Compounds and combinations thereof for treatment of neurological and psychiatric conditions

Abstract

The present disclosure relates to administering in certain patient populations a combination of: 1) about 100 to 110 mg, about 104 to 106 mg, or about 105 mg or less of bupropion hydrochloride or a molar equivalent of bupropion in the form of a free base or in the form of another salt; and 2) dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in the form of a free base or another salt, in the amount of about 40 to 50 mg, about 44 to 46 mg, or about 45 mg or less, the patient populations such as patients suffering from moderate renal injury, patients receiving companion strong CYP2D6 inhibitors, patients known as CYP2D6 weak metabolites, patients in need of NMDA antagonists that do not cause dissociation, and patients at risk of QT prolongation.

Description

[0001] Inventor: Heriot Tabutio

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 359,143 filed on July 7, 2022, U.S. Provisional Application No. 63 / 370,592 filed on August 5, 2022, U.S. Provisional Application No. 63 / 396,182 filed on August 8, 2022, U.S. Provisional Application No. 63 / 373,040 filed on August 19, 2022, and U.S. Provisional Application No. 63 / 401,541 filed on August 26, 2022; all of which are incorporated herein by reference in their entirety. Summary of the invention

[0004] The present disclosure contemplates administering in certain patient populations a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride or a molar equivalent of dextromethorphan in free base form or another salt form; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in free base form or another salt form.

[0005] Some embodiments include a method of reducing the risk of neurotoxicity in a human child comprising: i) administering a combination of about 45 mg dextromethorphan hydrobromide and about 105 mg bupropion hydrochloride to a human patient once daily or twice daily, wherein the human patient is a nursing mother of the human child and is experiencing major depressive disorder; and ii) advising the human patient not to breastfeed the human child while the combination is being administered to the human patient and for 5 days after the last dose of the combination.

[0006] Some embodiments include a method of treating major depressive disorder in a patient with moderate renal impairment, comprising administering to a human patient with moderate renal impairment and experiencing major depressive disorder a daily dose of (i) about 105 mg bupropion hydrochloride and (ii) about 45 mg dextromethorphan hydrobromide.

[0007] Some embodiments include a method of treating a patient suffering from a neurological condition by administering a combination of dextromethorphan and bupropion, the method comprising:

[0008] orally administering to the patient once daily a dosage form comprising: 105 mg or less of bupropion hydrochloride or a molar equivalent of bupropion as a free base or another salt form, and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan as a free base or another salt form, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;

[0009] wherein the patient is selected because: 1) suffers from the neurological condition, and 2) suffers from moderate renal impairment, wherein the patient is determined to suffer from moderate renal impairment by assaying a biological sample from the patient; and

[0010] wherein the risk of somnolence or dizziness to the patient after administering the dosage form containing the combination to the patient once daily with moderate renal impairment is lower than the risk of somnolence or dizziness to the patient when the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is administered to the patient twice daily for the same number of days.

[0011] Some embodiments include a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing a neurological condition, the method comprising the steps of:

[0012] Whether the patient has moderate renal impairment is determined by:

[0013] obtaining or having obtained a biological sample from the patient; and

[0014] The biological sample is or has been assayed to determine whether the patient has moderate renal impairment; and

[0015] if the patient has moderate renal impairment, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;

[0016] if the patient does not have renal impairment, orally administering to the patient twice daily a dosage form containing a combination of 105 mg bupropion hydrochloride or a molar equivalent of bupropion as a free base or another salt and 45 mg dextromethorphan hydrobromide or a molar equivalent of dextromethorphan as a free base or another salt;

[0017] wherein the risk of drowsiness or dizziness to said patient after administering said dosage form containing said combination once daily to said patient with moderate renal impairment is lower than the risk of drowsiness or dizziness to said patient when said patient is administered a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide twice daily for the same number of days.

[0018] Some embodiments include a method of treating a patient experiencing a neurological condition, the method comprising the steps of:

[0019] a) determining whether the patient is at risk for an adverse event associated with overexposure to dextromethorphan by:

[0020] obtaining or having obtained a biological sample from the patient; and performing or having performed an assay on the biological sample to determine whether the patient has moderate renal impairment, wherein a result that the patient has moderate renal impairment indicates that the patient is at risk for an adverse event associated with overexposure to dextromethorphan; and

[0021] b) if the patient is at risk for an adverse event associated with overexposure to dextromethorphan, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and

[0022] c) if the patient is not at risk for an adverse event associated with overexposure to dextromethorphan, orally administering to the patient twice daily a dosage form containing a combination of 105 mg bupropion hydrochloride, or a molar equivalent of bupropion as the free base or another salt form, and 45 mg dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan as the free base or another salt form.

[0023] Some embodiments include a method of treating a neurological condition with a combination of dextromethorphan and bupropion, comprising:

[0024] orally administering to a patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and

[0025] wherein the patient is selected because: 1) suffers from the neurological condition, and 2) suffers from moderate renal impairment, wherein the patient is determined to suffer from moderate renal impairment by assaying a biological sample from the patient; and

[0026] wherein the patient has a lower risk of an adverse event than the patient would have if the dosage form were administered to the patient twice daily.

[0027] Some embodiments include a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing a neurological condition, the method comprising the steps of:

[0028] Whether the patient has moderate renal impairment is determined by:

[0029] obtaining or having obtained a biological sample from the patient; and

[0030] The biological sample is or has been assayed to determine whether the patient has moderate renal impairment; and

[0031] if the patient has moderate renal impairment, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and

[0032] If the patient does not suffer from renal impairment, a dosage form containing a combination of 105 mg bupropion hydrochloride or a molar equivalent of bupropion as a free base or another salt form and 45 mg dextromethorphan hydrobromide or a molar equivalent of dextromethorphan as a free base or another salt form is orally administered to the patient twice daily.

[0033] Some embodiments include a method of treating a patient suffering from a neurological condition by administering a combination of dextromethorphan and bupropion, the method comprising:

[0034] orally administering to the patient once daily a dosage form comprising: 105 mg or less of bupropion hydrochloride or a molar equivalent of bupropion as a free base or another salt form, and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan as a free base or another salt form, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;

[0035] wherein the patient is selected because: 1) suffers from the neurological condition, and 2) suffers from moderate renal impairment, wherein the patient is determined to suffer from moderate renal impairment by assaying a biological sample from the patient; and

[0036] wherein the risk of somnolence and dizziness to said patient after administering said dosage form containing said combination once daily to said patient with moderate renal impairment is lower than the risk of somnolence and dizziness to said patient when said patient is administered a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide twice daily for the same number of days.

[0037] Some embodiments include a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing a neurological condition, the method comprising the steps of:

[0038] Whether the patient has moderate renal impairment is determined by:

[0039] obtaining or having obtained a biological sample from the patient; and

[0040] The biological sample is or has been assayed to determine whether the patient has moderate renal impairment; and

[0041] if the patient has moderate renal impairment, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;

[0042] if the patient does not have renal impairment, orally administering to the patient twice daily a dosage form containing a combination of 105 mg bupropion hydrochloride or a molar equivalent of bupropion as a free base or another salt and 45 mg dextromethorphan hydrobromide or a molar equivalent of dextromethorphan as a free base or another salt;

[0043] wherein the risk of somnolence and dizziness to said patient after administering said dosage form containing said combination once daily to said patient with moderate renal impairment is lower than the risk of somnolence and dizziness to said patient when said patient is administered a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide twice daily for the same number of days.

[0044] Some embodiments include a method of treating major depressive disorder in a human patient in need of concomitant treatment with a strong CYP2D6 inhibitor, comprising administering to the human patient once daily a combination of about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide, wherein the human patient is experiencing major depressive disorder and is receiving concomitant treatment with a strong CYP2D inhibitor. In some embodiments, the strong CYP2D6 inhibitor is paroxetine.

[0045] Some embodiments include a method of treating major depressive disorder in a patient receiving concomitant treatment with a strong CYP2D6 inhibitor, comprising administering to a human patient suffering from major depressive disorder and receiving concomitant treatment with a strong CYP2D inhibitor a daily dose of: (i) about 105 mg bupropion hydrochloride and (ii) about 45 mg dextromethorphan hydrobromide.

[0046] Some embodiments include a method of treating major depressive disorder in a patient known to be a poor metabolizer of CYP2D6, comprising administering to a human patient experiencing major depressive disorder and known to be a poor metabolizer of CYP2D6 a daily dose of: (i) about 105 mg bupropion hydrochloride and (ii) about 45 mg dextromethorphan hydrobromide.

[0047] Some embodiments include a method of treating major depressive disorder with an N-methyl D-aspartate (NMDA) receptor antagonist, comprising administering a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide no more than twice daily to a human patient experiencing major depressive disorder, wherein the dextromethorphan acts as a non-competitive antagonist of the NMDA receptor and a sigma-1 receptor agonist, and the human patient does not experience dissociation.

[0048] Some embodiments include a method of treating major depressive disorder in a human patient at risk for QT prolongation, comprising administering no more than twice daily to a human patient experiencing major depressive disorder and at risk for QT delay and torsade de pointes, a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide, wherein an electrocardiographic assessment of the QT interval is not performed on the human patient.

[0049] Some embodiments include a method of treating a patient suffering from major depressive disorder, comprising: administering a therapeutically effective amount of a combination of dextromethorphan and bupropion, wherein the patient has mild hepatic impairment as defined by Child-Pugh A or moderate hepatic impairment as defined by Child-Pugh B, and wherein the therapeutically effective amount is the same as an amount administered to a patient with normal liver function.

[0050] Some embodiments include a method of treating major depressive disorder, comprising: determining whether a human patient has liver damage; and

[0051] If the human patient has mild hepatic impairment as defined by Child-Pugh A or moderate hepatic impairment as defined by Child-Pugh B, administering to the human patient a combination of 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride twice daily; and

[0052] Avoid use of the combination of 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride in the human patient if the human patient has severe hepatic impairment as defined by Child-Pugh C. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 The effects of renal impairment, hepatic impairment, and CYP2D6 poor metabolizer status on the pharmacokinetics of a tablet containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride are depicted.

[0054] Figure 2 Depicted is the change from baseline in MADRS total score by week in human patients receiving tablets containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride twice daily. DETAILED DESCRIPTION

[0055] As noted above, the present disclosure is directed to administering a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride or a molar equivalent of dextromethorphan in free base form or another salt form; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in free base form or another salt form. For convenience, this combination is referred to herein as the "subject combination." In each instance in which the subject combination is mentioned herein, a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is specifically contemplated.

[0056] Strong CYP2D6 inhibitors include, but are not limited to, compounds such as fluoxetine, propafenone, quinidine, and paroxetine.

[0057] Dextromethorphan hydrobromide is a noncompetitive NMDA receptor antagonist and sigma-1 receptor agonist.

[0058] The chemical name of dextromethorphan hydrobromide is morphinan, 3-methoxy-17-methyl-, (9α, 13α, 14α), hydrobromide monohydrate. The empirical formula of dextromethorphan hydrobromide is C 18 H 25 NO·HBr·H2O, and the molecular weight is 370.33. The structural formula is:

[0059]

[0060] Dextromethorphan hydrobromide powder is white or almost white, crystalline, and slightly soluble in water.

[0061] Bupropion hydrochloride is an aminoketone and CYP450 2D6 inhibitor.

[0062] The chemical name of bupropion hydrochloride is: (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The empirical formula of bupropion hydrochloride is C 13 H 18 ClNO·HCl, and the molecular weight is 276.2. The structural formula is:

[0063]

[0064] Bupropion hydrochloride powder is white and very soluble in water.

[0065] The subject combination may be contained in an oral dosage form, including a tablet, such as an extended release tablet. In some embodiments, the subject combination is contained in a dosage form for oral administration and is available in the form of a round bilayer tablet.

[0066] In some embodiments, each tablet containing the subject combination contains 45 mg dextromethorphan hydrobromide in an immediate release formulation. In some embodiments, each tablet of the subject combination contains 105 mg bupropion hydrochloride in an extended release formulation. In some embodiments, each tablet of the subject combination contains 45 mg dextromethorphan hydrobromide in an immediate release formulation and 105 mg bupropion hydrochloride in an extended release formulation.

[0067] In some embodiments, tablets comprising the subject combination comprise l-cysteine ​​hydrochloride monohydrate. In some embodiments, tablets comprising the subject combination comprise carbomer homopolymer. In some embodiments, tablets comprising the subject combination comprise microcrystalline cellulose. In some embodiments, tablets comprising the subject combination comprise colloidal silicon dioxide. In some embodiments, tablets comprising the subject combination comprise cross-linked polyvinylpyrrolidone. In some embodiments, tablets comprising the subject combination comprise stearic acid. In some embodiments, tablets comprising the subject combination comprise magnesium stearate.

[0068] In some embodiments, a tablet containing the subject combination comprises the following inactive ingredients: l-cysteine ​​hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silicon dioxide, crospovidone, stearic acid, and magnesium stearate.

[0069] In some embodiments, the starting dose of the subject combination is 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride in one tablet administered once daily in the morning. In some embodiments, after 3 days, the dose is increased to one tablet (or one dosage form containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride) administered twice daily, for example at least 8 hours apart. In some embodiments, no more than two doses containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride are administered in the same day.

[0070] No dose adjustment is recommended in patients with mild hepatic impairment (Child-Pugh A) or moderate hepatic impairment (Child-Pugh B) compared to the dose recommended for patients with normal hepatic function.

[0071] The pharmacokinetics of the combination of 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride have not been evaluated in patients with severe hepatic impairment (Child-Pugh C). The combination of 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride is not recommended or should be avoided in patients with severe hepatic impairment.

[0072] The subject combination can be administered orally with or without food. In some embodiments, the tablet is swallowed whole, rather than crushed, split or chewed.

[0073] Patients with renal impairment may require special dosing.

[0074] In some embodiments, the renal impairment status of a subject can be determined by measuring the individual's "estimated glomerular filtration rate" or "eGFR." eGFR is calculated using the Modification of Diet in Renal Disease [MDRD] equation and is expressed in mL / min / 1.73 m 2 Unit:

[0075] (eGFR in mL / min) / 1.73m 2 = 175 × (serum creatinine in mg / dL) -1.154 × Age -0.203 ×0.742 (if female) ×1.212 (if black).

[0076] Additional details on the calculation of eGFR can be found, for example, in Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van Lente F: Chronic Kidney Disease Epidemiology Collaboration. Expressing the Modification of Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate with Standardized Serum Creatinine Values. Ann Intern Med. 2009; 150(9): 604-12.

[0077] Based on guidance from the U.S. Food and Drug Administration (FDA), renal impairment status is as follows.

[0078] Normal: eGFR ≥ 90 mL / min / 1.73 m 2

[0079] Mild: eGFR 60–89 mL / min / 1.73 m 2 (ie, ≥60 to <90)

[0080] Moderate: eGFR 30–59 mL / min / 1.73 m 2 (ie, ≥30 to <60)

[0081] Severe: eGFR 15–29 mL / min / 1.73 m 2 End-stage renal disease (ESRD) (i.e., ≥15 to <30) and not receiving hemodialysis: eGFR <15 mL / min / 1.73 m 2 and were not receiving hemodialysis or were receiving hemodialysis.

[0082] See Guidance for Industry Pharmacokinetics in Patients with Impaired Renal Function–Study Design, Data Analysis and Impact on Dosing and Labeling; USDepartment of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) February 2010. As used herein, a "renally impaired subject" may have mild, moderate, or severe renal impairment, or may have ESRD.

[0083] In some embodiments, for moderate renal impairment (estimated glomerular filtration rate (eGFR) or glomerular filtration rate (GFR) of 30 to 59 mL / min / 1.73 m 2 ), the recommended dosage of the subject combination is 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride or a daily dosage of a molar equivalent of another form of dextromethorphan and / or bupropion, such as one tablet (or a dosage form containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride) administered once daily, such as one tablet or other oral dosage form each morning, or a combination of 52.5 mg bupropion hydrochloride and about 22.5 mg dextromethorphan hydrobromide administered orally twice daily. In some embodiments, patients are monitored for adverse reactions that may be caused by dextromethorphan, such as drowsiness and dizziness.

[0084] Moderate renal impairment can be determined by an assay performed on a biological sample of the patient, such as a blood sample, such as an assay to determine creatinine levels. Serum creatinine levels from a blood sample can be used to estimate GFR.

[0085] Patients who concomitantly use the subject combination with a strong CYP2D6 inhibitor may need special dosing. The concomitant use of the subject combination with a strong CYP2D6 inhibitor increases the plasma concentration of dextromethorphan. In some embodiments, when co-administered with a strong CYP2D6 inhibitor, the recommended dose of the subject combination is one tablet once a day (or a dosage form containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride), such as one tablet or other oral dosage form every morning. In some embodiments, patients are monitored for adverse reactions that may be caused by dextromethorphan, such as drowsiness and dizziness.

[0086] Patients known to be CYP2D6 poor metabolizers (PM) may require special dosing. In some embodiments, the recommended dose for patients known to be CYP2D6 poor metabolizers is one tablet (or a dosage form containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride) once a day, such as one tablet or other oral dosage form every morning.

[0087] Special precautions may be required when switching a patient between a monoamine oxidase inhibitor (MAOI) antidepressant and the subject combination. In some embodiments, a period of at least 14 days must elapse between discontinuing an MAOI intended to treat depression and starting therapy with the subject combination. Conversely, in some embodiments, at least 14 days must be allowed after stopping the subject combination before starting a MAOI antidepressant.

[0088] There are data reporting the presence of bupropion and its metabolites in human breast milk. There are no data on the effects of bupropion or its metabolites on breast milk production. The limited data regarding the use of bupropion in lactating patients have not identified a clear association for adverse reactions in the breastfed infant.

[0089] Findings of neurotoxicity were observed in juvenile rats treated with a combination of dextromethorphan / quinidine on postnatal day (PND) 7 (which corresponds to the third trimester of gestation through the first few months of life and may extend into the first three years of life in humans). It is not known whether dextromethorphan is present in human milk. There are no data on the effects of dextromethorphan on breastfed infants or on milk production. Because of the potential for neurotoxicity, in some embodiments, patients should be advised that breastfeeding is not recommended during treatment with a combination of dextromethorphan and bupropion and for 5 days after the last dose.

[0090] In some embodiments, the human child of the patient receiving the subject combination is at risk for epilepsy. In some embodiments, the human child is about three years old or younger. In some embodiments, the human child of the patient receiving the subject combination is at risk for neurotoxicity.

[0091] For a lactating human mother, a combination of about 45 mg dextromethorphan hydrobromide and about 105 mg bupropion hydrochloride may be taken twice daily for about 1 week to about 6 weeks, about 6 weeks, or at least 6 weeks, followed by cessation of treatment for at least 5 days prior to initiation of breastfeeding of the child.

[0092] In some embodiments, after 5 days from the last dose of the combination, the breast milk produced by the human patient is substantially free of dextromethorphan.

[0093] In some embodiments, after 5 days from the last dose of the combination, the breast milk produced by the human patient is substantially free of bupropion.

[0094] In some embodiments, a human child of a patient receiving a subject combination is not exposed to detectable amounts of dextromethorphan during breastfeeding.

[0095] In some embodiments, a human child of a patient receiving a subject combination is not exposed to detectable amounts of bupropion during breastfeeding.

[0096] In some embodiments, the subject combination is administered to a human patient twice daily until the human patient experiences a decrease in the human patient's total MADRS score from baseline of at least about 7, at least about 11, at least about 13, or at least about 15.9. When the desired decrease in MADRS score is achieved, the human patient can stop treatment, wait at least 5 days, and then begin breastfeeding their child.

[0097] In some embodiments, the human child is a breastfed infant.

[0098] In some embodiments, a human patient experiences a greater reduction in the total MADRS score of the human patient from baseline after administration of the subject combination than the patient experiences when a placebo is administered. A human patient taking the subject combination may experience a greater reduction in MADRS score than when taking a placebo, for example, after 1 week of administration, after 2 weeks of administration, after 3 weeks of administration, after 4 weeks of administration, after 5 weeks of administration, after 6 weeks of administration, or other times.

[0099] In the subject combination, bupropion inhibits the metabolism of dextromethorphan via CYP2D6. When co-administered with bupropion, dextromethorphan exhibits nonlinear pharmacokinetics at steady state, with AUC and C max The changes in were greater than dose proportional and, for different doses of bupropion (75 to 150 mg), less than dose proportional.

[0100] When given in combination, steady-state plasma concentrations of dextromethorphan and bupropion are achieved within 8 days. The rate of accumulation of dextromethorphan at steady state is based on C max and AUC 0-12 are about 20 and about 32, respectively. The accumulation rate of bupropion at steady state is based on C max and AUC 0-12 They are 1.1 and 1.5 respectively.

[0101] After administration of the subject combination, the median T of dextromethorphan max is about 3 hours, while the median T of bupropion is maxThe C of hydroxybupropion metabolites max It occurs approximately 3 hours after dosing and is approximately 14 times the peak level of bupropion. The AUC of hydroxybupropion 0-12 It is about 19 times that of bupropion. C of erythrohydroxybupropion and threohydroxybupropion metabolites max The AUC values ​​for erythrohydroxybupropion and threohydroxybupropion are approximately 4 hours after administration and are approximately equal to and 5 times greater than those for bupropion, respectively. 0-12 The values ​​are about 1.2 times and about 7 times that of bupropion, respectively.

[0102] The subject combination may be taken with or without food. When the subject combination is administered with food, dextromethorphan C max and AUC 0-12 remained unchanged and decreased by 14%, respectively, while bupropion C max and AUC 0-12 An increase of 3% and 6% respectively.

[0103] Plasma protein binding of dextromethorphan is approximately 60-70%, and bupropion is 84%. Hydroxybupropion metabolites are protein bound to a similar extent as bupropion; whereas threohydroxybupropion metabolites are protein bound to about half the extent of bupropion.

[0104] Following 8 days of administration of the subject combination in extensive metabolizers, the mean elimination half-life of dextromethorphan was increased approximately 3-fold to approximately 22 hours compared to dextromethorphan administered without bupropion.

[0105] The mean elimination half-lives of dextromethorphan and bupropion are 22 hours and 15 hours, respectively. The apparent elimination half-lives of the hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion metabolites are approximately 35, 44, and 33 hours, respectively.

[0106] Esketamine is a noncompetitive NMDA receptor antagonist that is used in combination with an oral antidepressant to treat refractory depression in adults. Treatment of refractory depression is associated with the risk of dissociation. The labeling for esketamine states that, because of the risk of sedation and dissociation, patients must be monitored for at least 2 hours during each treatment period and then assessed to determine when the patient is considered clinically stable and ready to leave the health care setting.

[0107] Dissociation includes: delusional perception; depersonalization / derealization disorder; derealization; diplopia; dissociation; dysesthesia; sensation of cold; sensation of heat; sensation of temperature changes; hallucination; auditory hallucinations; visual hallucinations; hyperacusis; illusions; eye discomfort; oral dysesthesia; anesthesia of the mouth; anesthesia of the pharynx; photophobia; time perception altered; tinnitus; vision blurred; visual impairment.

[0108] The subject combination is a combination of dextromethorphan (a noncompetitive N-methyl D-aspartate (NDMA) receptor antagonist and sigma-1 receptor agonist) and bupropion (an aminoketone and CYP450 2D6 inhibitor) indicated for the treatment of major depressive disorder (MDD) in adults. Unlike esketamine, the subject combination can be administered in the absence of dissociation or dissociative events. In some embodiments, patients are not monitored for dissociation following administration of the subject combination.

[0109] The following information includes the kinds of dissociative and other effects that can be avoided by using the combination of dextromethorphan and bupropion.

[0110] In clinical trials, 48% to 61% of esketamine-treated patients developed sedation based on the Modified Observer's Assessment of Alertness / Sedation scale (MOAA / S), and 0.3% to 0.4% of esketamine-treated patients experienced loss of consciousness (MOAA / S score of 0). For the combination of dextromethorphan and bupropion, NMDA receptor antagonism can be achieved without a significant risk of sedation.

[0111] Because sedation may be delayed or prolonged, a healthcare provider must monitor patients receiving esketamine for at least 2 hours during each treatment period, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting. Such monitoring is not required for treatment with the subject combination of dextromethorphan and bupropion.

[0112] In cases where esketamine is used concomitantly with CNS depressants, patients treated with esketamine must be closely monitored for sedation. Such monitoring is not required for treatment with the subject combination of dextromethorphan and bupropion.

[0113] Esketamine is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). For the subject combination of dextromethorphan and bupropion, no such restrictions are required.

[0114] The most common psychological effects of esketamine are dissociative changes and / or perceptual changes (including distortions and illusions of time and space), derealization, and depersonalization (based on the Clinician-Administered Dissociative States Scale, 61% to 84% of esketamine-treated patients develop dissociative changes or perceptual changes). Given its potential to induce dissociative effects, psychotic patients must be carefully evaluated before esketamine is administered. Such an evaluation is not required for treatment with the theme combination of dextromethorphan and bupropion. Treatment with esketamine should only be initiated if the benefits outweigh the risks. In the case of treatment with the theme combination of dextromethorphan and bupropion, such a restriction is not required.

[0115] Due to the risk of dissociation, a healthcare provider must monitor patients receiving esketamine treatment for at least 2 hours during each treatment period, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting. For treatment with the subject combination of dextromethorphan and bupropion, no such monitoring, assessment, or restrictions are required.

[0116] Dissociation includes: delusional perception (including distortions of space and time and illusions); depersonalization / derealization disorder; derealization; diplopia; dissociation; dysesthesia; sensation of cold; sensation of heat; sensation of temperature changes; hallucinations; auditory hallucinations; visual hallucinations; mixed hallucinations; hyperacusis; hallucinations; eye discomfort; oral dysesthesia; paresthesia; oral paresthesia; pharyngeal paresthesia; photophobia; altered time perception; tinnitus; blurred vision; and visual impairment.

[0117] Esketamine is a Schedule III controlled substance (CIII) and has the potential for abuse and inappropriate diversion. The combination of dextromethorphan and bupropion is not a controlled substance. Each patient must be assessed for risk of abuse or misuse prior to prescribing, and all patients receiving esketamine must be monitored for the development of these behaviors or conditions, including drug-seeking behaviors, during treatment. No such monitoring or assessment is required for treatment with the subject combination of dextromethorphan and bupropion.

[0118] Esketamine is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), and is referred to as the esketamine REMS because of the risks of serious adverse outcomes from sedation, dissociation, and abuse and misuse. For the subject combination of dextromethorphan and bupropion, no such restrictions are required.

[0119] Important requirements of the esketamine REMS include the following:

[0120] Healthcare settings must be accredited by the program and ensure that esketamine:

[0121] – For distribution and administration only in healthcare settings.

[0122] - Patients treated in outpatient settings (eg, medical offices and clinics) must be enrolled in the program.

[0123] - Administered by the patient under the direct observation of a healthcare provider, who monitors the patient for at least 2 hours after administration of esketamine.

[0124] None of these requirements apply to the combination of dextromethorphan and bupropion.

[0125] The safety of esketamine was evaluated in 262 adults from two Phase 3 studies (Study 3 and Study 4) and one Phase 2 study for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.

[0126] Sedation was assessed by adverse event reporting and the Modified Observer Assessment of Alertness / Sedation (MOAA / S). In the MOAA / S, a score of 5 means "responds readily to name spoken in normal tone"; a score of 0 means "no response after painful squeeze of the trapezius muscle"; a score of 4 means "sluggish response to name spoken in normal tone"; a score of 3 means "responds only after name spoken loudly and / or repeatedly"; a score of 2 means "responds only after mild prodding or shaking"; and a score of 1 means "no response to mild prodding or shaking". Any decrease in the MOAA / S score from predose is considered to indicate the presence of sedation, and in short-term refractory depression (TRD) studies, this decrease occurred in more patients receiving esketamine than in those receiving placebo. A dose-related increase in the incidence of sedation (MOAA / S score <5) was observed in fixed-dose TRD studies. Table 1 presents the incidence of sedation (MOAA / S score <5) in the fixed-dose study in adult patients with TRD <65 years of age and in the flexible-dose study in patients with TRD ≥65 years of age.

[0127] Table 1: Incidence of Sedation (MOAA / S Score <5) in Double-Blind, Randomized, Placebo-Controlled Studies (Fixed-Dose Study in Adults <65 Years with Treatment-Resistant Depression and Flexible-Dose Study in Patients ≥65 Years with Treatment-Resistant Depression)

[0128]

[0129] *Patients evaluated using MOAA / S

[0130] In studies of treatment of depressive symptoms in adults with MDD and acute suicidal ideation or behavior, the incidence of sedation (MOAA / S score <5) was higher in patients treated with esketamine plus an oral antidepressant compared with patients treated with placebo plus an oral antidepressant (AD), which is similar to the findings in studies of treatment-resistant depression in Table 1.

[0131] Dissociation / perception changes

[0132] Esketamine may cause dissociative symptoms (including derealization and depersonalization) and perceptual changes (including distortion and illusion of time and space). In clinical trials, dissociation was temporary and occurred on the day of administration. Dissociation was evaluated by adverse event reports and the Dissociative State Scale (CADSS) managed by clinicians. A CADSS total score of more than 4 indicates the presence of dissociative symptoms, and during the short-term refractory depression study, the number of patients receiving esketamine who had this score increase to 4 or more was more than that of patients receiving placebo. In a fixed-dose refractory depression study, a dose-related increase in the incidence of dissociative symptoms (CADSS total score>4 and change>0) was observed. Table 2 presents the incidence of dissociation (CADSS total score>4 and change>0) in a fixed-dose study of adult patients <65 years of age with refractory depression and in a flexible-dose study of patients ≥65 years of age with refractory depression.

[0133] Table 2: Incidence of Dissociation (CADSS Total Score >4 and Change >0) in Double-Blind, Randomized, Placebo-Controlled Studies (Fixed-Dose Study in Adult Patients <65 Years with Treatment-Resistant Depression and Flexible-Dose Study in Patients ≥65 Years with Treatment-Resistant Depression)

[0134]

[0135]

[0136] *Number of patients evaluated using CADSS

[0137] In a study of treating depressive symptoms in adults with MDD and acute suicidal ideation or behavior, patients treated with esketamine plus an oral AD also demonstrated a higher percentage of patients with dissociation (CADSS total score >4 and change >0) (84%) compared to patients treated with placebo plus an oral AD (16%).

[0138] Because the subject combination can be administered without dissociation or dissociative events, it has a reduced risk of abuse compared to esketamine. Abuse is the intentional, non-therapeutic use of a drug, even if only once, to achieve a desired psychological or physiological effect. Clinical studies conducted on the combination of dextromethorphan and bupropion did not show drug-seeking behavior, but these observations were not systematic. Therefore, patients with a history of drug abuse may be closely observed for signs of misuse or abuse of the subject combination of dextromethorphan and bupropion (e.g., development of tolerance, escalation of dosage, drug-seeking behavior).

[0139] Unlike the combination of quinidine and dextromethorphan, the subject combination did not prolong the QT interval to any clinically relevant extent at a dose of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide given twice daily. Therefore, electrocardiographic evaluation of the QT interval is not routinely performed on human patients who are experiencing major depressive disorder and are at risk for QT prolongation and torsades de pointes.

[0140] The topic combination can be used as an adjunctive treatment for major depressive disorder or depression.

[0141] In addition to major depressive disorder, the subject combinations can also be used to treat other diseases of the condition in the patient population or situation described herein. For example, the subject combinations can be used to treat pain or neurological disorders. Examples of neurological disorders that can be treated with the subject combinations include, but are not limited to, affective disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, epilepsy, and headaches.

[0142] Affective disorders that may be treated by the subject combinations include, but are not limited to, depression, major depression, refractory depression, refractory bipolar depression, bipolar disorder including cyclothymia, seasonal affective disorder, mood disorders, chronic depressive disorder (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH) and attention deficit / hyperactivity disorder (AD / HD), bipolar disorder and mania, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychotic dysfunction, pseudobulbar mood, and mood lability.

[0143] Depression can be manifested by depressive symptoms. These symptoms can include psychological changes (such as mood changes), feelings of extreme sadness, despair, mental dullness, difficulty concentrating, pessimistic worries, agitation, anxiety, irritability, guilt, anger, worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-depreciation. The physical symptoms of depression can include insomnia, anorexia, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, irritability, aches, pains, headaches, cramps, digestive problems, and / or abnormal hormonal circadian rhythms.

[0144] Mental disorders that can be treated by the subject combination include, but are not limited to: anxiety disorders, including, but not limited to, phobia, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic-depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, paranoia, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease. Alzheimer's disease can also be referred to as Alzheimer's dementia. Other neurobehavioral symptoms of Alzheimer's disease that can be treated include disinhibition and emotional indifference.

[0145] Agitation may occur in Alzheimer's disease as the disease progresses. Agitation may present itself as inappropriate verbal, emotional, and / or physical behavior. Inappropriate behavior may include, but is not limited to, incoherent babbling, inappropriate emotional responses, demands for attention, threats, irritability, frustration, screaming, repetitive questioning, mood swings, swearing, abusive language, physical outbursts, emotional distress, restlessness, tearing, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body movements, hoarding, stalking, hitting, scratching, biting, aggressiveness, hyperactivity, and / or kicking.

[0146] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral and psychological symptoms (including agitation). AD is the most common form of dementia and afflicts approximately 6 million individuals in the United States, a figure that is expected to increase to approximately 14 million by 2050. It is reported that up to 70% of AD patients suffer from agitation and are characterized by emotional distress, aggressive behavior, destructive irritability, and disinhibition. Managing agitation is a priority for AD. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, early nursing home placement, and increased mortality. There is currently no therapy approved by the FDA for the treatment of agitation in AD patients.

[0147] It is known that neurobehavioral symptoms may occur during dementia, and it can be treated by the combination. Compared to the patient's cognitive impairment, caregivers or family members may feel more unbearable due to the patient's behavior / psychological symptoms. The common form of syndrome includes Alzheimer's disease, vascular dementia, Lewy body (abnormal protein aggregates formed in nerve cells) dementia and a group of diseases causing frontotemporal dementia (degeneration of the frontal lobe of the brain). The symptoms that dementia patients have are similar to the symptoms of mental disorders, but slightly different from each other. The neurobehavioral symptoms associated with dementia include depression, apathy, agitation, disinhibition, hallucinations, delusions, psychosis, impulse, aggressiveness, compulsion, hypersexuality and personality disorders. Neurobehavioral symptoms may also be found in other conditions (such as traumatic brain injury), such as disinhibition.

[0148] Agitation in patients with Alzheimer's disease can be assessed using the Cohen Mansfield Agitation Inventory (CMAI). The CMAI assesses a variety of behaviors, including hitting (including self-hitting), kicking, grabbing, pushing, throwing, biting, scratching, spitting, hurting self or others, tearing or destroying property, engaging in physical advances, pacing, wandering aimlessly, dressing inappropriately or undressing, trying to go to different places, intentionally falling down, eating or drinking inappropriate substances, handling things inappropriately, hiding things, hoarding things, engaging in repetitive quirks, general irritability, screaming, engaging in verbal advances, swearing or verbal aggression, repeating sentences or questions, making strange noises (laughing or crying), whining, being negative, and constantly asking for attention or help without reason.

[0149] Schizophrenia may be treated by a combination of positive and / or negative symptoms of schizophrenia, or residual symptoms of schizophrenia. Other conditions that may be treated include intermittent explosive disorder.

[0150] The brain dysfunction that can be treated by the subject combination includes but is not limited to the disease related to intellectual disability, such as senile dementia, Alzheimer's dementia, amnesia, amnesia / amnesia syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech disorder, voice spasm, Parkinson's disease, Lennox-Gastaut syndrome, autism, hypermobility syndrome and schizophrenia. Brain dysfunction also includes the disease caused by cerebrovascular disease, and the cerebrovascular disease includes but is not limited to apoplexy, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head injury, etc., wherein symptoms include impaired consciousness, senile dementia, coma, decreased attention and speech disorder.

[0151] Substance addictions that can be treated by the subject combination include, but are not limited to, drug dependence, cocaine addiction, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, antianxiety and hypnotic drugs, cannabis, marijuana, amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking, cigars and / or pipes, e-cigarettes or vaping, and chewing cigarette addiction.

[0152] Movement disorders that may be treated by the subject combinations include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's disease chorea, chorea rheumatica, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette's syndrome and Wilson's disease.

[0153] Dementias that may be treated by the subject combinations include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff Syndrome, and Pick's disease.

[0154] Motor neuron diseases that may be treated by the subject combinations include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sachs disease, Sandoff disease, and hereditary spastic paraplegia.

[0155] Neurodegenerative diseases that may be treated by the subject combinations include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CHD), and schizophrenia. disease, CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0156] Epileptic disorders that may be treated by the subject combinations include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile convulsions; partial seizures, including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsy continua partial; generalized seizures, including, but not limited to, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0157] Headache types that may be treated by the subject combination include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0158] Other neurological conditions that may be treated by the subject combinations include Rett Syndrome, autism, tinnitus, impaired consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; voice disorders caused by uncontrolled laryngeal muscle spasms, including but not limited to abductor spasmodic dysphonia, adductor spasmodic dysphonia, musculartension dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence, including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0159] In some embodiments, the subject combinations may be used to treat pain, joint pain, pain associated with sickle cell disease, pseudobulbar mood, depression (including refractory depression), disorders related to memory and cognition, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rhett syndrome, seizures, cough (including chronic cough), and the like.

[0160] In some embodiments, the subject combinations may be administered orally to relieve musculoskeletal pain, including low back pain, as well as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, periarticular disorders, axial spondyloarthritis (including ankylosing spondylitis), Paget's disease, fibrous dysplasia, SAPHO syndrome, transient hip osteoarthritis, vertebral compression fractures, osteoporosis, and the like.

[0161] In some embodiments, the subject combinations may be administered to relieve inflammatory pain, including musculoskeletal pain, arthritic pain, and complex regional pain syndrome.

[0162] Arthritis refers to inflammatory joint diseases that may be associated with pain. Examples of arthritis pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, periarticular disease, neuropathic arthropathy (including Charcot foot), axial spondyloarthritis (including ankylosing spondylitis), and SAPHO syndrome.

[0163] In some embodiments, the subject combinations are used to treat chronic musculoskeletal pain.

[0164] In some embodiments, the subject compositions may be administered to relieve complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is a type of inflammatory pain. CRPS may also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the limbs, which may be accompanied by edema and autonomic, motor and sensory changes.

[0165] In some embodiments, the subject compositions may be administered orally to relieve neuropathic pain.

[0166] Examples of neuropathic pain include pain caused by diabetic peripheral neuropathy or diabetic peripheral neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, central pain, pain caused by multiple sclerosis, etc. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and radiation or chemotherapy-related neuropathy, etc.

[0167] In some embodiments, the subject compositions may be administered to relieve fibromyalgia.

[0168] In some embodiments, the subject compositions may be co-administered with one or more strong inhibitors of CYP2D6. It has been found that concomitant use of the subject compositions with one or more strong CYP2D6 inhibitors increases the plasma concentration of dextromethorphan. Therefore, it is recommended to monitor patients for adverse effects or reactions that may be caused by dextromethorphan, such as drowsiness and dizziness.

[0169] When the subject combination is co-administered with one or more strong inhibitors of CYP2D6, it may be necessary to adjust the dosage. Adjusting the bupropion and / or dextromethorphan in the subject combination to a lower dosage or reducing the frequency of administration of the subject combination can reduce adverse effects or reactions in the patient, such as, but not limited to, drowsiness, dizziness, or a combination thereof. For example, when co-administered with one or more strong CYP2D6 inhibitors, the recommended dosage of the subject combination is one tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride once a day (such as once a day in the morning).

[0170] Compared with twice daily administration of the same number of days of the subject combination, once daily application of the subject combination to the patient receiving the strong CYP2D6 inhibitor of following can reduce adverse effects, such as but not limited to drowsiness, dizziness or its combination. In some embodiments, reducing the dosage or administration frequency of the subject combination can reduce drowsiness. In some embodiments, reducing the dosage or administration frequency can alleviate dizziness. Since dizziness may be relevant to falling, the dosage adjustment of the subject combination to a lower amount or lower administration frequency can reduce the risk of falling of the patient taking the subject combination. For example, twice daily administration of the same number of days of the subject combination can reduce the risk of falling of the patient taking the subject combination. For example, for elderly patients or patients suffering from dementia (such as Alzheimer's disease), this may be very important.

[0171] In some embodiments, the subject compositions can be administered to patients with moderate renal impairment. As explained herein, administration of the subject compositions to CYP2D6 poor metabolizers increases plasma concentrations of dextromethorphan compared to patients who are not CYP2D6 poor metabolizers. Therefore, it is recommended to monitor patients for adverse effects or reactions that may be caused by dextromethorphan, such as drowsiness and dizziness.

[0172] When the patient suffers from moderate renal impairment, the dosage may need to be adjusted. Adjusting the bupropion and / or dextromethorphan in the subject combination to a lower dosage or reducing the frequency of administration of the subject combination can reduce the patient's adverse effects or adverse reactions or reduce the risk of adverse effects or adverse reactions, such as but not limited to drowsiness, dizziness, or a combination thereof. For example, when administered to a patient with moderate renal impairment, the recommended dosage of the subject combination is one tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride once a day (such as once a day in the morning).

[0173] Compared with twice daily administration of the same number of days of the theme combination, once a day administration of the theme combination to the patient suffering from moderate renal impairment can reduce adverse effects or reduce the risk of adverse effects, such as but not limited to drowsiness, dizziness or its combination. In some embodiments, reducing the dosage or administration frequency of the theme combination may reduce drowsiness. In some embodiments, reducing dosage or administration frequency can alleviate dizziness. Because dizziness may be relevant to falling, the dosage of the theme combination is adjusted to a lower amount or lower administration frequency may reduce the risk of the patient taking the theme combination falling. For example, compared with twice daily administration of the same number of days of the theme combination, once a day administration of the theme combination can reduce the risk of the patient falling. For example, for elderly patients or patients suffering from dementia (such as Alzheimer's disease), this may be very important.

[0174] The term "treatment" includes the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals, or activities that otherwise affect the structure or any function of the body of humans or other animals.

[0175] The subject combination may be used to treat any disease or condition identified in the following U.S. Patents as treatable by a combination of bupropion and dextromethorphan: 8,569,328, 9,168,234, 9,189,905, 9,205,083, 9,238,032, 9,278,095, 9,314,462, 9,370,513, 9,375,429, 9,408,815, 9,421,176, 9,4 57,023、9,457,025、9,474,731、9,486,450、9,700,528、9,700,553、9,707,191、9,763,932、9,861,595、9,867,819、9,968,568、10,058,518、10,064,857、10,080,727、10,092,560、10,092,561、 10,105,327、10,105,361、10,251,879、10,463,634、10,512,643、10,548,857、10,596,167、10,772,850、10,780,064、10,780,066、10,786,469、10,786,496、10,799,497、10,806,710、10,864, 209, 10,874,663, 10,874,664, 10,874,665, 10,881,624, 10,881,657, 10,894,046, 10,894,047, 10,898,453, all of which are incorporated herein by reference in their entirety, including the specific embodiments and combinations described therein, because they disclose diseases that can be treated by a combination of bupropion and dextromethorphan.

[0176] The following U.S. provisional applications are also incorporated by reference in their entirety: Serial No. 63 / 359,143 filed on July 7, 2022; Serial No. 63 / 370,592 filed on August 5, 2022; Serial No. 63 / 396,182 filed on August 8, 2022; Serial No. 63 / 373,040 filed on August 19, 2022; and Serial No. 63 / 401,541 filed on August 26, 2022.

[0177] Example 1

[0178] In a combined study of seven subjects with moderate (GFR 30-60 mL / min) renal impairment compared to six matched controls with normal renal function (matched for sex, age, and weight range of the impaired subjects), exposure to both dextromethorphan and bupropion increased approximately 2-fold and clearance decreased by 50%.

[0179] Example 2

[0180] Approximately 7% to 10% of Caucasians and 3% to 8% of African Americans lack the ability to metabolize CYP2D6 substrates and are classified as poor metabolizers. In the 3 poor metabolizers, the pharmacokinetics of the subject combination resulted in a decrease in the C of dextromethorphan compared with the extensive metabolizers. max and AUC 0-12 An increase of approximately 3-fold and 3.4-fold, respectively. Exploration of steady-state kinetic data in 12 poor metabolizers treated with the subject combination in the efficacy trial showed that plasma concentrations of dextromethorphan were generally higher than the exposure of non-poor metabolizers.

[0181] Example 3

[0182] Co-administration of the SSRI paroxetine and a subject combination comprising dextromethorphan and bupropion was studied in 29 healthy volunteers. Paroxetine increased the overall exposure of dextromethorphan by 2.5-fold and had no effect on bupropion. When co-administered with the subject combination, the overall exposure of paroxetine increased by 1.2-fold. Based on these results, when the subject combination is prescribed with a drug that inhibits CYP2D6, the subject combination should be administered once daily. Be cautious when administering the subject combination in conjunction with a drug that is extensively metabolized by CYP2D6.

[0183] Example 4

[0184] Tablets for oral administration are prepared. The tablets are round bilayer tablets. Each tablet contains 45 mg of dextromethorphan hydrobromide (equivalent to 32.98 mg of dextromethorphan free base) in an immediate release formulation and 105 mg of bupropion hydrochloride (equivalent to 91.14 mg of bupropion free base) in an extended release formulation. Each tablet contains the following inactive ingredients: carbomer homopolymer, colloidal silicon dioxide, crospovidone, monocaprylic and capric glyceride, L-cysteine ​​hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide and / or yellow iron oxide.

[0185] Example 5

[0186] The properties of the Example 4 tablet containing a combination of dextromethorphan hydrobromide, which is a noncompetitive NMDA receptor antagonist and sigma-1 receptor agonist, and bupropion hydrochloride, which is an aminoketone and CYP450 2D6 inhibitor, were investigated.

[0187] The effects of renal impairment, hepatic impairment, and CYP2D6 poor metabolizer status on the exposure of the tablets of Example 4 are summarized in Figure 1 middle.

[0188] Figure 1 The results depicted in are based on plasma concentrations in human patients after 8 days of twice daily administration of tablets containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride. Data are GMRs and 90% CIs. The references used were matched healthy subjects studied for renal and hepatic impairment, respectively, and CYP2D6 extensive or super metabolizers. AUC denotes area under the plasma concentration-time curve from zero to 12 hours; BUP denotes bupropion; CI denotes confidence interval; C max is maximum plasma concentration; DM, dextromethorphan; GMR, geometric mean ratio; PK, pharmacokinetics.

[0189] exist Figure 1 In the results, the results for patients with moderate renal impairment were identified as "Group 1", the results for patients with moderate hepatic impairment were identified as "Group 2", and the results for patients who were poor metabolizers of CYP2D6 were identified as "Group 3". The results are summarized in Table 1 below.

[0190] Table 1

[0191]

[0192]

[0193] For example, in patients with moderate hepatic impairment (Group 2), the AUCs of dextromethorphan and bupropion were 0-12 and C max There was no significant difference compared with healthy patients.

[0194] AUC of dextromethorphan in patients with moderate hepatic impairment and healthy subjects 0-12 The mean ratio was 1.17, with a 90% confidence interval of 0.85-1.61.

[0195] C of dextromethorphan in patients with moderate hepatic impairment and healthy subjects max The mean ratio was 1.21, with a 90% confidence interval of 0.90-1.62.

[0196] AUC of bupropion in patients with moderate hepatic impairment and healthy subjects 0-12 The mean ratio was 1.36, with a 90% confidence interval of 0.86–2.15.

[0197] C of bupropion in patients with moderate hepatic impairment and healthy patients max The mean ratio was 1.44 with a 90% confidence interval of 0.90–2.30.

[0198] Based on these results, no dose adjustment is recommended in patients with known mild or moderate hepatic impairment.

[0199] In patients with moderate renal impairment, dextromethorphan AUC was observed 0-12 Increased 2.21 times, dextromethorphan C max Increased 2.10 times, bupropion AUC 0-12 Increased by 1.80 times, and bupropion C max Increased by 1.87 times.

[0200] Based on these results, dosage adjustments are recommended in patients known to have moderate renal impairment because these patients have higher concentrations of dextromethorphan and bupropion than patients with healthy renal function. For patients known to have moderate renal impairment, the recommended total daily dose is about 45 mg dextromethorphan hydrobromide and about 105 mg bupropion hydrochloride (e.g., one tablet containing about 45 mg dextromethorphan hydrobromide and about 105 mg bupropion hydrochloride for administration once daily, such as in the morning) or an equivalent dose of another form of dextromethorphan and / or bupropion.

[0201] Example 5

[0202] The effect of concomitant administration of 20 mg of paroxetine on dextromethorphan exposure was determined for patients taking the tablets of Example 4 containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride twice daily. Dextromethorphan AUC was 2.34 % (95% CI, 2.1-3.3) compared to patients taking the tablets twice daily without paroxetine. 0-12 Increased by 2.69 times, and dextromethorphan C max Increased by 2.38 times.

[0203] Example 6

[0204] The efficacy of the tablet of Example 4 for treating major depressive disorder in adults was demonstrated in a placebo-controlled clinical study (Study 1). In this study, adult patients (18 to 65 years old) who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for MDD were randomized to receive the tablet of Example 1 ("DM / BU", 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride) (N=156) twice daily or placebo (N=162) twice daily for 6 weeks. The average age of the patients in Study 1 was 41 years old, and 67% were female, 55% were Caucasian, 35% were black, and 5% were Asian. Here, "N" represents the number of adult patients.

[0205] The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MTRS). Depression Rating Scale, MADRS) total score from baseline to the 6th week change.MADRS is a scale rated by clinicians, which is used to assess the severity of depressive symptoms.According to 10 projects, patients are rated to assess sadness, inner tension, reduced sleep or loss of appetite, difficulty in concentrating, laziness, lack of interest, pessimism and suicidal tendencies.The scoring range of MADRS is 0 to 60, and the higher the score, the more serious the depression is.As measured by the decline of MADRS total score during the 6th week, DM / BU is statistically significantly superior to placebo in improving depressive symptoms (referring to Table 1).

[0206] Table 1: Primary efficacy results for change from baseline in MADRS total score at week 6 in adults with MDD

[0207]

[0208] SD = standard deviation; SE = standard error; LS mean = least squares mean; CI = confidence interval.

[0209] a Drug – Placebo

[0210] Weekly changes from baseline in MADRS total score are shown in Figure 1 The changes in MADRS total score from baseline to Week 1 and from baseline to Week 2 were prespecified secondary efficacy endpoints. The differences in the changes from baseline in MADRS total score between DM / BU and placebo were statistically significant at Week 1 and Week 2.

[0211] Examination of demographic subgroups by age, sex, and race did not reveal differences in response.

[0212] Unless otherwise indicated, all numbers used in the specification and claims to indicate the quantity of components, properties such as amounts, percentages, etc. should be understood in all cases to indicate both the exact value shown and the value modified by the term "about". Therefore, unless otherwise indicated, the numerical parameters listed in the specification and the attached claims are approximate values, which may vary depending on the desired properties to be obtained. At a minimum, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be interpreted in accordance with the number of reported significant digits and applying customary rounding techniques.

[0213] The use of the terms "comprising," "containing," or "including" herein also encompasses the use of "consisting essentially of" or "consisting of" in its place.

[0214] The affirmative recitation of elements anywhere herein should be understood to contemplate both the inclusion and exclusion of the elements.

[0215] Unless otherwise indicated herein or clearly contradicted with the context, the terms "one", "said" and similar references used in the context of describing the embodiment (especially in the context of the following claims) should be interpreted as covering singular and plural forms. Unless otherwise indicated herein or clearly contradicted with the context, all methods described herein can be performed in any suitable order. The use of any and all embodiments or exemplary language (e.g., "such as") provided herein is only intended to better illustrate the embodiment and does not limit the scope of any claim. Any language in this specification should not be interpreted as indicating that any unclaimed element is necessary for practicing the claim.

[0216] The grouping of alternative elements or embodiments disclosed herein should not be interpreted as limiting. Each group member may be mentioned and claimed individually, or mentioned and claimed in any combination with other members of the group or other elements found herein. For reasons of convenience and / or accelerating the application process, one or more members in the expected group may be included in the group or deleted from the group. When any such inclusion or deletion occurs, this specification is considered to include the modified group, so if used in the appended claims, the written description of all Markush groups is met.

[0217] Certain embodiments are described herein, including the best mode known to the inventor for implementing the claimed embodiments. Of course, variations of these described embodiments will be apparent to those of ordinary skill in the art after reading the foregoing description. The inventors expect that the skilled person will adopt such variations as appropriate, and the inventors expect that the claimed embodiments can be practiced in a manner other than the manner specifically described herein. Therefore, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. In addition, unless otherwise indicated herein or clearly contradicted by the context, any combination of the above elements of all possible variations is contemplated.

[0218] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Therefore, by way of example and not limitation, alternative embodiments may be used in accordance with the teachings herein. Therefore, the claims are not limited to the embodiments exactly shown and described.

Claims

1. A method of treating a human patient suffering from a neurological condition by administering a combination of dextromethorphan and bupropion, the method comprising: orally administering to the human patient daily a dosage form comprising: 105 mg or less of bupropion hydrochloride or a molar equivalent of bupropion as a free base or another salt form, and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan as a free base or another salt form, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; wherein the human patient is selected as having: 1) suffering from the neurological condition, and 2) suffering from moderate renal impairment, wherein the human patient is determined to have moderate renal impairment by assay of a biological sample from the patient; and wherein the risk of somnolence and dizziness to the human patient after administering the dosage form containing the combination to the human patient with moderate renal impairment once daily is lower than the risk of somnolence and dizziness to the human patient when the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is administered to the human patient twice daily for the same number of days.

2. The method of claim 1, wherein the patient is orally administered a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide once daily.

3. The method of claim 1, wherein the patient is orally administered a combination of about 52.5 mg bupropion hydrochloride and about 22.5 mg dextromethorphan hydrobromide twice daily.

4. A method of treating a human patient with a combination of dextromethorphan and bupropion, wherein the human patient is experiencing a neurological condition, the method comprising the steps of: Whether the human patient has moderate renal impairment is determined by: obtaining or having obtained a biological sample from said patient; as well as performing or having performed an assay on the biological sample to determine whether the human patient has moderate renal impairment; as well as if the human patient has moderate renal impairment, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; if the human patient does not suffer from renal impairment, orally administering to the patient twice daily a dosage form containing a combination of 105 mg bupropion hydrochloride or a molar equivalent of bupropion as a free base or another salt form and 45 mg dextromethorphan hydrobromide or a molar equivalent of dextromethorphan as a free base or another salt form; wherein the risk of somnolence and dizziness to the human patient following once daily administration of the dosage form containing the combination to the human patient with moderate renal impairment is lower than the risk of somnolence and dizziness to the human patient when the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is administered to the human patient twice daily for the same number of days.

5. A method of treating a human patient experiencing a neurological condition, the method comprising the steps of: a) determining whether the human patient is at risk for an adverse event associated with overexposure to dextromethorphan by: obtaining or having obtained a biological sample from the human patient; and performing or having performed an assay on the biological sample to determine whether the human patient has moderate renal impairment, wherein a result that the human patient has moderate renal impairment indicates that the human patient is at risk for an adverse event associated with overexposure to dextromethorphan; as well as b) if the human patient is at risk for an adverse event associated with overexposure to dextromethorphan, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and c) if the human patient is not at risk for an adverse event associated with overexposure to dextromethorphan, orally administering to the patient twice daily a dosage form containing a combination of 105 mg of bupropion hydrochloride, or a molar equivalent of bupropion as the free base or another salt form, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan as the free base or another salt form.

6. A method of treating a neurological condition using a combination of dextromethorphan and bupropion, comprising: orally administering to a patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and wherein the human patient is selected as having: 1) suffering from the neurological condition, and 2) suffering from moderate renal impairment, wherein the human patient is determined to have moderate renal impairment by assay of a biological sample from the patient; and wherein the human patient has a lower risk of an adverse event than the human patient would have if the dosage form were administered to the patient twice daily.

7. A method of treating a human patient with a combination of dextromethorphan and bupropion, wherein the human patient is experiencing a neurological condition, the method comprising the steps of: Whether the human patient has moderate renal impairment is determined by: obtaining or having obtained a biological sample from said patient; as well as performing or having performed an assay on the biological sample to determine whether the human patient has moderate renal impairment; as well as If the human patient has moderate renal impairment, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and If the human patient does not suffer from renal impairment, a dosage form containing a combination of 105 mg bupropion hydrochloride or a molar equivalent of bupropion as a free base or another salt form and 45 mg dextromethorphan hydrobromide or a molar equivalent of dextromethorphan as a free base or another salt form is orally administered to the patient twice daily.

8. A method of treating a human patient suffering from a neurological condition by administering a combination of dextromethorphan and bupropion, the method comprising: orally administering to the patient once daily a dosage form comprising: 105 mg or less of bupropion hydrochloride or a molar equivalent of bupropion as a free base or another salt form, and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan as a free base or another salt form, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; wherein the human patient is selected as having: 1) suffering from the neurological condition, and 2) suffering from moderate renal impairment, wherein the human patient is determined to have moderate renal impairment by assay of a biological sample from the patient; and wherein the risk of drowsiness or dizziness to the human patient following once daily administration of the dosage form containing the combination to the human patient with moderate renal impairment is lower than the risk of drowsiness or dizziness to the human patient when the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is administered to the human patient twice daily for the same number of days.

9. The method of claim 8, wherein the patient is orally administered a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide once daily.

10. The method of claim 8, wherein the patient is orally administered a combination of about 52.5 mg bupropion hydrochloride and about 22.5 mg dextromethorphan hydrobromide twice daily.

11. A method of treating a human patient with a combination of dextromethorphan and bupropion, wherein the human patient is experiencing a neurological condition, the method comprising the steps of: Whether the human patient has moderate renal impairment is determined by: obtaining or having obtained a biological sample from said patient; as well as performing or having performed an assay on the biological sample to determine whether the human patient has moderate renal impairment; as well as if the human patient has moderate renal impairment, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; if the human patient does not suffer from renal impairment, orally administering to the patient twice daily a dosage form containing a combination of 105 mg bupropion hydrochloride or a molar equivalent of bupropion as a free base or another salt form and 45 mg dextromethorphan hydrobromide or a molar equivalent of dextromethorphan as a free base or another salt form; wherein the risk of drowsiness or dizziness to the human patient following once daily administration of the dosage form containing the combination to the human patient with moderate renal impairment is lower than the risk of drowsiness or dizziness to the human patient when the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is administered to the human patient twice daily for the same number of days.

12. The method of claim 11, wherein if the human patient suffers from moderate renal impairment, a dosage form containing a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is orally administered to the patient once daily.

13. The method of claim 11, wherein if the human patient suffers from moderate renal impairment, a dosage form containing a combination of about 52.5 mg bupropion hydrochloride and about 22.5 mg dextromethorphan hydrobromide is orally administered to the patient twice daily.

14. A method of treating major depressive disorder in a human patient with moderate renal impairment, comprising administering to said human patient with moderate renal impairment and experiencing major depressive disorder a daily dose of: (i) from about 100 mg to about 110 mg of bupropion hydrochloride or a molar equivalent of dextromethorphan in free base form or another salt form; and (ii) from about 40 mg to about 50 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in free base form or another salt form, wherein said daily dose is optionally administered in a dosage form.

15. The method of claim 14, wherein the bupropion and the dextromethorphan are in tablet form, and wherein one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide is orally administered once daily.

16. The method of claim 14, wherein the bupropion and the dextromethorphan are in tablet form, and wherein one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide is orally administered daily.

17. A method of treating major depressive disorder in a human patient with moderate renal impairment, comprising administering to said human patient with moderate renal impairment and experiencing major depressive disorder a daily dose of: (i) about 105 mg bupropion hydrochloride and (ii) about 45 mg dextromethorphan hydrobromide, wherein said daily dose is optionally administered in the form of a dosage form.

18. The method of any one of the preceding claims, wherein the T of dextromethorphan is max For about 3 hours.

19. The method of any of the preceding claims, wherein the human patient has a glomerular filtration rate of about 30 mL / min / 1.72 m 2 and 59mL / min / 1.72m 2 between.

20. The method of any one of the preceding claims, wherein the administration is effected by oral administration once daily of one tablet containing about 105 mg bupropion hydrochloride and about 45 mg dextromethorphan hydrobromide.

21. The method of any one of the preceding claims, wherein steady-state plasma concentrations of dextromethorphan and bupropion are achieved within 8 days, and wherein the rate of accumulation of dextromethorphan at steady state is based on C max About 20.

22. The method of any one of the preceding claims, wherein steady-state plasma concentrations of dextromethorphan and bupropion are achieved within 8 days, and wherein the rate of accumulation of dextromethorphan at steady state is based on AUC 0-12 It is about 32.

23. The method of any one of the preceding claims, wherein the once-daily administration avoids an AUC of dextromethorphan in the human patient of 0-12 The AUC of dextromethorphan was compared to that resulting from twice daily administration of the tablets to human patients without renal impairment for 8 days. 0-12 Compared with the previous study, it increased by about 2.2 times.

24. The method of any one of the preceding claims, wherein the once-daily administration avoids C max The C of dextromethorphan was comparable to that obtained by administering the tablet twice daily for 8 days to human patients without renal impairment. max Compared with the previous study, it increased by about 2.1 times.

25. The method of any of the preceding claims, wherein the once-daily administration avoids an AUC of bupropion in the human patient of 0-12 Compared to the AUC of bupropion resulting from twice daily administration of the tablets for 8 days to human patients without renal impairment 0-12 Compared with the previous study, it increased by about 1.8 times.

26. The method of any of the preceding claims, wherein the once-daily administration avoids C max The C of bupropion was similar to that obtained by administering the tablet twice daily for 8 days to human patients without renal impairment. max Compared with the previous study, it increased by about 1.9 times.

27. A method of treating major depressive disorder using a noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist, comprising administering a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide to a human patient experiencing major depressive disorder no more than twice daily, wherein the human patient has a history of drug abuse, and wherein the human patient is not experiencing dissociation, wherein the combination is optionally administered in a dosage form.

28. The method of claim 27, wherein the dextromethorphan acts as a noncompetitive antagonist of the NMDA receptor and a sigma-1 receptor agonist.

29. The method of claim 27 or 28, wherein following administration of the combination, no dissociation assay is performed on the human patient.

30. The method of claim 27, 28 or 29, wherein the combination is self-administered by the human patient.

31. The method of claim 27, 28, 29 or 30, wherein the combination is administered outside of a health care setting.

32. The method of claim 27, 28, 29, 30 or 31, wherein the combination is administered without direct monitoring by a healthcare professional.

33. The method of claim 27, 28, 29, 30, 31 or 32, wherein after administering the combination, a healthcare provider does not perform a dissociation assay on the human patient.

34. The method of claim 27, 28, 29, 30, 31, 32 or 33, wherein a healthcare provider does not monitor the human patient for two hours after administration of the combination.

35. The method of claim 27, 28, 29, 30, 31, 32, 33 or 34, wherein the human patient is not evaluated to determine when the human patient is considered clinically stable and ready to leave the healthcare setting.

36. The method of claim 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein after administering the combination, a healthcare provider does not perform a dissociation assay on the human patient.

37. The method of claim 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36, wherein a healthcare provider does not monitor the human patient two hours after oral administration of the combination.

38. The method of claim 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 37, wherein the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is administered to the human patient twice daily.

39. The method of claim 38, wherein the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is orally administered to the human patient twice daily.

40. A method of treating major depressive disorder in a human patient in need of concomitant treatment with a strong CYP2D6 inhibitor, comprising administering to the human patient once daily a combination of about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide, wherein the human patient is experiencing major depressive disorder and is receiving concomitant treatment with a strong CYP2D6 inhibitor, wherein the combination is optionally administered in a dosage form.

41. The method of claim 40, wherein the strong CYP2D6 inhibitor is paroxetine.

42. The method of claim 40 or 41, wherein the once daily administration avoids an AUC of dextromethorphan in the human patient of 0-12 AUC of dextromethorphan resulting from twice daily administration of the solid dosage form to the human patient without the concomitant treatment with the strong CYP2D6 inhibitor for 8 days 0-12 Compared with the previous study, it increased by about 2.7 times.

43. The method of claim 40, 41 or 42, wherein the once daily administration avoids C max compared to C of dextromethorphan resulting from twice daily administration of the solid dosage form to the human patient without the concomitant treatment with the strong CYP2D6 inhibitor for 8 days. max Compared with the previous study, the results showed that the growth rate of 4.5% and 2.4% of the control group were significantly higher than that of the control group.

44. The method of claim 40, 41, 42, or 43, wherein administering the solid dosage form twice daily to the human patient for 8 days results in an AUC of bupropion in the human patient of 0-12 AUC of bupropion compared to that resulting from twice daily administration of the solid dosage form to human patients without concomitant treatment with the strong CYP2D6 inhibitor for 8 days 0-12 Compared to about the same.

45. The method of claim 40, 41, 42, 43, or 44, wherein administering the solid dosage form twice daily to the human patient for 8 days results in a C of bupropion in the human patient of max The C of bupropion resulting from twice daily administration of the solid dosage form to human patients without concomitant treatment with the strong CYP2D6 inhibitor for 8 days was max Compared to about the same.

46. ​​A method of reducing the risk of neurotoxicity in a human child, comprising: i) administering a combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride to a human patient once daily or twice daily, wherein the human patient is a nursing mother of the human child and is experiencing major depressive disorder; and ii) advising the human patient not to breastfeed the human child while the combination is being administered to the human patient and for 5 days after the last dose of the combination, wherein the combination is optionally administered in a dosage form.

47. The method of claim 46, wherein the human child is at risk for epilepsy.

48. The method of claim 46 or 47, wherein the human child is about three years old or younger.

49. The method of claim 46, 47 or 48, wherein the human child is at risk for neurotoxicity.

50. The method of claim 46, 47, 48, or 49, wherein the combination of about 45 mg dextromethorphan hydrobromide and about 105 mg bupropion hydrochloride is administered to the human patient twice daily for about 1 week to about 6 weeks.

51. The method of claim 46, 47, 48, 49 or 50, wherein the combination of about 45 mg dextromethorphan hydrobromide and about 105 mg bupropion hydrochloride is administered to the human patient twice daily for about 6 weeks.

52. The method of claim 46, 47, 48, 49, 50, or 51, wherein the combination of about 45 mg dextromethorphan hydrobromide and about 105 mg bupropion hydrochloride is administered to the human patient twice daily for at least 6 weeks.

53. The method of claim 46, 47, 48, 49, 50, 51 or 52, wherein after 5 days from the last dose of the combination, breast milk produced by the human patient is substantially free of dextromethorphan.

54. The method of claim 46, 47, 48, 49, 50, 51, 52 or 53, wherein after 5 days from the last dose of the combination, breast milk produced by the human patient is substantially free of bupropion.

55. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, or 54, wherein the human child is not exposed to detectable amounts of dextromethorphan.

56. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55, wherein the human child is not exposed to detectable amounts of bupropion.

57. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56, wherein the combination of about 45 mg dextromethorphan hydrobromide and about 105 mg bupropion hydrochloride is administered to the human patient twice daily until the human patient experiences a decrease in the human patient's total MADRS score of at least about 7 from baseline.

58. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, or 57, wherein the combination of about 45 mg dextromethorphan hydrobromide and about 105 mg bupropion hydrochloride is administered to the human patient twice daily until the human patient experiences a decrease in the human patient's total MADRS score of at least about 11 from baseline.

59. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 or 58, wherein the combination of about 45 mg dextromethorphan hydrobromide and about 105 mg bupropion hydrochloride is administered to the human patient twice daily until the human patient experiences a decrease in the human patient's total MADRS score of at least about 13 from baseline.

60. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59, wherein the combination of about 45 mg dextromethorphan hydrobromide and about 105 mg bupropion hydrochloride is administered to the human patient twice daily until the human patient experiences a decrease in the human patient's total MADRS score of at least 15.9 from baseline.

61. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60, wherein the human child is a breastfed infant.

62. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, or 61, wherein the reduction from baseline in the total MADRS score of the human patient administered the combination is greater than the reduction when administered a placebo.

63. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 or 62, wherein after 1 week of administration, the reduction from baseline in total MADRS score in the human patient administered the combination is greater than the reduction when administered a placebo.

64. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, or 63, wherein after 2 weeks of administration, the reduction from baseline in total MADRS score in the human patient administered the combination is greater than the reduction when administered a placebo.

65. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 or 64, wherein after 3 weeks of administration, the reduction from baseline in total MADRS score in the human patient administered the combination is greater than the reduction when administered a placebo.

66. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65, wherein after 4 weeks of administration, the reduction from baseline in total MADRS score in the human patient administered the combination is greater than the reduction when administered a placebo.

67. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 or 66, wherein after 5 weeks of administration, the reduction from baseline in total MADRS score in the human patient administered the combination is greater than the reduction when administered a placebo.

68. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, or 67, wherein after 6 weeks of administration, the reduction from baseline in total MADRS score in the human patient administered the combination is greater than the reduction when administered a placebo.

69. The method of claim 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67 or 68, wherein administration of the combination does not result in prolongation of the QT interval in the human patient.

70. A method of treating a human patient suffering from major depressive disorder, comprising: administering a therapeutically effective amount of a combination of dextromethorphan and bupropion, wherein the human patient has mild hepatic impairment as defined by Child-Pugh A or moderate hepatic impairment as defined by Child-Pugh B, and wherein the therapeutically effective amount is the same as that administered to a human patient with normal hepatic function, wherein the combination is optionally administered in a dosage form.

71. The method of claim 70, wherein the combination is administered twice daily and comprises: (i) about 45 mg dextromethorphan hydrobromide and (ii) about 105 mg bupropion hydrochloride.

72. A method for treating major depressive disorder, comprising: Determine whether a human patient has liver damage; as well as If the human patient has mild hepatic impairment as defined by Child-Pugh A or moderate hepatic impairment as defined by Child-Pugh B, administering to the human patient a combination of 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride twice daily; and avoiding use of said combination of 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride in said human patient if said human patient has severe hepatic impairment as defined by Child-Pugh C; The combination is optionally administered in the form of a dosage form.

73. The method of claim 72, wherein the human patient has mild hepatic impairment defined as Child-Pugh A.

74. The method of claim 72, wherein the human patient has moderate hepatic impairment defined as Child-Pugh B.

75. The method of claim 72, wherein the human patient has severe hepatic impairment as defined by Child-Pugh C and the combination of 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride is to be avoided in the human patient.

76. The method of any of the preceding claims, wherein the dosage form is a solid dosage form.

77. The method of claim 76, wherein the solid dosage form further comprises a carbomer homopolymer.

78. The method of claim 76 or 77, wherein the solid dosage form further comprises colloidal silicon dioxide.

79. The method of claim 76, 77 or 78, wherein the solid dosage form further comprises crospovidone.

80. The method of claim 76, 77, 78 or 79, wherein the solid dosage form further comprises caprylic / decanoic acid glyceryl.

81. The method of claim 76, 77, 78, 79 or 80, wherein the solid dosage form further comprises L-cysteine ​​hydrochloride monohydrate.

82. The method of claim 76, 77, 78, 79, 80 or 81, wherein the solid dosage form further comprises magnesium stearate.

83. The method of claim 76, 77, 78, 79, 80, 81 or 82, wherein the solid dosage form further comprises microcrystalline cellulose.

84. The method of claim 76, 77, 78, 79, 80, 81, 82, or 83, wherein the solid dosage form further comprises polyvinyl alcohol.

85. The method of claim 76, 77, 78, 79, 80, 81, 82, 83 or 84, wherein the solid dosage form further comprises red iron oxide.

86. The method of claim 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85, wherein the solid dosage form further comprises sodium lauryl sulfate.

87. The method of claim 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 or 86, wherein the solid dosage form further comprises stearic acid.

88. The method of claim 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86 or 87, wherein the solid dosage form further comprises talc.

89. The method of claim 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87 or 88, wherein the solid dosage form further comprises titanium dioxide.

90. The method of claim 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88 or 89, wherein the solid dosage form further comprises yellow iron oxide.

91. The method of claim 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90, wherein the solid dosage form is a tablet.

92. The method of claim 91, wherein the tablet is a bilayer tablet.

93. The method of claim 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, or 92, wherein the solid dosage form is administered orally.

94. The method of claim 93, wherein the solid dosage form is administered orally in the morning.

95. The method of any one of the preceding claims, wherein the dextromethorphan hydrobromide is in the form of an immediate release formulation.

96. The method of any of the preceding claims, wherein bupropion hydrochloride is in the form of an extended release formulation.

97. The method of any of the preceding claims, wherein the neurological condition is major depressive disorder.

98. The method of any of the preceding claims, wherein the neurological condition is agitation associated with Alzheimer's disease.

99. The method of any of the preceding claims, wherein the neurological condition is agitation associated with dementia.

100. The method of any of the preceding claims, wherein the nervous system condition is neuropathic pain.

101. The method of any of the preceding claims, wherein the neurological condition is generalized anxiety disorder.

102. The method of any of the preceding claims, wherein the human patient is at risk for falling.

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