate drug concentration and effect;

(2) the specific proportion of the pharmaceutical composition has excellent synergistic effect, and the mass ratio of the deuterated dextromethorphan to the duloxetine is preferably 1: 1-10; further preferably, the mass ratio of the deuterated dextromethorphan to the duloxetine is 1: 4-10.

(3) The effect of the pharmaceutical composition of the invention in a specific ratio is superior to the effect of the combination of non-deuterated dextromethorphan and duloxetine.

(4) The pharmaceutical composition can be widely applied to cough and various neurological symptomatic diseases, and has the effect of broad-spectrum application.

Detailed Description

The present invention will be described in further detail with reference to examples, but the embodiments of the invention are not limited thereto.

The raw materials adopted in the embodiment of the invention are dextromethorphan hydrobromide, deuterated dextromethorphan, duloxetine hydrochloride and bupropion hydrochloride, and the mass of each substance used for the experiment is calculated by free concentration, namely the dextromethorphan hydrobromide is calculated by dextromethorphan, the duloxetine hydrochloride is calculated by duloxetine and the bupropion hydrochloride is calculated by bupropion.

Example 1 hepatic microsome stability experiment

1.1 Experimental procedure:

1.0.1M Potassium phosphate buffer (pH7.4)

Buffer A: a buffer solution was prepared in which the concentration of potassium dihydrogen phosphate was 13.61mg/mL and the concentration of EDTA was 0.4 mg/mL.

Buffer B: a buffer solution containing 17.42mg/mL of dipotassium phosphate and 0.4mg/mL of EDTA was prepared.

Buffer C: buffer B was added to Buffer A, and the pH was adjusted to 7.4 with a pH meter to obtain 0.1M potassium phosphate Buffer (containing 1.0mM EDTA, pH 7.4).

2. Preparation of working solution

Stock solution 1: an appropriate amount of dextromethorphan hydrobromide, deuterated dextromethorphan (with a structure shown in formula I), duloxetine hydrochloride and bupropion hydrochloride powder is precisely weighed and dissolved by adding methanol/water (v/v ═ 1:1) to ensure that the concentration of dextromethorphan is 5.4mg/mL (free concentration) or 6.0mg/mL (free concentration), the concentration of deuterated dextromethorphan is 5.5mg/mL, the concentration of duloxetine is 54.0 and 55.0mg/mL (free concentration) and the concentration of bupropion is 48.0mg/mL (free concentration). Diluting 54, 55.0mg/mL duloxetine solution and 48.0mg/mL bupropion solution to proper concentrations by methanol/water (v/v is 1:1), taking equal volumes of the duloxetine solution before and after dilution and the dextromethorphan solution, mixing the bupropion solution with the dextromethorphan solution, the duloxetine solution and the deuterated dextromethorphan solution, and enabling the concentration ratio of dextromethorphan/duloxetine and dextromethorphan/bupropion to be 1:1, 1:2, wherein the concentration ratio of deuterated dextromethorphan/duloxetine is 1: 0. 1: 0.5, 1: 1. 1: 2. 1: 4. 1:6, 1: 8. 1:10, stock solution 1.

Working solution: 60. mu.L of the mixed stock solution 1 obtained in step (1) was diluted with 140. mu.L of potassium phosphate buffer to obtain a working solution.

3. Prepare 96-well plates, label T0, T20, T60 wells.

4. Adding 18.8 mu L (20mg protein/mL) of liver microsomes into 456.2 mu L of buffer solution, then adding 25 mu L of dextromethorphan/deuterated dextromethorphan + duloxetine, dextromethorphan + bupropion obtained in the step (II), and uniformly mixing by using a liquid transfer gun.

5. The mixture was dispensed into wells labeled T0, T20, and T60 in duplicate, 30. mu.L per well. Immediately, 50ng/mL propranolol (internal standard IS) acetonitrile stop solution (150. mu.L/well) was added to T0 well, followed by 15. mu.L NADPH solution (5mg/mL) and mixed well.

6. After the set time had elapsed, stop solution (150. mu.L/well) was added to stop the reaction, mixed well, and then 100. mu.L of purified water (including T0) was added to the wells at each time point, mixed well again.

7. The 96-well plate was centrifuged at 4000rpm for 5 minutes.

8. 200 μ L of the supernatant was transferred to a new 96-well plate for LC/MS/MS analysis.

1.2 data analysis:

the analyte/internal standard peak area ratio was converted to percent remaining (percent remaining) as follows:

when the remaining ratio% (% remaining IS) IS the analyte-to-IS peak area ratio at each time point/t IS 0, the analyte-to-IS peak area ratio × 100 calculates a slope based on the remaining ratio at each time point, and calculates the half-life of dextromethorphan or deuterated dextromethorphan.

1.3 Experimental results:

1.4 microsome experiment conclusion:

deuterated dextromethorphan and duloxetine are mixed in a ratio of 1: 1-1: when the ratio of 10 is higher, the half-life period is obviously longer than that of the deuterated dextromethorphan single drug (ratio of 1: 0), the deuterated dextromethorphan single drug and duloxetine (ratio of 1: 0.5), the synergistic effect with the duloxetine is well embodied in the range of the ratio, and the ratio of the deuterated dextromethorphan single drug to the duloxetine is 1: 4-1: the effect of 10 is more excellent.

And deuterated dextromethorphan and duloxetine are mixed in a ratio of 1: the half-life period of the drug is equivalent to that of a single deuterated dextromethorphan drug (the ratio is 1: 0) when the drug is 0.5, the effect of duloxetine cannot be embodied, and no synergistic effect is found.

The mixture ratio is 1: 1-1: the effect of each proportion of the combination of 2 dextromethorphan and duloxetine is equivalent, and the half-life period of the combination of deuterated dextromethorphan and duloxetine in the same proportion is obviously higher than that of the combination of dextromethorphan and duloxetine. Additionally, dextromethorphan is mixed with bupropion in a 1: 1-1: when the mixture ratio is 2, the mixture ratio is only 1: 1-1: 2 dextromethorphan in combination with duloxetine.

Example 2 mouse tolerability dose groping experiment

2.1 Experimental animals

35 male C57BL/6 mice, weighing 20-22g, were purchased from Experimental animals technologies, Inc. of Wei Tony Hua, Beijing.

2.2 Experimental drugs: deuterated dextromethorphan and duloxetine hydrochloride

Administration group (dose): deuterated dextromethorphan/duloxetine group (12mg/kg +24mg/kg), deuterated dextromethorphan/duloxetine group (12mg/kg +48mg/kg), deuterated dextromethorphan/duloxetine group (12mg/kg +72mg/kg), deuterated dextromethorphan/duloxetine group (12mg/kg +96mg/kg), deuterated dextromethorphan/duloxetine group (12mg/kg +120mg/kg), deuterated dextromethorphan/duloxetine group (12mg/kg +144mg/kg), deuterated dextromethorphan/duloxetine group (12mg/kg +168 mg/kg).

2.3 preparation:

a certain amount of medicaments are weighed and dissolved in physiological saline by calculating free base to prepare deuterated dextromethorphan/duloxetine (1.2mg/ml +2.4mg/ml), deuterated dextromethorphan/duloxetine (1.2mg/ml +4.8mg/ml), deuterated dextromethorphan/duloxetine (1.2mg/ml +7.2mg/ml), deuterated dextromethorphan/duloxetine (1.2mg/ml +9.6mg/ml), deuterated dextromethorphan/duloxetine (1.2mg/ml +12mg/ml), deuterated dextromethorphan/duloxetine (1.2mg/ml +14.4mg/ml) and deuterated dextromethorphan/duloxetine (1.2mg/ml +16.8 mg/ml).

2.4 Experimental methods:

male C57BL/6 mice, randomly divided into 7 groups by body weight, each group of 5 mice, respectively deuterated dextromethorphan/duloxetine group (12mg/kg +24mg/kg, 1:2), deuterated dextromethorphan/duloxetine group (12mg/kg +48mg/kg, 1:4), deuterated dextromethorphan/duloxetine group (12mg/kg +72mg/kg, 1:6), deuterated dextromethorphan/duloxetine group (12mg/kg +96mg/kg, 1:8), deuterated dextromethorphan/duloxetine group (12mg/kg +120mg/kg, 1:10), deuterated dextromethorphan/duloxetine group (12mg/kg +144mg/kg, 1:12), deuterated dextromethorphan/duloxetine group (12mg/kg +168mg/kg, 1:14), each group of mice was administered 1 time according to the corresponding test article, the administration volume was 10ml/kg, and after administration, the safety of the mice was observed.

2.5 results of the experiment

Deuterated dextromethorphan/duloxetine (12mg/kg +24mg/kg), deuterated dextromethorphan/duloxetine (12mg/kg +48mg/kg), deuterated dextromethorphan/duloxetine (12mg/kg +72mg/kg), deuterated dextromethorphan/duloxetine (12mg/kg +96mg/kg) and deuterated dextromethorphan/duloxetine (12mg/kg +120mg/kg) groups of mice showed no significant change in signs, deuterated dextromethorphan/duloxetine (12mg/kg +144mg/kg) groups of mice showed slight tremor, deuterated dextromethorphan/duloxetine (12mg/kg +168mg/kg) groups of mice were tremor significant, and 3 mice died.

2.6 conclusion of the experiment

When the dosage of the deuterated dextromethorphan/duloxetine is equal to or more than 12mg/kg +168mg/kg, the mice show obvious neurotoxicity, so that the dosage ratio range which can be tolerated by the mice is less than 1: 12.

Example 3 mouse antitussive protocol

3.1 reagents and instruments

Ammonium hydroxide, ACS reagent, 28.0-30.0% NH₃"Shanghai" chemical science and technology Co., Ltd, lot number CEC 1070004. Ultrasonic atomizer WH-2000, Guangdong Yuehua medical instruments Co., Ltd.

3.2 Experimental animals

40 male C57BL/6 mice, weighing 20-22g, were purchased from Experimental animals technologies, Inc. of Wei Tony Hua, Beijing.

3.3 Experimental drugs:

dextromethorphan hydrobromide, deuterated dextromethorphan, duloxetine hydrochloride and bupropion hydrochloride

Administration group (dose): a blank solvent group, a dextromethorphan (free concentration)/bupropion (free concentration) group (12mg/kg +30mg/kg), a dextromethorphan (free concentration)/duloxetine (free concentration) group (12mg/kg +30mg/kg), a deuterated dextromethorphan/duloxetine (free concentration) group (12mg/kg +30mg/kg)

3.4 preparation:

weighing a certain amount of medicine, and dissolving the medicine in physiological saline to prepare deuterated dextromethorphan/bupropion (1.2mg/ml +3mg/ml), deuterated dextromethorphan/duloxetine (1.2mg/ml +3mg/ml) and dextromethorphan/duloxetine (1.2mg/ml +3mg/ml) respectively.

3.5 Experimental methods:

the method comprises the following steps of dividing male C57BL/6 mice into 4 groups at random according to the number of cough times of primary screening, wherein each group comprises 10 mice, namely a blank solvent group, a deuterated dextromethorphan/bupropion group, a dextromethorphan/duloxetine group and a deuterated dextromethorphan/duloxetine group, administering the mice of each group for 1 time according to corresponding test products, wherein the administration volume is 10ml/kg, after administering for 60min, putting the mice into an inverted 600ml beaker filled with saturated steam of strong ammonia water, immediately timing for 10s, taking out the mice, putting the mice into another inverted 600ml beaker, starting timing, observing the cough of the mice, and recording the total number of cough within 5 min.

3.6 statistical methods:

all experimental data are expressed as means. Statistical analysis was performed using Graphad Prism 5 software. Comparisons between groups were tested by one-way ANOVA, LSD for the uniform variance group, Dunnett's T3 for the non-uniform variance group, and P <0.05 for statistical significance.

3.7 Experimental results:

note: p <0.05vs blank vehicle group

3.8 conclusion of the experiment

After 60min of administration, the antitussive effect of the deuterated dextromethorphan/duloxetine on mice is better than that of dextromethorphan/bupropion and dextromethorphan/duloxetine, and compared with a solvent control group, the deuterated dextromethorphan/duloxetine has a significant difference.

EXAMPLE 4 pharmaceutical composition

And (2) filling a No. 0 capsule by adopting deuterated dextromethorphan and duloxetine hydrochloride (calculated by duloxetine) according to the following mass ratio, wherein the total amount of deuterated dextromethorphan and duloxetine in each unit capsule is 100 mg.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.