Compounds and combinations thereof for treating neurological and psychiatric symptoms

Abstract

The present disclosure relates to the administration of a combination of 1) bupropion hydrochloride of about 100 to 110 mg, about 104 to 106 mg, or about 105 mg or less, or the free base form or other salt form of bupropion in an equivalent molar amount, and 2) dextromethorphan hydrobromide of about 40 to 50 mg, about 44 to 46 mg, or about 45 mg or less, or the free base form or other salt form of dextromethorphan in an equivalent molar amount, in certain patient populations such as patients with moderate renal impairment, patients concomitantly using a potent CYP2D6 inhibitor, patients known to be in the poor metabolizer group of CYP2D6, those in need of an NMDA antagonist that does not cause dissociation, and those at risk of QT prolongation.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims priority based on U.S. Provisional Patent Application No. 63 / 359,143 filed on July 7, 2022, U.S. Provisional Patent Application No. 63 / 370,592 filed on August 5, 2022, U.S. Provisional Patent Application No. 63 / 396,182 filed on August 8, 2022, U.S. Provisional Patent Application No. 63 / 373,040 filed on August 19, 2022, and U.S. Provisional Patent Application No. 63 / 401,541 filed on August 26, 2022, and the entire contents of all of these are incorporated by reference.

Summary of the Invention

Means for Solving the Problems

[0002] This disclosure relates to the administration of a combination of 1) about 100 - 110 mg, about 104 - 106 mg, or about 105 mg of bupropion hydrochloride, or the free base form or other salt forms of dextromethorphan in an equivalent molar amount, and 2) about 40 - 50 mg, about 44 - 46 mg, or about 45 mg of dextromethorphan hydrobromide, or the free base form or other salt forms of dextromethorphan in an equivalent molar amount in a specific patient population.

[0003] Some embodiments include i) administering to a human patient, who is a mother nursing a human infant and experiencing a major depressive disorder, a combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride once or twice a day, and ii) advising the human patient not to breastfeed the human infant during the time the combination is being administered to the human patient and for 5 days after the last administration of the combination, including a method for reducing the risk of neurotoxicity to a human infant.

[0004] Some embodiments include administering to a human patient having moderate renal impairment and experiencing a major depressive disorder a daily dose of (i) about 105 mg of bupropion hydrochloride and (ii) about 45 mg of dextromethorphan hydrobromide, and include a method for treating major depressive disorder in a patient having moderate renal impairment.

[0005] Some embodiments include a method of treating a patient having a neurological symptom by administering a combination of dextromethorphan and bupropion, the method comprising: orally administering once daily to the patient a dosage form comprising up to 105 mg of bupropion hydrochloride, or a corresponding molar amount of the free base or other salt form of bupropion, and up to 45 mg of dextromethorphan hydrobromide, or a corresponding molar amount of the free base or other salt form of dextromethorphan, 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; the patient has (1) a neurological symptom and (2) moderate renal impairment, and the patient is selected because the patient has been determined to have moderate renal impairment by an assay on a biological sample from the patient; the risk of drowsiness or dizziness in the patient having moderate renal impairment is lower when the dosage form comprising the combination is orally administered to the patient once daily than when a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is administered to the patient twice daily for the same number of days.

[0006] Some embodiments include a method of treating a patient with a combination of dextromethorphan and bupropion, the patient experiencing a neurological symptom, the method comprising: 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, including the step of determining whether the patient has moderate renal impairment, If the patient has moderate renal impairment, an oral dosage form comprising a combination of not more than 105 mg of bupropion hydrochloride, or an equivalent molar amount of free base or other salt form of bupropion, and not more than 45 mg of dextromethorphan hydrobromide, or an equivalent molar amount of free base or other salt form of dextromethorphan, 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, is orally administered to the patient once a day, If the patient has no renal impairment, an oral dosage form comprising a combination of 105 mg of bupropion hydrochloride, or an equivalent molar amount of free base or other salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or an equivalent molar amount of free base or other salt form of dextromethorphan, is orally administered to the patient twice a day, The risk of drowsiness or dizziness in patients with moderate renal impairment is lower when the dosage form containing the combination is orally administered to the patient once a day than when a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is administered to the patient twice a day for the same number of days.

[0007] Some embodiments include a method of treating a patient experiencing neurological symptoms, the method comprising a) Obtaining a biological sample from the patient or having obtained it previously, and assaying the biological sample or having assayed it previously to determine whether the patient has moderate renal impairment, wherein the result that the patient has moderate renal impairment indicates that there is a risk of adverse events associated with overexposure to dextromethorphan in the patient, thereby determining whether there is a risk of adverse events associated with overexposure to dextromethorphan in the patient, b) If there is a risk of adverse events associated with overexposure to dextromethorphan in the patient, administering orally to the patient once a day a dosage form comprising a combination of not more than 105 mg of bupropion hydrochloride or a corresponding molar amount of the free base or other salt form of bupropion and not more than 45 mg of dextromethorphan hydrobromide or a corresponding molar amount of the free base or other salt form of dextromethorphan, 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 there is no risk of adverse events associated with overexposure to dextromethorphan in the patient, administering orally to the patient twice a day a dosage form comprising a combination of 105 mg of bupropion hydrochloride or a corresponding molar amount of the free base or other salt form of bupropion and 45 mg of dextromethorphan hydrobromide or a corresponding molar amount of the free base or other salt form of dextromethorphan, comprising the steps of.

[0008] Some embodiments include a dosage form comprising up to 105 mg of bupropion hydrochloride, or a corresponding molar amount of the free base or other salt form of bupropion, and up to 45 mg of dextromethorphan hydrobromide, or a corresponding molar amount of the free base or other salt form of dextromethorphan, 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, the method for treating neurological symptoms with a combination of dextromethorphan and bupropion comprising orally administering the dosage form to the patient once a day, wherein the patient has 1) neurological symptoms and 2) moderate renal impairment, and the patient is selected because the patient has been determined to have moderate renal impairment by an assay on a biological sample from the patient, wherein the risk of adverse events that the patient has is reduced as compared to the risk of adverse events that the patient would have if the dosage form were administered to the patient twice a day.

[0009] Some embodiments include a method for treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing neurological symptoms, and the method comprises obtaining or having previously obtained a biological sample from the patient, and performing or having previously performed an assay on the biological sample to determine whether the patient has moderate renal impairment, thereby including the step of determining whether the patient has moderate renal impairment, When the patient has moderate renal impairment, a dosage form comprising a combination of not more than 105 mg of bupropion hydrochloride, or the corresponding molar amount of the free base or other salt form of bupropion, and not more than 45 mg of dextromethorphan hydrobromide, or the corresponding molar amount of the free base or other salt form of dextromethorphan, 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, is orally administered to the patient once a day, When the patient has no renal impairment, a dosage form comprising a combination of 105 mg of bupropion hydrochloride, or the corresponding molar amount of the free base or other salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or the corresponding molar amount of the free base or other salt form of dextromethorphan, is orally administered to the patient twice a day.

[0010] Some embodiments include a method of treating a patient having neurological symptoms by administering a combination of dextromethorphan and bupropion, the method comprising: orally administering to the patient once a day a dosage form comprising not more than 105 mg of bupropion hydrochloride, or the corresponding molar amount of the free base or other salt form of bupropion, and not more than 45 mg of dextromethorphan hydrobromide, or the corresponding molar amount of the free base or other salt form of dextromethorphan, 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, the patient is selected because the patient has 1) neurological symptoms and 2) moderate renal impairment, and the patient has been determined to have moderate renal impairment by an assay on a biological sample from the patient, The risk of drowsiness and dizziness in patients with moderate renal impairment is lower when an oral dosage form containing a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is administered to the patient once a day for the same number of days than when the combination is administered to the patient twice a day.

[0011] Some embodiments include a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing neurological symptoms, and the method comprises obtaining a biological sample from the patient or having previously obtained it, and performing an assay on the biological sample or having previously performed it to determine whether the patient has moderate renal impairment, thereby including the step of determining whether the patient has moderate renal impairment, wherein when the patient has moderate renal impairment, an oral dosage form containing a combination of bupropion hydrochloride at 105 mg or less, or a corresponding molar amount of the free base or other salt form of bupropion, and dextromethorphan hydrobromide at 45 mg or less, or a corresponding molar amount of the free base or other salt form of dextromethorphan, 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, is orally administered to the patient once a day, wherein when the patient does not have renal impairment, an oral dosage form containing a combination of 105 mg of bupropion hydrochloride, or a corresponding molar amount of the free base or other salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a corresponding molar amount of the free base or other salt form of dextromethorphan, is orally administered to the patient twice a day, The risk of drowsiness and dizziness in patients with moderate renal impairment is lower when an oral dosage form containing a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is administered once daily to the patient over the same number of days than when the combination is administered twice daily to the patient.

[0012] Some embodiments include a method of treating major depressive disorder in a human patient in need of combination therapy with a potent CYP2D6 inhibitor, the method comprising administering to the human patient, once daily, a combination of (i) about 105 mg of bupropion hydrochloride and (ii) about 45 mg of dextromethorphan hydrobromide, wherein the human patient has experienced major depressive disorder and is receiving combination therapy with a potent CYP2D6 inhibitor. In some embodiments, the potent CYP2D6 inhibitor is paroxetine.

[0013] Some embodiments include a method of treating major depressive disorder in a patient receiving combination therapy with a potent CYP2D6 inhibitor, the method comprising administering to the patient, once daily, a daily dosage of (i) about 105 mg of bupropion hydrochloride and (ii) about 45 mg of dextromethorphan hydrobromide, wherein the patient has major depressive disorder and is receiving combination therapy with a CYP2D6 inhibitor.

[0014] Some embodiments include a method of treating major depressive disorder in a human patient known to be in the poor metabolizer group of CYP2D6, the method comprising administering to the human patient, once daily, a daily dosage of (i) about 105 mg of bupropion hydrochloride and (ii) about 45 mg of dextromethorphan hydrobromide, wherein the human patient has experienced major depressive disorder and is known to be in the poor metabolizer group of CYP2D6.

[0015] Some embodiments include treating major depressive disorder using an N-methyl-D-aspartic acid (NMDA) receptor antagonist, which comprises administering to a human patient experiencing major depressive disorder a combination of less than twice daily, 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide, wherein dextromethorphan acts as a non-competitive antagonist of the NMDA receptor and as a sigma-1 receptor agonist, and wherein the human patient has not experienced dissociation.

[0016] Some embodiments include treating major depressive disorder in a human patient at risk of QT prolongation, which comprises administering to a human patient experiencing major depressive disorder and at risk of QT prolongation and polymorphic ventricular tachycardia a combination of less than twice daily, 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide, wherein an electrocardiogram-based evaluation of the QT interval is not performed in the human patient.

[0017] Some embodiments include treating a patient having major depressive disorder, which comprises administering a therapeutically effective amount of a combination of dextromethorphan and bupropion, wherein the patient has mild liver dysfunction as defined by Child-Pugh A or moderate liver dysfunction as defined by Child-Pugh B, and wherein the therapeutically effective amount is the same amount that would be administered to a patient with normal liver function.

[0018] Some embodiments include determining whether a human patient has liver dysfunction, and, if the human patient has mild liver dysfunction as defined by Child-Pugh A or moderate liver dysfunction as defined by Child-Pugh B, administering to the human patient a combination of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride less than twice daily. If the human patient has severe liver dysfunction defined as Child-Pugh C, avoid using in the human patient a combination of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride. A method for treating major depressive disorder, including

Brief Description of the Drawings

[0019]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0020] As described above, the present disclosure relates to the administration of a combination of: 1) about 100 - 110 mg, about 104 - 106 mg, or about 105 mg of bupropion hydrochloride, or an equivalent molar amount of dextromethorphan in free base form or other salt forms; and 2) about 40 - 50 mg, about 44 - 46 mg, or about 45 mg of dextromethorphan hydrobromide, or an equivalent molar amount of dextromethorphan in free base form or other salt forms. For convenience, this combination is referred to herein as the "subject combination". In all examples where the subject combination is referred to herein, the combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is particularly intended.

[0021] Potent CYP2D6 inhibitors include, but are not limited to, fluoxetine, propafenone, quinidine, and paroxetine.

[0022] Dextromethorphan hydrobromide is a non-competitive NMDA receptor antagonist and a sigma-1 receptor agonist.

[0023] The chemical name of dextromethorphan hydrobromide is Morphinan, 3-methoxy-17-methyl-, (9α,13α,14α), hydrobromide monohydrate. Dextromethorphan hydrobromide has the empirical formula C 18 H 25 NO·HBr·H2O and a molecular weight of 370.33. The structural formula is

Chem.

[0024] The powder of dextromethorphan hydrobromide is white or almost white crystalline and is slightly soluble in water.

[0025] Bupropion hydrochloride is an aminoketone and a CYP450 2D6 inhibitor.

[0026] The chemical name of bupropion hydrochloride is (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. Bupropion hydrochloride has the empirical formula C 13 H 18 ClNO·HCl and a molecular weight of 276.2. The structural formula is

Chem.

[0027] The powder of bupropion hydrochloride is white and is readily soluble in water.

[0028] The combination of the subject matter can be included in an oral dosage form including tablets such as sustained release tablets. In some embodiments, the combination of the subject matter is included in a dosage form for oral administration and is available as a round two-layer tablet.

[0029] In some embodiments, each tablet containing the combination of the subject matter comprises 45 mg of dextromethorphan hydrobromide in an immediate release formulation. In some embodiments, each tablet of the combination of the subject matter comprises 105 mg of bupropion hydrochloride in a sustained release formulation. In some embodiments, each tablet of the combination of the subject matter comprises 45 mg of dextromethorphan hydrobromide in an immediate release formulation and 105 mg of bupropion hydrochloride in a sustained release formulation.

[0030] In some embodiments, tablets containing the combination of the subject matter comprise l-cysteine hydrochloride monohydrate. In some embodiments, tablets containing the combination of the subject matter comprise carbomer homopolymer. In some embodiments, tablets containing the combination of the subject matter comprise microcrystalline cellulose. In some embodiments, tablets containing the combination of the subject matter comprise colloidal silicon dioxide. In some embodiments, tablets containing the combination of the subject matter comprise crospovidone. In some embodiments, tablets containing the combination of the subject matter comprise stearic acid. In some embodiments, tablets containing the combination of the subject matter comprise magnesium stearate.

[0031] In some embodiments, tablets containing the combination of the subject matter comprise the following inactive ingredients: l-cysteine hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silicon dioxide, crospovidone, stearic acid, and magnesium stearate.

[0032] In some embodiments, the starting dose of the combination of the subject matter is 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride in one tablet administered once daily in the foam. In some embodiments, after 3 days, the dose is increased to twice daily, in one tablet (or one dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride), administered, for example, at intervals of at least 8 hours. In some embodiments, more than 2 doses containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride are not administered on the same day.

[0033] In patients with mild (Child-Pugh A) or moderate hepatic impairment (Child-Pugh B), dose adjustment is not recommended compared to the dose recommended for patients with normal hepatic function.

[0034] In patients with severe hepatic impairment (Child-Pugh C), the pharmacokinetics of the combination of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride have not been evaluated. In patients with severe hepatic impairment, the use of the combination of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride is not recommended or should be avoided.

[0035] The combination of the subject can be administered orally, with or without food. In some embodiments, the tablets are swallowed whole and not crushed, divided, chewed, or otherwise altered.

[0036] Patients with renal impairment may require special dosing.

[0037] In some embodiments, the state of renal impairment of a subject can be determined by measuring the individual's "estimated glomerular filtration rate" or "eGFR". eGFR in mL / min / 1.73m 2 is calculated by the Modification of Diet in Renal Disease [MDRD] equation: (eGFR in mL / min) / 1.73m 2 = 175 × (serum creatinine in mg / dL) -1.154 × age -0.203 × 0.742 (for females) × 1.212 (for African Americans)

[0038] For details regarding the calculation of eGFR, see, for example, 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.

[0039] The states of renal dysfunction based on the guidance of the Food and Drug Administration (FDA) are as follows. · Normal: eGFR ≥ 90 mL / min / 1.73m 2 · Mild: eGFR 60 - 89 mL / min / 1.73m 2 (i.e., ≥ 60 - < 90) · Moderate: eGFR 30 - 59 mL / min / 1.73m 2 (i.e., ≥ 30 - < 60) · Severe: eGFR 15 - 29 mL / min / 1.73m 2 (i.e., ≥ 15 - < 30) · End-stage renal disease: eGFR < 15 mL / min / 1.73m 2 and who is either not receiving hemodialysis or is receiving hemodialysis.

[0040] See the industry guidance on pharmacokinetics in patients with renal dysfunction - impact on study design, data analysis, and dosing and labeling. U.S. Department 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, "subjects with hepatic dysfunction" may have mild, moderate, or severe hepatic dysfunction or ESRD.

[0041] In some embodiments, the recommended dose of the combination of the subject for patients with moderate renal impairment (estimated glomerular filtration rate (eGFR) or glomerular filtration rate (GFR) of 30 - 59 mL / min / 1.73m 2 is a daily dose of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride, or an equivalent molar amount of other forms of dextromethorphan and / or bupropion, for example, one tablet (or one dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) administered once daily, for example, one tablet or one oral dosage form every morning, or a combination of 52.5 mg of bupropion and approximately 22.5 mg of dextromethorphan hydrobromide administered orally twice daily. In some embodiments, patients are monitored for side effects that may be attributable to dextromethorphan such as drowsiness and dizziness.

[0042] Moderate renal impairment can be determined by an assay such as an assay that determines the creatinine value of a biological sample from a patient, such as a blood sample. The plasma creatinine value from a blood sample can be used to estimate GFR.

[0043] Patients using the combination of the subject in conjunction with a strong CYP2D6 inhibitor may require special dosing. Use of the combination of the subject in conjunction with a strong CYP2D6 inhibitor increases the plasma concentration of dextromethorphan. In some embodiments, the recommended dose of the combination of the subject when co - administered with a strong CYP2D6 inhibitor is one tablet (or a dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride), such as one tablet or other oral dosage form every morning, once daily. In some embodiments, patients are monitored for side effects that may be attributable to dextromethorphan such as drowsiness and dizziness.

[0044] Patients who are known to be in the poor metabolizer (PM) group of CYP2D6 may require special dosing. In some embodiments, the recommended dose for patients known to be in the poor metabolizer group of CYP2D6 is one tablet in the morning every day or other oral dosage forms, such as one tablet per day (or a dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride).

[0045] Special precautions may be necessary when switching a patient from a monoamine oxidase inhibitor (MAOI) antidepressant to the subject combination or from the subject combination to a MAOI antidepressant. In some embodiments, at least 14 days must elapse between discontinuation of the MAOI for the treatment of depression and initiation of treatment with the subject combination. Conversely, in some embodiments, at least 14 days must be allowed to elapse after discontinuation of the subject combination before initiating a MAOI antidepressant.

[0046] There is data reporting the presence of bupropion and its metabolites in human breast milk. There is no data on the effect of bupropion or its metabolites on breast milk production. Limited data on the use of bupropion in nursing patients has not clarified a clear association with adverse reactions in infants being breastfed.

[0047] Neurotoxicity findings were seen in postnatal day (PND) 7 young rats treated with the combination of dextromethorphan / quinidine, which corresponds to the third trimester of pregnancy to several months after birth and may be extended up to 3 years after birth in humans. It is not known whether dextromethorphan is present in human breast milk. There is no data on the effect of dextromethorphan in infants being breastfed or on breast milk production. Due to the potential for neurotoxicity, in some embodiments, patients should be advised that breastfeeding is not recommended during the treatment period with the combination of dextromethorphan and bupropion and for 5 days after the last dose.

[0048] In some embodiments, human infants of patients receiving the subject combination are at risk of seizures. In some embodiments, the human infant is about 3 years old or less. In some embodiments, human infants of patients receiving the subject combination are at risk of neurotoxicity.

[0049] In the case of lactating human mothers, they may ingest a combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride for about one week to about six weeks, about six weeks, or at least about six weeks, and then discontinue treatment at least 5 days before starting to breastfeed their child.

[0050] In some embodiments, a human patient produces breast milk substantially free of dextromethorphan 5 days after the last administration of the combination.

[0051] In some embodiments, a human patient produces breast milk substantially free of bupropion 5 days after the last administration of the combination.

[0052] In some embodiments, human infants of patients receiving the subject combination are not exposed to detectable amounts of dextromethorphan during breastfeeding.

[0053] In some embodiments, human infants of patients receiving the subject combination are not exposed to detectable amounts of bupropion during breastfeeding.

[0054] In some embodiments, the subject combination is administered until the total MADRS score of the human patient is reduced by at least about 7, at least about 11, at least about 13, or at least about 15.9. When the MADRS score reaches the desired reduction, the human patient may discontinue treatment, wait at least 5 days, and then start breastfeeding her child.

[0055] In some embodiments, the human infant is a suckling infant being breastfed.

[0056] In some embodiments, the human patient experiences a decrease from baseline in the total MADRS score in human patients that is greater than what the patient would experience if administered a placebo due to being administered the subject combination. A human patient ingesting the subject combination may experience a greater decrease in the MADRS score than if ingesting a placebo one week after administration, two weeks after administration, three weeks after administration, four weeks after administration, five weeks after administration, six weeks after administration, or for a period beyond that.

[0057] In the subject combination, bupropion inhibits the metabolism of dextromethorphan via CYP2D6. Dextromethorphan exhibits non-linear pharmacokinetics at steady state when co-administered with bupropion, and when the dose of dextromethorphan (30 - 60 mg) was varied, the AUC and C max changed more than proportionally to the dose, and when the dose of bupropion (75 - 150 mg) was varied, the change was less than proportional.

[0058] When the subject combination is administered, the steady-state plasma concentrations of dextromethorphan and bupropion are achieved within 8 days. The accumulation ratios of dextromethorphan at steady state are approximately 20 and approximately 32, respectively, based on C max and AUC 0-12 respectively. The accumulation ratios of bupropion at steady state are approximately 1.1 and approximately 1.5, respectively, based on C max and AUC 0-12 respectively.

[0059] After administration of the subject combination, the median T max of dextromethorphan is approximately 3 hours, and the median T max of bupropion is approximately 2 hours. The C max of the hydroxybupropion metabolite occurs approximately 3 hours after administration and is at a peak level approximately 14 times that of bupropion. The AUC 0-12 of hydroxybupropion is approximately 19 times that of bupropion. The Cmax occur at approximately the same time after administration and are approximately equal to bupropion and about five times that of bupropion, respectively. The AUC of erythrohydroxybupropion and threohydroxybupropion 0-12 values are approximately 1.2 times and about 7 times that of bupropion, respectively.

[0060] The combination of the subject can be administered with or without food. When the combination of the subject is administered with food, the C max and AUC 0-12 of dextromethorphan show no change and a 14% decrease, respectively, while the C max and AUC 0-12 of bupropion increase by 3% and 6%, respectively.

[0061] The plasma protein binding of dextromethorphan is approximately 60 - 70%, and that of bupropion is 84%. The degree of protein binding of the hydroxybupropion metabolites is similar to that of bupropion, while the degree of protein binding of the threohydroxybupropion metabolite is approximately half of that found in bupropion.

[0062] After administering the combination of the subject to the high - metabolism group for 8 days, the mean elimination half - life of dextromethorphan increased to approximately 22 hours, about 3 times that of dextromethorphan administered without bupropion.

[0063] The mean elimination half - lives of dextromethorphan and bupropion were 22 hours and 15 hours, respectively. The apparent elimination half - lives of the hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion metabolites were approximately 35, 44, and 33 hours, respectively.

[0064] Esketamine is a non-competitive NMDA receptor antagonist and, when used in combination with oral antidepressants, is indicated for the treatment of treatment-resistant depression in adults. The treatment of treatment-resistant depression carries a risk of dissociation. Since the label of esketamine carries a risk of sedation and dissociation, patients must be monitored for at least two hours during each treatment session and then an assessment is to be made to determine the time when the patient is clinically stable and ready to leave the medical facility.

[0065] Dissociation includes delusional perception, depersonalization / derealization disorder, derealization, diplopia, dissociation, paresthesia, cold sensation, heat sensation, sense of body temperature change, hallucination, auditory hallucination, visual hallucination, hyperacusis, illusion, eye discomfort, oral paresthesia, sensory paralysis, oral sensory paralysis, pharyngeal sensory paralysis, photophobia, change in time perception, tinnitus, poor vision, visual impairment.

[0066] The combination of the subject is dextromethorphan, which is a non-competitive N-methyl D-aspartic acid (NDMA) receptor antagonist and a sigma-1 receptor agonist, and bupropion, which is an aminoketone and a CYP450 2D6 inhibitor and is indicated for the treatment of major depressive disorder (MDD) in adults. Unlike esketamine, the combination of the subject can be administered without dissociation or dissociative events. In some embodiments, patients are not monitored for dissociation after being administered the combination of the subject.

[0067] The following information includes the types of dissociation and other effects that can be avoided with the combination of dextromethorphan and bupropion.

[0068] In clinical trials, based on the Modified Observer's Alertness / Sedation Scale (MOAA / S), 48% - 61% of patients treated with esketamine became sedated and 0.3% - 0.4% of patients treated with esketamine experienced loss of consciousness (MOAA / S score 0). With the combination of dextromethorphan and bupropion, NMDA receptor antagonism can be achieved without a significant risk of sedation.

[0069] Patients receiving esketamine must be monitored by medical staff for at least two hours during each treatment session due to the potential for delayed or prolonged sedation, and then an assessment is made to determine when the patient is clinically stable and ready to leave the medical setting. Such monitoring is not required for the treatment with the combination of dextromethorphan and bupropion.

[0070] Patients being treated with esketamine must be carefully monitored for sedation when combined with CNS depressants. Such monitoring is not required for the treatment with the combination of dextromethorphan and bupropion.

[0071] Esketamine is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Such a restriction is not required for the combination of dextromethorphan and bupropion.

[0072] The most common mental effects of esketamine are dissociative and / or changes in perception (including distortion of time, space, and illusions), derealization, and depersonalization (61% - 84% of patients treated with esketamine developed dissociative or perceptual changes based on clinical dissociation scales). Due to the potential to induce dissociative effects, psychotic patients must be carefully evaluated before esketamine administration. Such an evaluation is not required for the treatment with the combination of dextromethorphan and bupropion. Treatment with esketamine should only be initiated if the benefits outweigh the risks. Such a restriction is not required for the treatment with the combination of dextromethorphan and bupropion.

[0073] Due to the risk of dissociation, patients receiving esketamine must be monitored by medical staff for at least 2 hours during each treatment session, and then an assessment is conducted to determine the time when the patient is clinically stable and considered ready to leave the medical facility. Such monitoring, assessment, or restrictions are not required for the treatment with the combination of dextromethorphan and bupropion.

[0074] Dissociation includes delusional perception, depersonalization / derealization disorder, derealization, diplopia, dissociation, paresthesia, cold sensation, heat sensation, sense of body temperature change, hallucination, auditory hallucination, visual hallucination, mixed hallucination, hyperacusis, illusion, eye discomfort, oral paresthesia, perceptual abnormality, oral paresthesia, pharyngeal paresthesia, photophobia, change in time perception, tinnitus, visual field defect, and visual impairment.

[0075] Esketamine is a Schedule III controlled substance (CIII) and can be misused or diverted. The combination of dextromethorphan and bupropion is not a controlled substance. The risk of misuse or abuse for each patient must be evaluated before prescribing, and all patients receiving esketamine must be monitored during treatment to determine if these behaviors or conditions, including drug-seeking behavior, are present. Such monitoring or assessment is not required for the treatment with the combination of dextromethorphan and bupropion.

[0076] Esketamine is only available through a restricted program under the Risk Evaluation and Mitigation Strategy (REMS) and is called Esketamine REMS due to the risk of sedation, dissociation, misuse, and harmful outcomes due to abuse and misuse reporting. Such restrictions are not required for the combination of dextromethorphan and bupropion.

[0077] Important requirements of Esketamine REMS include the following. · The medical facility must be certified for the program and esketamine is - Dispensed and administered only at the medical facility. - Patients receiving treatment at external facilities (e.g., clinics and medical centers) must enroll in this program. - Administered to the patient under the direct observation of a healthcare provider, who monitors the patient for at least 2 hours after esketamine administration. Guarantee that

[0078] None of these requirements apply to the combination of dextromethorphan and bupropion as the subject matter.

[0079] Esketamine was evaluated for safety in 262 adults in two Phase 3 trials (Trial 3 and Trial 4) and one Phase 2 trial to treat depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.

[0080] Sedation was evaluated by reporting adverse events and the Modified Observer's Alertness / Sedation Scale (MOAA / S). In the MOAA / S, a score of 5 means "responds immediately when called by name in a normal voice", a score of 0 means "does not respond to suprasternal notch pressure with pain", a score of 4 means "responds slowly when called by name in a normal voice", a score of 3 means "responds only when called by name loudly and / or repeatedly", a score of 2 means "responds only to a light stimulus or rocking", and a score of 1 means "does not respond to a light stimulus or rocking". A decrease in the MOAA / S score from pre-dose is considered to indicate the presence of sedation, and such a decrease occurred in many patients receiving esketamine compared to placebo in short-term treatment-resistant depression (TRD) trials. An increase in the incidence of dose-related sedation (MOAA / S score < 5) was seen in the fixed-dose trials of TRD. Table 1 shows the incidence of sedation (MOAA / S score < 5) in the fixed-dose trials of adult patients with TRD under 65 years of age and the flexible-dose trials of patients with TRD 65 years of age and older.

[0081]

Table 1

[0082] In a study to treat the depressive symptoms of adults with major depressive disorder (MDD) with acute suicidal ideation or behavior, similar to the study results of treatment-resistant depression in Table 1, the incidence of sedation (MOAA / S score < 5) was higher in patients treated with esketamine and oral antidepressants (AD) compared to patients treated with placebo and oral antidepressants.

[0083] (Dissociation / altered perception) Esketamine causes dissociative symptoms (including derealization and depersonalization), and nearby changes (distortion of time and space, and illusions). In clinical trials, dissociation was transient and occurred on the day of administration. Dissociation was evaluated by reporting of adverse events and the Clinician Administered Dissociative States Scale (CADSS). A total CADSS score of more than 4 indicates the presence of dissociative symptoms, and an increase to such a score of 4 or more occurred in many patients treated with esketamine compared to placebo in a short-term treatment-resistant depression study. An increased incidence of dissociation symptoms related to dose (CADSS total score > 4 and change > 0) was seen in a fixed-dose study of treatment-resistant depression. Table 2 shows the incidence of dissociation (CADSS total score > 4 and change > 0) in a fixed-dose study of adult patients with treatment-resistant depression under 65 years old, and a flexible-dose study of patients with treatment-resistant depression 65 years old and above.

[0084]

Table 2

[0085] In a study to treat the depressive symptoms of adults with (MDD) with acute suicidal ideation or behavior, the proportion of patients showing dissociation (CADSS total score > 4 and change > 0) was also higher (84%) in patients treated with esketamine and oral AD compared to patients treated with placebo and oral AD (16%).

[0086] The combination of the subject matter can be administered without dissociation or dissociative events, thus reducing the risk of abuse compared to ketamine. Abuse is the intentional non-therapeutic use, even once, for the desired mental or physiological effects of a drug. In clinical trials of the combination of dextromethorphan and bupropion, drug-seeking behavior was not revealed, although these observations were not systematic. Therefore, patients with a history of drug abuse need to be carefully observed for signs of misuse or abuse (such as the development of tolerance, increased dosage, drug-seeking behavior) of the combination of dextromethorphan and bupropion.

[0087] Unlike the combination of quinidine and dextromethorphan, at the dosage of the combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide administered twice daily, the dosage of the combination of the subject matter does not prolong the QT interval to a clinically relevant extent. Therefore, in human patients with a history of major depressive disorder and at risk of QT prolongation and polymorphic ventricular tachycardia, evaluation of the QT interval on an electrocardiogram is not normally performed in human patients.

[0088] The combination of the subject matter can be used for the adjunctive treatment of major depressive disorder or depression.

[0089] In addition to major depressive disorder, the combination of the subject matter can be used to treat other diseases in the patient populations or situations described herein. For example, the combination of the subject matter can be used to treat pain or neuropathic pain. Examples of neuropathic pain that can be treated with the combination of the subject matter include, but are not limited to, mood disorders, mental disorders, cerebral dysfunction, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0090] Emotional disorders that can be treated by the combination of the subject matter include, but are not limited to, depression, major depression, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorder including bipolar affective disorder, seasonal affective disorder, mood disorder, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), attention deficit / hyperactivity disorder (AD / HD), bipolar disorder and manic states, obsessive-compulsive disorder, bulimia nervosa, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug intoxication or abuse, nicotine addiction, psychotic dysfunction, emotional regulation disorder, and emotional instability.

[0091] Depression can be manifested by depressive symptoms. These symptoms can include changes such as mood changes, intense sadness, despair, mental numbness, decreased concentration, pessimistic worry, restlessness, anxiety, irritability, guilt, anger, worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-abasement. Physical symptoms of depression can include insomnia, anorexia nervosa, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, pain, headache, convulsions, gastrointestinal problems, and / or abnormal circadian rhythm of hormones.

[0092] Mental disorders that can be treated by the combination of the subject matter include, but are not limited to, anxiety disorders such as phobia, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depression, hypomania, unipolar depression, depression, stress disorder, somatic symptom disorder, personality disorder, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizophrenia, aggression, aggression in Alzheimer's disease, excitement, excitement in Alzheimer's disease. Alzheimer's disease can also be referred to as Alzheimer's type dementia. Other neurobehavioral symptoms of Alzheimer's disease that can be treated include disinhibition and apathy.

[0093] Agitation in Alzheimer's disease occurs as the disease progresses. Agitation can manifest itself as inappropriate verbal, emotional, and / or physical behavior. Inappropriate behaviors can include, but are not limited to, fragmented mumbling, inappropriate emotional reactions, demands for attention, threats, irritability, frustration, crying, repetitive questioning, mood swings, swearing, invective, physical outbursts, mental distress, restlessness, sundowning, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, groping, repetitive body movements, hoarding, stalking, hitting, scratching, biting, aggressive, hyperactive, and / or kicking.

[0094] 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, affecting an estimated 6 million people in the United States, and the number is predicted to increase to approximately 14 million by 2050. Agitation has been reported in up to 70% of patients with AD and is characterized by emotional distress, aggressive behavior, disruptive hypersensitivity, and lack of inhibition. Management of agitation is a priority in AD. Agitation in patients with AD is associated with increased caregiver burden, functional decline, accelerated cognitive decline, earlier institutionalization, and increased mortality. Currently, there are no FDA-approved treatments for agitation in patients with AD.

[0095] Neurobehavioral symptoms are known to occur during dementia and can be treated by combination. Caregivers or family may feel more burdened by their behavioral / psychological symptoms than by the patient's cognitive impairment. The common forms of symptoms are groups of diseases that contribute to Alzheimer's disease, vascular dementia, Lewy body dementia (abnormal aggregates of proteins that occur within nerve cells), and frontotemporal dementia (degeneration of the frontal lobe of the brain). The symptoms that dementia patients have are similar to mental disorders, but some are slightly different from each other. Neurobehavioral symptoms associated with dementia include depression, apathy, excitement, disinhibition, hallucinations, delusions, psychosis, impulsivity, aggression, obsessive thoughts, excessive sexual desire, and personality disorders. Neurobehavioral symptoms such as disinhibition can also be seen in other symptoms such as traumatic brain injury.

[0096] Excitement in patients with Alzheimer's disease can be evaluated using the Cohen-Mansfield Agitation Inventory, or CMAI. The CMAI evaluates various behaviors including hitting (including oneself), kicking, grabbing at people, pushing, throwing objects, biting, scratching, spitting, hurting oneself or others, breaking or destroying objects, engaging in physical sexual solicitation, pacing, wandering aimlessly, wearing inappropriate clothing or undressing, trying to go to inappropriate places, deliberately falling, consuming inappropriate substances, handling objects inappropriately, hiding objects, hoarding objects, repeatedly performing unique mannerisms, overall restlessness, shouting, making verbal sexual solicitations, swearing or verbal attacks, repeating phrases or questions, making strange sounds (strange laughter or crying sounds), complaining, being negative, constantly inappropriately seeking attention or help.

[0097] Schizophrenia can be treated by combination including the positive and / or negative symptoms of schizophrenia, or the residual symptoms of schizophrenia. Other treatable symptoms include intermittent explosive disorder.

[0098] Brain dysfunctions that can be treated by the combination of the subject matter include, but are not limited to, dysfunctions associated with intellectual disabilities such as senile dementia, Alzheimer's dementia, memory loss, amnesia / amnesic syndrome, epilepsy, disturbance of consciousness, coma, decreased attention, language disorder, vocal cord spasm, Parkinson's disease, Lennox-Gastaut syndrome, autism, attention deficit hyperactivity disorder, and schizophrenia. In addition, brain dysfunctions include, but are not limited to, dysfunctions caused by cerebrovascular diseases such as stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, and head trauma, and the symptoms include disturbance of consciousness, senile dementia, coma, decreased attention, and language disorder.

[0099] Drug abuse and intoxication that can be treated by the combination of the subject matter include, but are not limited to, cocaine, psychostimulants (crack, cocaine, speed, heroin, etc.), nicotine, alcohol, opioids, antianxiety drugs and hypnotics, marijuana (cannabis), amphetamines, hallucinogens, fenciclovir, volatile solvents, and volatile nitrites. Nicotine intoxication includes all known forms of nicotine intoxication such as smoking tobacco, cigars, and / or pipes, e-cigarettes or vaping, and chewing tobacco intoxication.

[0100] Movement disorders that can be treated by the combination of the subject matter include, but are not limited to, akathisia, akinesia, associated movement, athetoisis, ataxia, ballism, hemiballism, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's chorea, rheumatic chorea, Sydenham chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, Tourette syndrome, and Wilson's disease.

[0101] Dementias that can be treated by the combination of the subject matter include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

[0102] Motor neuron diseases that can be treated by the combination of the subject matter 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, Sandhoff disease, and hereditary spastic paraplegia.

[0103] Neurological diseases that can be treated by the combination of the subject matter include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbospinal 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, autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paraparesis, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0104] Seizure disorders that can be treated by the combination of the subject matter include, but are not limited to, epileptic seizures, non-epileptic seizures, epilepsy, febrile convulsions; partial seizures including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and continuous partial epilepsy; 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.

[0105] Types of headaches that can be treated by the combination of the subject matter include, but are not limited to, migraine, tension-type headache, and cluster headache.

[0106] Other neurological disorders that can be treated by the combination of the subject matter include, but are not limited to, Rett syndrome, autism, tinnitus, disorders of consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; voice disorders due to uncontrollable laryngeal muscle spasms including, but not limited to, abductor spastic dysphonia, adductor spastic dysphonia, muscle tension dysphonia, vocal tremor; chemotherapy-induced neurotoxicity such as diabetic neuropathy, methotrexate neurotoxicity; incontinence including, but not limited to, stress incontinence, urge incontinence, and fecal incontinence; and erectile dysfunction.

[0107] In some embodiments, the combination of the subject matter can be used to treat pain, arthralgia, pain associated with sickle cell disease, mood regulation disorders, depression (including treatment-resistant depression), disorders related to memory and cognition, movement disorders, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), etc.

[0108] In some embodiments, the combination of the subject matter can be administered to relieve skeletal muscle pain including pain associated with low back pain, and arthritis, juvenile arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatic) arthritis, non-articular rheumatism, periarticular disorders, axial spondyloarthritis including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoporosis of the hip, vertebral crush fractures, osteoporosis, etc.

[0109] In some embodiments, the combination of the subject matter can be administered to relieve inflammatory pain including skeletal muscle pain, arthritis pain, and complex regional pain syndrome.

[0110] Arthritis refers to inflammatory joint diseases that can be associated with pain. Examples of arthritis include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatic) arthritis, non-articular rheumatism, periarticular disorders, neuropathic arthritis including Charcot foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.

[0111] In some embodiments, the subject combination is used to treat chronic musculoskeletal pain.

[0112] In some embodiments, the subject composition may be administered to alleviate 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 other types of CRPS. CRPS is a type of inflammatory pain. CRPS also has a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the extremities that may be accompanied by swelling, autonomic, motor, and sensory changes.

[0113] In some embodiments, the subject composition is administered to alleviate neuropathic pain.

[0114] Examples of neuropathic pain include pain due to diabetic peripheral neuropathy or diabetic peripheral neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, pain due to 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, neuropathy associated with radiotherapy or chemotherapy, etc.

[0115] In some embodiments, the subject composition may be administered to alleviate fibromyalgia.

[0116] In some embodiments, the subject composition may be co-administered with one or more potent CYP2D6 inhibitors. It has been found that co-administration of the subject combination with one or more CYP2D6 inhibitors increases the plasma concentration of dextromethorphan. Therefore, it is recommended to monitor patients for potential side effects or adverse reactions associated with dextromethorphan, such as drowsiness and dizziness.

[0117] When the subject composition is co-administered with one or more potent CYP2D6 inhibitors, dosage adjustment may be necessary. Adjustment to lower dosages of bupropion and / or dextromethorphan in the subject combination, or preparation to reduce the frequency of administration of the subject combination, can, but is not limited to, reduce side effects or adverse reactions such as drowsiness, dizziness, or combinations thereof in the patient. For example, the recommended dosage of the subject combination when co-administered with one or more potent CYP2D6 inhibitors is a tablet containing no more than 45 mg of dextromethorphan hydrobromide and no more than 105 mg of bupropion hydrochloride, once daily, such as once a day in the morning.

[0118] Once-daily administration of the subject combination to patients receiving a potent CYP2D6 inhibitor can, but is not limited to, reduce side effects such as drowsiness, dizziness, or combinations thereof, compared to twice-daily administration of the subject combination over the same number of days. In some embodiments, drowsiness can be reduced by reducing the dosage or frequency of administration of the subject combination. In some embodiments, dizziness can be reduced by reducing the dosage or frequency of administration. Since dizziness can lead to falls, adjusting the appropriate dosage of the subject combination to a lower amount or a lower frequency of administration can reduce the risk of falls in patients taking the subject combination. For example, once-daily intake of the subject combination can reduce the risk of falls in patients compared to twice-daily intake of the subject combination over the same number of days. This can be important, for example, in elderly patients or patients suffering from dementia such as Alzheimer's disease.

[0119] In some embodiments, the subject composition can be administered to patients with moderate renal impairment. As described herein, it has been found that administration of the subject composition to poor metabolizers of CYP2D6 results in increased plasma concentrations of dextromethorphan compared to patients who are not poor metabolizers of CYP2D6. Therefore, it is recommended to monitor patients for potential side effects or adverse reactions due to dextromethorphan such as drowsiness and dizziness.

[0120] If a patient has moderate renal impairment, dose adjustment may be necessary. Adjustment to lower doses of bupropion and / or dextromethorphan in the combination of interest, or preparation to reduce the frequency of administration of the combination of interest, may, among other things, reduce side effects or adverse reactions such as drowsiness, dizziness, or combinations thereof in the patient, or the risk of side effects or adverse reactions. For example, the recommended dose of the combination of interest when administered to a patient with moderate renal impairment is a tablet containing no more than 45 mg of dextromethorphan hydrobromide and no more than 105 mg of bupropion hydrochloride, once daily, such as once daily in the morning.

[0121] Once-daily administration of the combination of interest to a patient with moderate renal impairment may, among other things, reduce side effects such as drowsiness, dizziness, or combinations thereof, or the risk of side effects, compared to twice-daily administration of the combination of interest over the same number of days. In some embodiments, drowsiness may be reduced by reducing the dose or frequency of administration of the combination of interest. In some embodiments, dizziness may be reduced by reducing the dose or frequency of administration. Since dizziness can lead to falls, adjusting the appropriate dose of the combination of interest to a lower amount or a lower frequency of administration can reduce the risk of falls in patients taking the combination of interest. For example, once-daily intake of the combination of interest can reduce the risk of falls in a patient compared to twice-daily intake of the combination of interest over the same number of days. This can be important, for example, in elderly patients or patients suffering from dementia such as Alzheimer's disease.

[0122] The term "treating" or "treatment" includes diagnosing, treating, alleviating, managing, or preventing a disease in a human or other animal, or any activity that otherwise affects the structure or function of the body of a human or other animal.

[0123] The combination of the subject matter may be used to treat a disease or condition identified as treatable by the combination of bupropion and dextromethorphan in any of the following U.S. patents: 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; 9,457,023; 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 hereby incorporated by reference in their entirety for their disclosures of diseases treatable by the combination of bupropion and dextromethorphan, including the specific embodiments and combinations described therein.

[0124] Also, the following U.S. provisional applications: 63 / 359,143 filed on July 7, 2022; 63 / 370,592 filed on August 5, 2022; 63 / 396,182 filed on August 8, 2022; 63 / 373,040 filed on August 19, 2022; and 63 / 401,541 filed on August 26, 2022 are hereby incorporated by reference in their entirety.

[0125] (Example 1) In a study of the combination of the subject in 7 subjects with moderate (GFR 30-60 mL / min) renal impairment compared to 6 controls (gender, age, and weight range matched to subjects with impairment) with normal renal function conditions, the exposure of both dextromethorphan and bupropion increased approximately 2-fold, and the clearance decreased by 50%.

[0126] (Example 2) Approximately 7%-10% of Caucasians and 3%-8% of African Americans lack the ability to metabolize CYP2D6 substrates and are classified into the poor metabolizer group. In 3 poor metabolizer groups, the pharmacokinetics of the combination of the subject were dextromethorphan C max and AUC 0-12 which increased approximately 3-fold and 3.4-fold, respectively, compared to the extensive metabolizer group. Examination of the steady-state pharmacokinetic data of 12 poor metabolizer groups treated with the combination of the subject in the efficacy study showed plasma concentrations of dextromethorphan generally higher than the exposure in the non-poor metabolizer group.

[0127] (Example 3) Co-administration of the SSRI paroxetine with the combination of the subject containing dextromethorphan and bupropion was tested in 29 healthy volunteers. Paroxetine increased the systemic exposure of dextromethorphan 2.5-fold and had no effect on bupropion. When co-administered with the combination of the subject, the systemic exposure of paroxetine increased 1.2-fold. Based on these results, when the combination of the subject is prescribed with an agent that inhibits CYP2D6, the combination of the subject should be administered once a day. Caution should be exercised when administering the combination of the subject in combination with an agent that is rapidly metabolized via CYP2D6.

[0128] (Example 4) The tablets are prepared for oral administration. They are round, two-layer 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 a sustained-release formulation. Each tablet contains the following inactive ingredients: carbomer homopolymer, colloidal silicon dioxide, crospovidone, glyceryl monocaprylocaprate, 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.

[0129] (Example 5) The characteristics of the tablets of the examples containing a combination of dextromethorphan hydrobromide, a non-competitive NMDA receptor antagonist and a sigma-1 receptor agonist, and bupropion hydrochloride, an aminoketone and a CYP450 2D6 inhibitor, were tested.

[0130] Figure 1 summarizes the effects of renal dysfunction, liver dysfunction, and the status of the CYP2D6 poor metabolizer group on exposure to the tablets of Example 4.

[0131] The results shown in Figure 1 are based on plasma concentrations in human patients after administration of tablets containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride twice daily for 8 days. The data are GMR and 90% CI. The reference used was healthy subjects matched to the renal and liver function impairment studies and were the extensive metabolizer group or ultra-rapid metabolizer group of CYP2D6 metabolism, respectively. AUC represents the area under the plasma concentration-time curve from 0 to 12 hours, BUP represents bupropion, CI is the confidence interval, C max is the maximum plasma concentration, DM represents dextromethorphan, GMR represents the geometric mean ratio, and PK represents pharmacokinetics.

[0132] In Figure 1, the results for patients with moderate renal impairment are designated as "Group 1", the results for patients with moderate hepatic impairment are designated as "Group 2", and the results for patients in the CYP2D6 poor metabolizer group are designated as "Group 3". The results are summarized in Table 1 below.

[0133] Table 1

Table 3

[0134] For example, for patients with moderate hepatic impairment (Group 2), the AUC of dextromethorphan and bupropion 0-12 and C max were not significantly different from those in healthy patients.

[0135] In patients with moderate hepatic impairment, the mean ratio of the AUC of dextromethorphan 0-12 compared to that in healthy patients was 1.17 with a 90% confidence interval of 0.85 - 1.61.

[0136] In patients with moderate hepatic impairment, the mean ratio of the C of dextromethorphan max compared to that in healthy patients was 1.21 with a 90% confidence interval of 0.90 - 1.62.

[0137] In patients with moderate hepatic impairment, the mean ratio of the AUC of bupropion 0-12 compared to that in healthy patients was 1.36 with a 90% confidence interval of 0.86 - 2.15.

[0138] In patients with moderate hepatic impairment, the mean ratio of the C of bupropion max compared to that in healthy patients was 1.44 with a 90% confidence interval of 0.90 - 2.30.

[0139] Based on these results, it is recommended that patients known to have mild or moderate hepatic impairment not have their dosages adjusted.

[0140] In patients with moderate renal impairment, the AUC of dextromethorphan 0-12 increased 2.21-fold, the C of dextromethorphan max increased 2.10-fold, the AUC of bupropion 0-12 increased 1.80-fold, and the C of bupropion max increased 1.87-fold.

[0141] Based on these results, in patients known to have moderate renal impairment, since the concentrations of dextromethorphan and bupropion are higher than those in patients with healthy renal function, dose adjustment is recommended in patients known to have moderate renal impairment. The recommended total daily dose in patients known to have moderate renal impairment is approximately 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride (for example, one tablet containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride is administered once a day, such as in the morning), or an equivalent amount of other forms of dextromethorphan and / or bupropion.

[0142] (Example 5) The effect on dextromethorphan exposure of co-administering 20 mg of paroxetine to patients taking the tablets of Example 4 containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride twice a day was measured. Compared with patients taking the tablets twice a day without taking paroxetine, the AUC of dextromethorphan 0-12 increased 2.69-fold, and the C of dextromethorphan max increased 2.38-fold.

[0143] (Example 6) In a placebo-controlled clinical trial (Study 1), the efficacy of the tablets of Example 4 for the treatment of major depressive disorder in adults was demonstrated. In this study, adult patients (aged 18 to 85 years) meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM5) for mental disorders due to MDD were randomly assigned to receive the tablets of Example 1 ("DM / BU", 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) twice daily for 6 weeks (N = 156), or to receive placebo twice daily (N = 162). The patients in Study 1 had a median age of 41 years, 67% were female, 55% were Caucasian, 35% were black, and 5% were Asian. Here, "N" represents the number of adult patients.

[0144] The primary endpoint was the change from baseline to week 6 in the total score of the Montgomery-Åsberg Depression Rating Scale (MADRS). The MADRS is a clinician-rated scale used to assess the severity of depressive symptoms. Patients were evaluated on 10 items of feelings of sadness, inner tension, decreased sleep or appetite, difficulty concentrating, fatigue, lack of interest, pessimism, and suicidal thoughts. The MADRS score ranges from 0 to 60, with higher scores indicating more severe depression. DM / BU was statistically significantly superior to placebo in the improvement of depressive symptoms measured by the decrease in the total MADRS score at week 6 (see Table 1).

[0145]

Table 4

[0146] Figure 1 shows the change from baseline in the total MADRS score by week. The change in the total MADRS score from baseline to week 1 and the change in the total MADRS score from baseline to week 2 were predefined secondary efficacy endpoints. The difference between DM / BU and placebo in the change from baseline in the total MADRS score was statistically significant at week 1 and week 2.

[0147] In tests of demographic subgroups by age, sex, and race, no differences in response were suggested.

[0148] Unless otherwise specified, all numbers expressing quantities of ingredients, amounts, percentages, and the like used in the specification and claims are to be understood as referring to exact values as set forth and also to values modified by terms such as "about," "approximately," or "substantially" in all instances. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0149] The use of the terms "comprising" or "comprises" in this specification is also intended to contemplate the use of "consisting essentially of," "consists essentially of," "consisting of," or "consists of" instead.

[0150] Any affirmative statement of an element anywhere in this specification is to be understood as intending both to include and to exclude that element.

[0151] The terms "a", "an", "the", and similar references used in the context of describing embodiments (particularly in the context of the following claims) are to be construed to cover both the singular and the plural forms unless otherwise stated or clearly contradicted by the context. The use of any and all examples provided herein, or exemplary language (e.g., "such as") is intended to better clarify the embodiments and is not intended to limit the scope of any claims. Descriptions in this specification should not be construed as indicating elements other than those essential to the implementation of the claims.

[0152] The grouping of alternative elements or embodiments disclosed herein should not be construed as a limitation. The components of each group may be referred to and claimed individually, or in any combination with other components of the group or other elements found herein. For reasons of convenience and / or expediting procedures, it is anticipated that one or more components of a group will be included in or deleted from the group. If such inclusion or deletion occurs, this specification is considered to cover the modified group and, when used in the appended claims, meets all descriptions of the Markush group.

[0153] In this specification, several embodiments are described, including the best mode known to the inventors for carrying out the embodiments described in the claims. Of course, variations of these described embodiments will be apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to appropriately use such variations, and the inventors intend for the embodiments described in the claims to be implemented in ways other than those specifically described herein. Accordingly, the claims cover modifications of the subject matter recited in the claims and all equivalents as permitted by the applicable law. Further, combinations of the above-described elements in all possible variations are contemplated unless otherwise stated herein or clearly contradicted by the context.

[0154] 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. Accordingly, alternative embodiments can be utilized in accordance with the teachings herein as examples, not limitations. Thus, the claims are not precisely limited to the embodiments as shown and described.

[0155] (Appendix) (Appendix 1) A method for treating a human patient having a neurological disorder by administering a combination of dextromethorphan and bupropion, comprising orally administering to the human patient daily a dosage form comprising 105 mg or less of bupropion hydrochloride, or a corresponding molar amount of the free base or other salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a corresponding molar amount of the free base or other salt form of dextromethorphan, 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, wherein the human patient is selected for having 1) a neurological disorder and 2) moderate renal impairment, and the human patient is determined to have moderate renal impairment by an assay on a biological sample from the patient, and wherein, for the human patient having moderate renal impairment, the risk of drowsiness and dizziness after orally administering the dosage form comprising the combination once daily to the human patient is lower than the risk that would occur if a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide were administered to the human patient twice daily over the same number of days. Method.

[0156] (Appendix 2) The method according to appendix 1, wherein a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is orally administered to the patient once a day.

[0157] (Appendix 3) The method according to appendix 1, wherein a combination of about 52.5 mg of bupropion hydrochloride and about 22.5 mg of dextromethorphan hydrobromide is orally administered to the patient twice a day.

[0158] (Appendix 4) A method of treating a human patient with a combination of dextromethorphan and bupropion, wherein the human patient is experiencing neurological symptoms, and the method comprises obtaining a biological sample from the patient or having obtained it previously, and performing an assay on the biological sample or having performed it previously to determine whether the human patient has moderate renal impairment, thereby determining whether the human patient has moderate renal impairment; if the human patient has moderate renal impairment, orally administering to the patient once a day a dosage form comprising a combination of bupropion hydrochloride at 105 mg or less, or the corresponding molar amount of the free base or other salt form of bupropion, and dextromethorphan hydrobromide at 45 mg or less, or the corresponding molar amount of the free base or salt form of dextromethorphan, 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; When the human patient does not have renal dysfunction, a dosage form containing 105 mg of bupropion hydrochloride, or an equivalent molar amount of the free base of bupropion or other salt forms, and 45 mg of dextromethorphan hydrobromide, or an equivalent molar amount of the free base of dextromethorphan or other salt forms, is orally administered to the patient twice a day, comprising In the case of the human patient having moderate renal dysfunction, the risk of drowsiness and dizziness after orally administering the dosage form containing the combination once a day to the human patient is lower than the risk that would occur when a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is administered to the human patient twice a day for the same number of days. Method.

[0159] (Appendix 5) A method for treating a human patient experiencing neurological symptoms, the method comprising a) Obtaining a biological sample from the patient or having obtained it previously, and performing an assay on the biological sample or having performed it previously to determine whether the human patient has moderate renal dysfunction, and thereby determining whether there is a risk of adverse events associated with overexposure to dextromethorphan in the human patient, wherein the result that the human patient has moderate renal dysfunction indicates that there is a risk of adverse events associated with overexposure to dextromethorphan in the human patient. b) If the human patient is at risk of adverse events associated with excessive exposure to dextromethorphan, orally administering to the human patient once a day a dosage form comprising a combination of not more than 105 mg of hydrochloric acid bupropion, or a corresponding molar amount of the free base or other salt form of bupropion, and not more than 45 mg of dextromethorphan hydrobromide, or a corresponding molar amount of the free base or other salt form of dextromethorphan, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of hydrochloric acid bupropion to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; c) If the human patient is not at risk of adverse events associated with excessive exposure to dextromethorphan, orally administering to the human patient twice a day a dosage form comprising a combination of 105 mg of hydrochloric acid bupropion, or a corresponding molar amount of the free base or other salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a corresponding molar amount of the free base or other salt form of dextromethorphan; comprising: A method.

[0160] (Appendix 6) A method for treating nervous system symptoms with a combination of dextromethorphan and bupropion, comprising orally administering to the patient once a day a dosage form comprising a combination of not more than 105 mg of hydrochloric acid bupropion, or a corresponding molar amount of the free base or other salt form of bupropion, and not more than 45 mg of dextromethorphan hydrobromide, or a corresponding molar amount of the free base or other salt form of dextromethorphan, 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 hydrochloric acid bupropion to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; The human patient is selected for having 1) neurological symptoms and 2) moderate renal impairment, and the human patient is determined to have moderate renal impairment by an assay on a biological sample from the human patient. The risk of adverse events in the human patient is reduced as compared to the risk of adverse events the patient would have if the dosage form were administered to the patient twice daily. A method.

[0161] (Appendix 7) A method for treating a human patient experiencing neurological symptoms with a combination of dextromethorphan and bupropion, obtaining or having previously obtained a biological sample from the patient, and performing or having previously performed an assay on the biological sample to determine whether the human patient has moderate renal impairment, thereby determining whether the human patient has moderate renal impairment; when the human patient has moderate renal impairment, orally administering to the patient once daily a dosage form comprising a combination of 105 mg or less of bupropion hydrochloride, or an equivalent molar amount of the free base or other salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or an equivalent molar amount of the free base or other salt form of dextromethorphan, 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; when the human patient does not have renal impairment, orally administering to the patient twice daily a dosage form comprising a combination of 105 mg of bupropion hydrochloride, or an equivalent molar amount of the free base or other salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or an equivalent molar amount of the free base or other salt form of dextromethorphan; comprising method.

[0162] (Appendix 8) A method for treating a human patient having neurological symptoms by administering a combination of dextromethorphan and bupropion, comprising orally administering to the patient once a day a dosage form containing 105 mg or less of bupropion hydrochloride, or an equivalent molar amount of the free base or other salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or an equivalent molar amount of the free base or other salt form of dextromethorphan, 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, the human patient is selected for having 1) neurological symptoms and 2) moderate renal impairment, and the human patient is determined to have moderate renal impairment by an assay on a biological sample from the human patient, in the case of the human patient having moderate renal impairment, the risk of drowsiness or dizziness after orally administering the dosage form containing the combination to the human patient once a day is lower than when administering a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide to the human patient twice a day over the same number of days, method.

[0163] (Appendix 9) The method according to Appendix 8, wherein a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is orally administered to the patient once a day.

[0164] (Appendix 10) The method according to Appendix 8, wherein a combination of about 52.5 mg of bupropion hydrochloride and about 22.5 mg of dextromethorphan hydrobromide is orally administered to the patient twice a day.

[0165] (Appendix 11) A method for treating a human patient experiencing nervous system symptoms with a combination of dextromethorphan and bupropion, obtaining a biological sample from the patient or having previously obtained it, and, performing an assay on the biological sample or having previously performed it to determine whether the human patient has moderate renal impairment, whereby, determining whether the human patient has moderate renal impairment; when the human patient has moderate renal impairment, an oral dosage form comprising a combination of not more than 105 mg of bupropion hydrochloride or an equivalent molar amount of the free base or other salt form of bupropion and not more than 45 mg of dextromethorphan hydrobromide or an equivalent molar amount of the free base or other salt form of dextromethorphan, 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, administering the dosage form to the patient twice a day; when the human patient does not have renal impairment, an oral dosage form comprising a combination of 105 mg of bupropion hydrochloride or an equivalent molar amount of the free base or other salt form of bupropion and 45 mg of dextromethorphan hydrobromide or an equivalent molar amount of the free base or other salt form of dextromethorphan, administering the dosage form to the patient twice a day; comprising, in the case of a human patient with moderate renal impairment, the risk of drowsiness or dizziness after administering the dosage form comprising the combination once a day orally to the human patient is lower than when administering a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide to the human patient twice a day over the same number of days, method.

[0166] (Appendix 12) When the human patient has moderate renal impairment, a dosage form containing a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is orally administered to the patient once a day, according to the method described in Supplementary Note 11.

[0167] (Supplementary Note 13) When the human patient has moderate renal impairment, a dosage form containing a combination of about 52.5 mg of bupropion hydrochloride and about 22.5 mg of dextromethorphan hydrobromide is orally administered to the patient twice a day, according to the method described in Supplementary Note 11.

[0168] (Supplementary Note 14) (i) about 100 mg to about 110 mg of bupropion hydrochloride, or the corresponding molar amount of the free base or other salt form of dextromethorphan, and (ii) about 40 mg to about 50 mg of dextromethorphan hydrobromide, or the corresponding molar amount of the free base or other salt form of dextromethorphan, are administered to a human patient with moderate renal impairment who has experienced a major depressive disorder, and the daily dose is optionally administered in a dosage form. A method for treating major depressive disorder in a human patient with moderate renal impairment.

[0169] (Supplementary Note 15) Bupropion and dextromethorphan are in one tablet, and one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide is orally administered once a day, according to the method described in Supplementary Note 14.

[0170] (Supplementary Note 16) Bupropion and dextromethorphan are in one tablet, and one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide is orally administered daily, according to the method described in Supplementary Note 14.

[0171] (Supplementary Note 17) (i) administering a daily dose of about 105 mg of bupropion hydrochloride and (ii) about 45 mg of dextromethorphan hydrobromide to a human patient having moderate renal impairment and experiencing major depressive disorder, said daily dose being optionally administered in a dosage form A method for treating major depressive disorder in a human patient having moderate renal impairment.

[0172] (Appendix 18) The T of dextromethorphan max is about 3 hours, the method according to any one of Appendices 1 to 17.

[0173] (Appendix 19) Said human patient has an estimated glomerular filtration rate between 30 mL / min / 1.72 m 2 and 59 mL / min / 1.72 m 2 The method according to any one of Appendices 1 to 18.

[0174] (Appendix 20) Said administering step is achieved by oral once-daily administration of one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide, the method according to any one of Appendices 1 to 19.

[0175] (Appendix 21) The steady-state plasma concentrations of dextromethorphan and bupropion are achieved within 8 days, and the accumulation rate of dextromethorphan at steady state is about 20 based on C max The method according to any one of Appendices 1 to 20.

[0176] (Appendix 22) The steady-state plasma concentrations of dextromethorphan and bupropion are achieved within 8 days, and the accumulation rate of dextromethorphan at steady state is about 32 based on AUC 0-12 The method according to any one of Appendices 1 to 21.

[0177] (Appendix 23) By administering once a day, the AUC of dextromethorphan in the human patient 0-12 is about 2.2 times higher than the AUC of dextromethorphan that would occur if the tablets were administered twice a day for 8 days to a human patient without renal impairment, 0-12 The method according to any one of Appendices 1 to 22, which avoids an increase.

[0178] (Appendix 24) By administering once a day, the C of dextromethorphan in the human patient max is about 2.1 times higher than the C of dextromethorphan that would occur if the tablets were administered twice a day for 8 days to a human patient without renal impairment, max The method according to any one of Appendices 1 to 23, which avoids an increase.

[0179] (Appendix 25) By administering once a day, the AUC of bupropion in the human patient 0-12 is about 1.8 times higher than the AUC of bupropion that would occur if the tablets were administered twice a day for 8 days to a human patient without renal impairment, 0-12 The method according to any one of Appendices 1 to 24, which avoids an increase.

[0180] (Appendix 26) By administering once a day, the C of bupropion in the human patient max is about 1.9 times higher than the C of bupropion that would occur if the tablets were administered twice a day for 8 days to a human patient without renal impairment, max The method according to any one of Appendices 1 to 25, which avoids an increase.

[0181] (Appendix 27) A method of treating major depressive disorder using a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, comprising administering to a human patient experiencing major depressive disorder a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide, wherein the human patient has a history of substance abuse, the human patient has no experience of dissociation, and the combination is optionally administered in a dosage form.

[0182] (Appendix 28) The method according to Appendix 27, wherein dextromethorphan acts as a non-competitive NMDA receptor antagonist and a sigma-1 receptor agonist.

[0183] (Appendix 29) The method according to Appendix 27 or 28, wherein the human patient is not monitored for dissociation after administration of the combination.

[0184] (Appendix 30) The method according to Appendix 27, 28, or 29, wherein the combination is self-administered by the human patient.

[0185] (Appendix 31) The method according to Appendix 27, 28, 29, or 30, wherein the combination is administered outside a medical setting.

[0186] (Appendix 32) The method according to Appendix 27, 28, 29, 30, or 31, wherein the combination is administered without direct supervision by a medical professional.

[0187] (Appendix 33) The method according to Appendix 27, 28, 29, 30, 31, or 32, wherein the human patient is not monitored for dissociation by medical staff after administration of the combination.

[0188] (Appendix 34) The human patient is not monitored by a healthcare provider for 2 hours after administration of the combination, by the method described in Appendices 27, 28, 29, 30, 31, 32, or 33.

[0189] (Appendix 35) The human patient is not evaluated to determine the time when the human patient is considered clinically stable and ready to leave the medical site, by the method described in Appendices 27, 28, 29, 30, 31, 32, 33, or 34.

[0190] (Appendix 36) The human patient is not monitored by a healthcare provider for dissociation after administration of the combination, by the method described in Appendices 27, 28, 29, 30, 31, 32, 33, 34, or 35.

[0191] (Appendix 37) The human patient is not monitored by a healthcare provider for 2 hours after oral administration of the combination, by the method described in Appendices 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36.

[0192] (Appendix 38) The combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is administered to the human patient twice a day, by the method described in Appendices 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 37.

[0193] (Appendix 39) The combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is orally administered to the human patient twice a day, by the method described in Appendix 38.

[0194] (Appendix 40) A method for treating major depressive disorder in a human patient in need of combination therapy with a potent 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 has experienced major depressive disorder and is receiving combination therapy with the potent CYP2D6 inhibitor, and wherein the combination is administered in any dosage form.

[0195] (Appendix 41) The method according to Appendix 40, wherein the potent CYP2D6 inhibitor is paroxetine.

[0196] (Appendix 42) By said once-daily administration, the AUC of dextromethorphan in the human patient 0-12 is avoided from increasing by about 2.7-fold compared to the AUC of dextromethorphan that would occur after administering the solid dosage form to the human patient twice daily for 8 days without combination therapy with the potent CYP2D6 inhibitor. The method according to Appendix 40 or 41. 0-12

[0197] (Appendix 43) By said once-daily administration, the C of dextromethorphan in the human patient max is avoided from increasing by about 2.4-fold compared to the C of dextromethorphan that would occur after administering the solid dosage form to the human patient twice daily for 8 days without combination therapy with the potent CYP2D6 inhibitor. The method according to Appendix 40, 41, or 42. max

[0198] (Appendix 44) By administering the solid dosage form to the human patient twice daily for 8 days, the AUC of bupropion in the human patient 0-12 is substantially the same as the AUC of bupropion that would occur after administering the solid dosage form to a human patient twice daily for 8 days without combination therapy with the potent CYP2D6 inhibitor. The method according to Appendix 40, 41, 42, or 43. 0-12

[0199] (Supplementary Note 45) By administering the solid dosage form to the human patient twice a day for 8 days, the C of bupropion in the human patient max would be approximately the same as the C of bupropion that would occur after administering the solid dosage form to a human patient twice a day for 8 days without concomitant therapy with the potent CYP2D6 inhibitor. The method according to Supplementary Note 40, 41, 42, 43, or 44 max

[0200] (Supplementary Note 46) i) Administering to a human patient once or twice a day a combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride, wherein the human patient is the mother of a human infant who is breastfed and who has experienced a major depressive disorder, and ii) Advising the human patient not to breastfeed the human infant during the time the combination is being administered to the human patient and for 5 days after the last administration of the combination, wherein the combination is optionally administered in dosage form. A method for reducing the risk of neurotoxicity to a human infant

[0201] (Supplementary Note 47) The human infant has a risk of seizures. The method according to Supplementary Note 46

[0202] (Supplementary Note 48) The human infant is about 3 years of age or younger. The method according to Supplementary Note 46 or 47

[0203] (Supplementary Note 49) The human infant has a risk of neurotoxicity. The method according to Supplementary Note 46, 47, or 48

[0204] (Supplementary Note 50) The combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient twice a day for about 1 week to about 6 weeks. The method according to Supplementary Note 46, 47, 48, or 49

[0205] ​ (Supplementary Note 51) The combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient twice a day for about 6 weeks by the method described in Supplementary Notes 46, 47, 48, 49, or 50.

[0206] (Supplementary Note 52) The combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient twice a day for at least 6 weeks by the method described in Supplementary Notes 46, 47, 48, 49, 50, or 51.

[0207] (Supplementary Note 53) The human patient produces breast milk substantially free of dextromethorphan 5 days after the final administration of the combination by the method described in Supplementary Notes 46, 47, 48, 49, 50, 51, or 52.

[0208] (Supplementary Note 54) The human patient produces breast milk substantially free of bupropion 5 days after the final administration of the combination by the method described in Supplementary Notes 46, 47, 48, 49, 50, 51, 52, or 53.

[0209] (Supplementary Note 55) The human infant is not exposed to a detectable amount of dextromethorphan by the method described in Supplementary Notes 46, 47, 48, 49, 50, 51, 52, 53, or 54.

[0210] (Supplementary Note 56) The human infant is not exposed to a detectable amount of bupropion by the method described in Supplementary Notes 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55.

[0211] (Supplementary Note 57) The combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient twice a day until the human patient experiences a decrease of at least about 7 from the baseline in the total MADRS score of the human patient, by the method described in Appendices 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56.

[0212] (Appendix 58) The combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient twice a day until the human patient experiences a decrease of at least about 11 from the baseline in the total MADRS score of the human patient, by the method described in Appendices 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, or 57.

[0213] (Appendix 59) The combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient twice a day until the human patient experiences a decrease of at least about 13 from the baseline in the total MADRS score of the human patient, by the method described in Appendices 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, or 58.

[0214] (Appendix 60) The combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride is administered to the human patient twice a day until the human patient experiences a decrease of at least 15.9 from the baseline in the total MADRS score of the human patient, by the method described in Appendices 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

[0215] (Appendix 61) The human infant is a breastfed infant, by the method described in Appendices 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60.

[0216] (Appendix 62) The decrease from baseline in the total MADRS score of the human patient when the combination is administered is greater than when placebo is administered, by the method described in Appendices 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, or 61.

[0217] (Appendix 63) After 1 week of administration, the decrease from baseline in the total MADRS score of the human patient when the combination is administered is greater than when placebo is administered, by the method described in Appendices 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62.

[0218] (Appendix 64) After 2 weeks of administration, the decrease from baseline in the total MADRS score of the human patient when the combination is administered is greater than when placebo is administered, by the method described in Appendices 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, or 63.

[0219] (Appendix 65) After 3 weeks of administration, the decrease from baseline in the total MADRS score of the human patient when the combination is administered is greater than when placebo is administered, by the method described in Appendices 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64.

[0220] (Appendix 66) After 4 weeks of administration, the decrease from baseline in the total MADRS score of the human patient when the combination is administered is greater than when placebo is administered, by the method described in Appendices 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65.

[0221] (Supplementary Note 67) After 5 weeks of administration, the decrease from baseline in the total MADRS score of the human patient when the combination is administered is greater than when placebo is administered, by the method described in Supplementary Notes 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, or 66.

[0222] (Supplementary Note 68) After 6 weeks of administration, the decrease from baseline in the total MADRS score of the human patient when the combination is administered is greater than when placebo is administered, by the method described in Supplementary Notes 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, or 67.

[0223] (Supplementary Note 69) Administration of the combination does not result in prolongation of the QT interval of the human patient, by the method described in Supplementary Notes 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, or 68.

[0224] (Supplementary Note 70) A method of treating a human patient having a major depressive disorder, comprising administering a therapeutically effective amount of a combination of dextromethorphan and bupropion, wherein the human patient has mild liver dysfunction defined as Child-Pugh A or moderate liver dysfunction defined as Child-Pugh B, the therapeutically effective amount is the same amount as would be administered to a human patient with normal liver function, and the combination is optionally administered in a dosage form.

[0225] (Supplementary Note 71) The combination is administered twice daily, and the combination comprises (i) about 45 mg of dextromethorphan hydrobromide and (ii) about 105 mg of bupropion hydrochloride, by the method described in Supplementary Note 70.

[0226] (Supplementary Note 72) Determining whether a human patient has liver dysfunction, when the human patient has mild liver dysfunction defined as Child-Pugh A or moderate liver dysfunction defined as Child-Pugh B, administering to the human patient a combination of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride twice a day, when the human patient has severe liver dysfunction defined as Child-Pugh C, avoiding using the combination of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride in the human patient, comprising, the combination is administered in an optional dosage form, A method for treating major depressive disorder.

[0227] (Supplementary Note 73) The method according to Supplementary Note 72, wherein the human patient has mild liver dysfunction defined as Child-Pugh A.

[0228] (Supplementary Note 74) The method according to Supplementary Note 72, wherein the human patient has moderate liver dysfunction defined as Child-Pugh B.

[0229] (Supplementary Note 75) The method according to Supplementary Note 72, wherein the human patient has severe liver dysfunction defined as Child-Pugh C and the use of the combination of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride is avoided.

[0230] (Supplementary Note 76) The method according to any one of Supplementary Notes 1 to 75, wherein the dosage form is a solid dosage form.

[0231] (Supplementary Note 77) The method according to Supplementary Note 76, wherein the solid dosage form further comprises a carbomer homopolymer.

[0232] (Appendix 78) The solid dosage form is the method according to Appendix 76 or 77, further comprising colloidal silicon dioxide.

[0233] (Appendix 79) The solid dosage form is the method according to Appendix 76, 77, or 78, further comprising crospovidone.

[0234] (Appendix 80) The solid dosage form is the method according to Appendix 76, 77, 78, or 79, further comprising glyceryl monocaprylocaprate.

[0235] (Appendix 81) The solid dosage form is the method according to Appendix 76, 77, 78, 79, or 80, further comprising L-cysteine hydrochloride monohydrate.

[0236] (Appendix 82) The solid dosage form is the method according to Appendix 76, 77, 78, 79, 80, or 81, further comprising magnesium stearate.

[0237] (Appendix 83) The solid dosage form is the method according to Appendix 76, 77, 78, 79, 80, 81, or 82, further comprising microcrystalline cellulose.

[0238] (Appendix 84) The solid dosage form is the method according to Appendix 76, 77, 78, 79, 80, 81, 82, or 83, further comprising polyvinyl alcohol.

[0239] (Appendix 85) The solid dosage form is the method according to Appendix 76, 77, 78, 79, 80, 81, 82, 83, or 84, further comprising red iron oxide.

[0240] (Appendix 86) The solid dosage form further comprises sodium lauryl sulfate, and is prepared by the method described in Appendices 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85.

[0241] (Appendix 87) The solid dosage form further comprises stearic acid, and is prepared by the method described in Appendices 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, or 86.

[0242] (Appendix 88) The solid dosage form further comprises talc, and is prepared by the method described in Appendices 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, or 87.

[0243] (Appendix 89) The solid dosage form further comprises titanium dioxide, and is prepared by the method described in Appendices 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, or 88.

[0244] (Appendix 90) The solid dosage form further comprises yellow iron oxide, and is prepared by the method described in Appendices 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, or 89.

[0245] (Appendix 91) The solid dosage form is a tablet, and is prepared by the method described in Appendices 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90.

[0246] (Appendix 92) The tablet is a two-layer tablet, and is prepared by the method described in Appendix 91.

[0247] (Appendix 93) The solid dosage form is for oral administration, and is prepared by the method described in Appendices 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, or 92.

[0248] (Appendix 94) The solid dosage form is administered orally in the morning by the method described in Supplementary Note 93.

[0249] (Supplementary Note 95) Dextromethorphan hydrobromide is an immediate-release preparation by the method described in any one of Supplementary Notes 1 to 94.

[0250] (Supplementary Note 96) Bupropion hydrochloride is a sustained-release preparation by the method described in any one of Supplementary Notes 1 to 95.

[0251] (Supplementary Note 97) The neurological symptoms are major depressive disorder by the method described in any one of Supplementary Notes 1 to 96.

[0252] (Supplementary Note 98) The neurological symptoms are excitation associated with Alzheimer's disease by the method described in any one of Supplementary Notes 1 to 97.

[0253] (Supplementary Note 99) The neurological symptoms are excitation associated with dementia by the method described in any one of Supplementary Notes 1 to 98.

[0254] (Supplementary Note 100) The neurological symptoms are fibromyalgia by the method described in any one of Supplementary Notes 1 to 99.

[0255] (Supplementary Note 101) The neurological symptoms are generalized anxiety disorder by the method described in any one of Supplementary Notes 1 to 100.

[0256] (Supplementary Note 102) The human patient is at risk of falling by the method described in any one of Supplementary Notes 1 to 101.

Claims

1. A method of treating a human patient having a neurological disorder by administering a combination of dextromethorphan and bupropion, comprising: orally administering to the human patient daily a dosage form comprising 105 mg or less of bupropion hydrochloride, or an equivalent molar amount of the free base or other salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or an equivalent molar amount of the free base or other salt form of dextromethorphan, 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; wherein the human patient is selected for having 1) a neurological disorder and 2) moderate renal impairment, and the human patient is determined to have moderate renal impairment by an assay on a biological sample from the patient; and wherein, for the human patient having moderate renal impairment, the risk of drowsiness and dizziness after orally administering the dosage form comprising the combination once daily to the human patient is lower than the risk that would occur if a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide were administered to the human patient twice daily for the same number of days. A method.

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

3. The method of claim 1, wherein a combination of about 52.5 mg of bupropion hydrochloride and about 22.5 mg of dextromethorphan hydrobromide is orally administered to the patient 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 disorder, the method comprising: obtaining a biological sample from the patient or having previously obtained a biological sample from the patient; and performing an assay on the biological sample or having previously performed an assay on the biological sample to determine whether the human patient has moderate renal impairment; thereby determining whether the human patient has moderate renal impairment. When the human patient has moderate renal impairment, an oral dosage form containing 105 mg or less of bupropion hydrochloride, or the corresponding molar amount of the free base or other salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or the corresponding molar amount of the free base or salt form of dextromethorphan, is administered orally to the patient once a day, 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, the step of When the human patient does not have renal impairment, an oral dosage form containing 105 mg of bupropion hydrochloride, or the corresponding molar amount of the free base or other salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or the corresponding molar amount of the free base or other salt form of dextromethorphan, is administered orally to the patient twice a day, the step of comprising In the case of the human patient having moderate renal impairment, the risk of drowsiness and dizziness after orally administering the dosage form containing the combination to the human patient once a day is lower than the risk that would occur if a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide were administered to the human patient twice a day over the same number of days. Method.

5. A method for treating a human patient experiencing neurological symptoms, the method comprising a) obtaining a biological sample from the patient or having obtained it previously, and assaying the biological sample or having assayed it previously to determine whether the human patient has moderate renal impairment and whether there is a risk of adverse events associated with overexposure to dextromethorphan in the human patient, wherein the result that the human patient has moderate renal impairment indicates that there is a risk of adverse events associated with overexposure to dextromethorphan in the human patient, the step of b) If there is a risk of adverse events associated with excessive exposure to dextromethorphan in the human patient, administering orally to the human patient once a day a dosage form comprising a combination of not more than 105 mg of bupropion hydrochloride, or an equivalent molar amount of the free base or other salt form of bupropion, and not more than 45 mg of dextromethorphan hydrobromide, or an equivalent molar amount of the free base or other salt form of dextromethorphan, 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; c) If there is no risk of adverse events associated with excessive exposure to dextromethorphan in the human patient, administering orally to the human patient twice a day a dosage form comprising a combination of 105 mg of bupropion hydrochloride, or an equivalent molar amount of the free base or other salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or an equivalent molar amount of the free base or other salt form of dextromethorphan; comprising a method.

6. A method for treating neurological symptoms with a combination of dextromethorphan and bupropion, comprising the step of orally administering to the patient once a day a dosage form comprising a combination of not more than 105 mg of bupropion hydrochloride, or an equivalent molar amount of the free base or other salt form of bupropion, and not more than 45 mg of dextromethorphan hydrobromide, or an equivalent molar amount of the free base or other salt form of dextromethorphan, 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, wherein the human patient is selected for having 1) neurological symptoms and 2) moderate renal impairment, and the human patient is determined to have moderate renal impairment by an assay on a biological sample from the human patient. A method in which the risk of adverse events in the human patient is reduced as compared to the risk of adverse events that the patient would have if the dosage form was administered to the patient twice a day. Method. **Claim 7** A method for treating a human patient experiencing neurological symptoms with a combination of dextromethorphan and bupropion, obtaining a biological sample from the patient or having obtained it previously, and performing an assay on the biological sample or having performed it previously to determine whether the human patient has moderate renal impairment, whereby a step of determining whether the human patient has moderate renal impairment; if the human patient has moderate renal impairment, orally administering to the patient once a day a dosage form comprising a combination of bupropion hydrochloride at 105 mg or less, or a corresponding molar amount of free base or other salt form of bupropion, and dextromethorphan hydrobromide at 45 mg or less, or a corresponding molar amount of free base or other salt form of dextromethorphan, 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; if the human patient does not have renal impairment, orally administering to the patient twice a day a dosage form comprising a combination of 105 mg of bupropion hydrochloride, or a corresponding molar amount of free base or other salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a corresponding molar amount of free base or other salt form of dextromethorphan; comprising Method. **Claim 8** A method for treating a human patient having neurological symptoms by administering a combination of dextromethorphan and bupropion, An oral dosage form containing not more than 105 mg of bupropion hydrochloride, or the corresponding molar amount of the free base or other salt form of bupropion, and not more than 45 mg of dextromethorphan hydrobromide, or the corresponding molar amount of the free base or other salt form of dextromethorphan, is orally administered to the patient once a day, and 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. The human patient is selected for 1) having neurological symptoms and 2) having moderate renal impairment, and the human patient is determined to have moderate renal impairment by an assay on a biological sample from the human patient. In the case of the human patient having moderate renal impairment, the risk of drowsiness or dizziness after orally administering the dosage form containing the combination to the human patient once a day is lower than when a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is administered to the human patient twice a day for the same number of days. Method.

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

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

11. A method for treating a human patient experiencing neurological symptoms with a combination of dextromethorphan and bupropion, obtaining a biological sample from the patient or having obtained it previously, and performing an assay on the biological sample or having performed it previously to determine whether the human patient has moderate renal impairment, comprising the step of determining whether the human patient has moderate renal impairment thereby. When the human patient has moderate renal impairment, an oral dosage form comprising a combination of not more than 105 mg of bupropion hydrochloride, or the corresponding molar amount of the free base or other salt form of bupropion, and not more than 45 mg of dextromethorphan hydrobromide, or the corresponding molar amount of the free base or other salt form of dextromethorphan, is orally administered to the patient twice a day, 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, step; When the human patient does not have renal impairment, an oral dosage form comprising a combination of 105 mg of bupropion hydrochloride, or the corresponding molar amount of the free base or other salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or the corresponding molar amount of the free base or other salt form of dextromethorphan, is orally administered to the patient twice a day, step; comprising; In the case of a human patient with moderate renal impairment, the risk of drowsiness or dizziness after orally administering the dosage form comprising the combination once a day to the human patient is lower than that when a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is administered to the human patient twice a day for the same number of days. Method.

12. The method according to claim 11, wherein when the human patient has moderate renal impairment, a dosage form comprising a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is orally administered to the patient once a day.

13. The method according to claim 11, wherein when the human patient has moderate renal impairment, a dosage form comprising a combination of about 52.5 mg of bupropion hydrochloride and about 22.5 mg of dextromethorphan hydrobromide is orally administered to the patient twice a day.

14. (i) about 100 mg to about 110 mg of bupropion hydrochloride, or an equivalent molar amount of the free base or other salt form of dextromethorphan, and (ii) about 40 mg to about 50 mg of dextromethorphan hydrobromide, or an equivalent molar amount of the free base or other salt form of dextromethorphan, in a daily dose, which is administered to a human patient having moderate renal impairment and experiencing a major depressive disorder, wherein the daily dose is optionally administered in a dosage form, A method for treating a major depressive disorder in a human patient having moderate renal impairment. **Claim 15** The method according to claim 14, wherein bupropion and dextromethorphan are in one tablet, and one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide is administered orally once a day. **Claim 16** The method according to claim 14, wherein bupropion and dextromethorphan are in one tablet, and one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide is administered orally daily. **Claim 17** (i) about 105 mg of bupropion hydrochloride and (ii) about 45 mg of dextromethorphan hydrobromide in a daily dose, which is administered to a human patient having moderate renal impairment and experiencing a major depressive disorder, wherein the daily dose is optionally administered in a dosage form, A method for treating a major depressive disorder in a human patient having moderate renal impairment. **Claim 18** The T of the dextrometer fan ｍａｘ is about 3 hours, the method according to any one of claims 1 to 17. **Claim 19** The human patient has an estimated glomerular filtration rate between 30 mL / min / 1.72 m ２ and 59 mL / min / 1.72 m ２ The method according to any one of claims 1 to 18. **Claim 20** The method according to any one of claims 1 to 19, wherein the administering step is achieved by oral administration once a day of one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide. **Claim 21** The steady-state plasma concentrations of dextromethorphan and bupropion are achieved within 8 days, and the accumulation rate of dextromethorphan at steady state is about 20 based on C ｍａｘ The method according to any one of claims 1 to 20, which is about 20 based on C **Claim 22** The steady-state plasma concentrations of dextromethorphan and bupropion are achieved within 8 days, and the accumulation rate of dextromethorphan at steady state is about 32 based on the AUC ０－１２ according to any one of claims 1 to 21. **Claim 23** By administering once a day, the AUC of dextromethorphan in the human patient ０－１２ is the AUC of dextromethorphan that would occur when the tablets are administered twice a day for 8 days to a human patient without renal dysfunction ０－１２ The method according to any one of claims 1 to 22, which avoids an increase of about 2.2 times as compared with **Claim 24** By administering once a day, the C of dextromethorphan in the human patient ｍａｘ is about 2.1 times higher than the C of dextromethorphan that would occur when the tablets are administered twice a day for 8 days to a human patient without renal dysfunction. ｍａｘ The method according to any one of claims 1 to 23, which avoids such an increase. **Claim 25** By administering once a day, the AUC of bupropion in the human patient ０－１２ is such that it avoids increasing by about 1.8 times as compared to the AUC of bupropion that would occur when the tablets are administered twice a day for 8 days to a human patient without renal dysfunction ０－１２ The method according to any one of claims 1 to 24. **Claim 26** By administering once a day, the C of bupropion in the human patient ｍａｘ is such that it avoids an approximately 1.9-fold increase compared to the C of bupropion that would occur when the tablets are administered twice a day for 8 days to a human patient without renal dysfunction. The method according to any one of claims 1 to 25 ｍａｘ ​ **Claim 27** A method for treating a major depressive disorder using a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, which comprises administering to a human patient experiencing a major depressive disorder not more than twice a day a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide, wherein the human patient has a history of drug abuse, the human patient has no experience of dissociation, and the combination is optionally administered in a dosage form.

28. The method according to claim 27, wherein the dextromethorphan acts as a non-competitive NMDA receptor antagonist and a sigma-1 receptor agonist.

29. The method according to claim 27 or 28, wherein the human patient is not monitored for dissociation after administration of the combination.

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

31. The method according to claim 27, 28, 29, or 30, wherein the combination is administered outside a medical setting.

32. The method according to claim 27, 28, 29, 30, or 31, wherein the combination is administered without direct supervision by a medical professional.

33. The method according to claim 27, 28, 29, 30, 31, or 32, wherein the human patient is not monitored for dissociation by a healthcare provider after administration of the combination.

34. The method according to claim 27, 28, 29, 30, 31, 32, or 33, wherein the human patient is not monitored by a healthcare provider for 2 hours after administration of the combination.

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

36. The method according to claim 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein the human patient is not monitored for dissociation by a healthcare provider after administration of the combination.

37. The method according to claim 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein the human patient is not monitored by a healthcare provider for 2 hours after oral administration of the combination.

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

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

40. A method for treating major depressive disorder in a human patient in need of combination therapy with a potent 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 has experienced major depressive disorder and is receiving combination therapy with the potent CYP2D6 inhibitor, and the combination is optionally administered in dosage form.

41. The method according to claim 40, wherein the potent CYP2D6 inhibitor is paroxetine.

42. By the administration once a day, the AUC of dextromethorphan in the human patient ０－１２ is the AUC of dextromethorphan that would occur after administering the solid dosage form to the human patient twice a day for 8 days without co-treatment with the potent CYP2D6 inhibitor ０－１２ The method according to claim 40 or 41, which avoids an approximately 2.7-fold increase compared to

43. By administering once daily, the C of dextromethorphan in the human patient ｍａｘ would be about 2.4 times higher than the C of dextromethorphan that would occur after administering the solid dosage form twice daily for 8 days to the human patient without co-treatment with the potent CYP2D6 inhibitor ｍａｘ The method according to claim 40, 41 or 42, which avoids an increase of about 2.4-fold

44. By administering the solid dosage form to the human patient twice daily for 8 days, the AUC of bupropion in the human patient ０－１２ is substantially the same as the AUC of bupropion that would occur after administering the solid dosage form to a human patient twice daily for 8 days without co-treatment with the potent CYP2D6 inhibitor ０－１２ The method according to claim 40, 41, 42, or 43.

45. By administering the solid dosage form to the human patient twice a day for 8 days, the C of bupropion in the human patient ｍａｘ will be the C of bupropion that would occur after administering the solid dosage form to a human patient twice a day for 8 days without concomitant therapy with the potent CYP2D6 inhibitor ｍａｘ and is substantially the same, the method according to claim 40, 41, 42, 43, or 44.

46. i) Administering to a human patient, who is a mother of a human infant secreting breast milk and has experienced major depressive disorder, once or twice daily a combination of about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride; and ii) Advising the human patient not to breastfeed the human infant during the period when the combination is being administered to the human patient and for 5 days after the last administration of the combination, wherein the combination is optionally administered in dosage form, a method for reducing the risk of neurotoxicity to a human infant.

47. The method according to claim 46, wherein the human infant is at risk of seizures.

48. The method according to claim 46 or 47, wherein the human infant is about 3 years old or younger.

49. The method according to claim 46, 47, or 48, wherein the human infant is at risk of neurotoxicity.

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

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

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

53. The method according to claim 46, 47, 48, 49, 50, 51, or 52, wherein the human patient produces breast milk substantially free of dextromethorphan 5 days after the final administration of the combination.

54. The method according to claim 46, 47, 48, 49, 50, 51, 52, or 53, wherein the human patient produces breast milk substantially free of bupropion 5 days after the final administration of the combination.

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

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

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

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

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

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

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

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

63. After one week of administration, the decrease from baseline in the total MADRS score of the human patient when the combination is administered is greater than when a placebo is administered, according to the method of claims 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62.

64. After two weeks of administration, the decrease from baseline in the total MADRS score of the human patient when the combination is administered is greater than when a placebo is administered, according to the method of claims 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, or 63.

65. After three weeks of administration, the decrease from baseline in the total MADRS score of the human patient when the combination is administered is greater than when a placebo is administered, according to the method of claims 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64.

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

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

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

69. Administration of the combination does not result in prolongation of the QT interval of the human patient, the method according to 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.

70. A method of treating a human patient having a major depressive disorder, comprising administering a therapeutically effective amount of a combination of dextromethorphan and bupropion, wherein the human patient has mild liver dysfunction defined as Child-Pugh A or moderate liver dysfunction defined as Child-Pugh B, the therapeutically effective amount being the same amount as would be administered to a human patient with normal liver function, and the combination is optionally administered in a dosage form.

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

72. Determining whether the human patient has liver dysfunction, If the human patient has mild liver dysfunction defined as Child-Pugh A or moderate liver dysfunction defined as Child-Pugh B, administering to the human patient, twice a day, a combination of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride; If the human patient has severe liver dysfunction defined as Child-Pugh C, avoiding using the combination of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride in the human patient; comprising; the combination is optionally administered in a dosage form; A method for treating major depressive disorder.

73. The method according to claim 72, wherein the human patient has mild liver dysfunction defined as Child-Pugh A.

74. The method according to claim 72, wherein the human patient has moderate liver dysfunction defined as Child-Pugh B.

75. The method according to claim 72, wherein the human patient has severe liver dysfunction defined as Child-Pugh C, and the use of the combination of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride is avoided.

76. The method according to any one of claims 1 to 75, wherein the dosage form is a solid dosage form.

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

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

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

80. The method according to claim 76, 77, 78, or 79, wherein the solid dosage form further comprises glyceryl monocaprylocaprate.

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

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

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

84. The solid dosage form further comprises polyvinyl alcohol, the method according to any one of claims 76, 77, 78, 79, 80, 81, 82, or 83.

85. The solid dosage form further comprises iron(III) oxide red, the method according to any one of claims 76, 77, 78, 79, 80, 81, 82, 83, or 84.

86. The solid dosage form further comprises sodium lauryl sulfate, the method according to any one of claims 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85.

87. The solid dosage form further comprises stearic acid, the method according to any one of claims 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, or 86.

88. The solid dosage form further comprises talc, the method according to any one of claims 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, or 87.

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

90. The solid dosage form further comprises iron(III) oxide yellow, the method according to any one of claims 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, or 89.

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

92. The tablet is a two-layer tablet, the method according to claim 91.

93. The solid dosage form is for oral administration, the method according to any one of claims 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, or 92.

94. The solid dosage form is for oral administration in the morning, the method according to claim 93.

95. Dextromethorphan hydrobromide is an immediate-release formulation, the method according to any one of claims 1 to 94.

96. Bupropion hydrochloride is a sustained-release formulation, the method according to any one of claims 1 to 95.

97. The neurological symptom is a major depressive disorder, the method according to any one of claims 1 to 96.

98. The neurological symptom is excitement associated with Alzheimer's disease, the method according to any one of claims 1 to 97.

99. The method according to any one of claims 1 to 98, wherein the neurological symptom is excitement associated with dementia.

100. The method according to any one of claims 1 to 99, wherein the neurological symptom is fibromyalgia.

101. The method according to any one of claims 1 to 100, wherein the neurological symptom is generalized anxiety disorder.

102. The method according to any one of claims 1 to 101, wherein the human patient is at risk of falling.

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