Treatment of the low dextrorphan metabolism group by combination use of bupropion and dextromethorphan

Abstract

This specification discloses a method for treating symptoms of the nervous system by combining a dextrometorphan and bupropion. This method is targeted at patients with a CYP2D6 poor metabolizer group suffering from a neurological or psychiatric disease such as a major depressive disorder.

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims priority to U.S. Provisional Application No. 63 / 357,471, filed on June 30, 2022, U.S. Provisional Application No. 63 / 370,577, filed on August 5, 2022, and U.S. Provisional Application No. 63 / 370,769, filed on August 8, 2022, the entire disclosures of which are incorporated herein by reference.

[0002] (Technical Field) The present disclosure relates to the treatment of various neuropsychiatric disorders or symptoms by the combination of bupropion and dextromethorphan in patients having a CYP2D6 - poor metabolizer genotype or a CYP2D6 - poor metabolizer phenotype.

Summary of the Invention

Means for Solving the Problems

[0003] Disclosed herein is a method for treating symptoms of the nervous system (such as depression, e.g., major depressive disorder, agitation associated with Alzheimer's disease (or agitation associated with Alzheimer's - type dementia), agitation associated with dementia, anxiety (or generalized anxiety disorder), neuropathic pain, or peripheral diabetic neuropathic pain, etc.) in CYP2D6 - poor metabolizers, the method comprising administering to a human patient known to be a CYP2D6 - poor metabolizer in need thereof, once daily, for example, a daily dose of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide.

[0004] This specification discloses a method for treating patients with major depressive disorder by administering a combination of dextromethorphan and bupropion. This method is targeted at patients with major depressive disorder, neurological disorders or symptoms such as CYP2D6 poor metabolizer genotype or CYP2D6 poor metabolizer phenotype, or mental disorders or symptoms. Usually, the CYP2D6 genotype or phenotype is determined by examining a biological sample from the patient. In this method, the dosage form is administered orally, for example, once a day to the patient. The dosage form contains a combination of bupropion hydrochloride at 105 mg or less, or a molar equivalent amount of the free base or other salt form of bupropion, and dextromethorphan hydrobromide at 45 mg or less, or a molar equivalent 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 equal to 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. Alternatively, a dosage of approximately 52.5 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base form or other salt form of bupropion, and 22.5 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base form or other salt form of dextromethorphan may be orally administered twice a day. As a result, in the case of patients with the CYP2D6 poor metabolizer genotype, the risk of dizziness, which is a potential side effect of dextromethorphan exposure, is lower after orally administering the dosage form containing the combination once a day to the patient than when administering a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide twice a day to the patient over the same number of days.

[0005] In some embodiments, when the patient does not have a CYP2D6 poor metabolizer genotype or CYP2D6 poor metabolizer phenotype, the dosage form is orally administered to the patient twice a day, and the dosage form includes a combination of 105 mg or more of bupropion hydrochloride, or an equivalent molar amount of free base or other salt form of bupropion, and 45 mg or more of dextromethorphan hydrobromide, or an equivalent molar amount of free base or other salt form of dextromethorphan.

[0006] Some embodiments A method for treating a patient having a neurological disorder by administering a combination of dextromethorphan and bupropion, comprising orally administering to the patient once a day a dosage form comprising 105 mg or less of bupropion hydrochloride, or an equivalent molar amount of free base or other salt form of bupropion, and 45 mg or less 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 in the dosage form is approximately equal to 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, comprising wherein the patient is selected for 1) having the neurological disorder and 2) being a CYP2D6 poor metabolizer group, wherein the patient is determined to be a CYP2D6 poor metabolizer group by an assay on a biological sample from the patient, In the case of the patient being a CYP2D6 poor metabolizer group, the risk of drowsiness or dizziness after orally administering the dosage form comprising the combination to the 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 patient twice a day over the same number of days. method, comprising.

[0007] Some embodiments A method of treating a patient experiencing neurological 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 patient is a CYP2D6 poor metabolizer, determining whether the patient is a CYP2D6 poor metabolizer, if the patient is a CYP2D6 poor metabolizer, orally administering once daily to the patient a dosage form comprising a combination of not more than 105 mg of bupropion hydrochloride, or a corresponding molar amount of free base or other salt form of bupropion, and not more than 45 mg of dextromethorphan hydrobromide, or a corresponding molar amount of free base or other salt form of dextromethorphan, wherein the molar ratio of bupropion to dextromethorphan is approximately equal to 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 patient is not a CYP2D6 poor metabolizer, orally administering twice daily to the patient 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, for a patient who is a CYP2D6 poor metabolizer, the risk of drowsiness or dizziness after orally administering once daily to the patient the dosage form comprising the combination 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 twice daily to the patient over the same number of days, method, comprising.

[0008] Some embodiments are, A method for treating a patient experiencing neurological symptoms, comprising: a) 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 is in the CYP2D6 poor metabolizer group, or to determine whether there is a risk of adverse events associated with excessive exposure to dextromethorphan in the patient, wherein a result that the patient is in the CYP2D6 poor metabolizer group indicates that there is a risk of adverse events associated with excessive exposure to dextromethorphan in the patient; b) if there is a risk of adverse events associated with excessive exposure to dextromethorphan in the patient, orally administering once daily to the patient a dosage form comprising a combination of not more than 105 mg of hydrochloric acid bupropion or a corresponding molar amount of free base or other salt form of bupropion and not more than 45 mg of dextromethorphan hydrobromide or a corresponding molar amount of free base or other salt form of dextromethorphan, wherein the molar ratio of bupropion to dextromethorphan is approximately equal to 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 there is no risk of adverse events associated with excessive exposure to dextromethorphan in the patient, orally administering twice daily to the patient a dosage form comprising a combination of 105 mg of hydrochloric acid bupropion 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 comprising.

[0009] Some embodiments are: A method for treating neurological symptoms with a combination of dextromethorphan and bupropion, comprising: Administering to a patient once daily orally 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 in the dosage form is approximately equal to 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 patient is selected for having 1) symptoms of the nervous system and 2) being a CYP2D6 poor metabolizer, and the patient is determined to be a CYP2D6 poor metabolizer 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 daily, Method, comprising.

[0010] Some embodiments are, A method of treating a patient experiencing symptoms of the nervous system 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 to determine whether the patient is a CYP2D6 poor metabolizer, or having previously performed it, the step of determining whether the patient is a CYP2D6 poor metabolizer, and When the patient is a CYP2D6 poor metabolizer, orally administering to the patient once a day 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 equal to 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 patient is not a CYP2D6 poor metabolizer, orally administering to the patient twice a day a dosage form comprising 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 a method comprising.

[0011] Some embodiments are A method for treating a patient having a neurological disorder by administering a combination of dextromethorphan and bupropion, orally administering to the patient once a day 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 equal to 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 for having 1) symptoms of the nervous system and 2) being in the CYP2D6 poor metabolizer group, and the patient is determined to be in the CYP2D6 poor metabolizer group by assay of a biological sample from the patient. In the case of the patient who is in the CYP2D6 poor metabolizer group, the risk of drowsiness and dizziness after oral administration of the dosage form containing the combination to the patient once a day 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 patient twice a day for the same number of days. Method comprising.

[0012] Some embodiments are A method for treating a patient experiencing symptoms of the nervous system 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 to determine whether the patient is in the CYP2D6 poor metabolizer group or having previously performed it, a step of determining whether the patient is in the CYP2D6 poor metabolizer group; if the patient is in the CYP2D6 poor metabolizer group, orally administering to the patient once a day a dosage form comprising a combination of 105 mg or less of bupropion hydrochloride, or a corresponding molar amount of the free base of bupropion or another salt form, and 45 mg or less of dextromethorphan hydrobromide, or a corresponding molar amount of the free base of dextromethorphan or another salt form, wherein the molar ratio of bupropion to dextromethorphan is approximately equal to 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 patient is not in the CYP2D6 poor metabolizer group, administering an oral dosage form containing 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, to the patient twice a day; comprising, in the case of the patient who is in the CYP2D6 poor metabolizer group, the risk of drowsiness and dizziness after administering the dosage form containing the combination to the patient once a day is lower than the risk that would occur when administering a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide to the patient twice a day over the same number of days, method, comprising.

Brief Description of the Drawings

[0013]

Figure 1

Modes for Carrying Out the Invention

[0014] Disclosed herein is a method for treating neurological symptoms (such as depression, for example major depressive disorder, agitation associated with Alzheimer's disease (or agitation associated with Alzheimer's type dementia), agitation associated with dementia, anxiety (or generalized anxiety disorder), neuropathic pain, or peripheral diabetic neuropathic pain, etc.) in the CYP2D6 poor metabolizer group, the method comprising administering 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide in a daily dose, such as once a day, to a human patient known to be in the CYP2D6 poor metabolizer group in need thereof.

[0015] In some embodiments, a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is present in the tablet.

[0016] In some embodiments, by once-daily administration, the AUC of dextromethorphan that occurs after administering the tablet twice daily for 8 days to a human patient who is a high CYP2D6 metabolizer or an ultra-rapid CYP2D6 metabolizer 0-12 is avoided from increasing by about 3.4-fold compared to the AUC of dextromethorphan in a human patient. 0-12

[0017] In some embodiments, by once-daily administration, the C of dextromethorphan that occurs after administering the tablet twice daily for 8 days to a human patient who is a high CYP2D6 metabolizer or an ultra-rapid CYP2D6 metabolizer max is avoided from increasing by about 3-fold compared to the C of dextromethorphan. max

[0018] In some embodiments, the tablet is orally administered in the morning.

[0019] Immediate-release formulation In some embodiments, dextromethorphan is an immediate-release formulation.

[0020] In some embodiments, bupropion is a sustained-release formulation.

[0021] In some embodiments, the tablet further comprises a carbomer homopolymer.

[0022] In some embodiments, the tablet further comprises colloidal silicon dioxide.

[0023] In some embodiments, the tablet further comprises crospovidone.

[0024] In some embodiments, the tablet further comprises glyceryl monocaprylocaprate.

[0025] ​​In some embodiments, the tablet further comprises L-cysteine hydrochloride monohydrate.

[0026] In some embodiments, the tablet further comprises magnesium stearate.

[0027] In some embodiments, the tablet further comprises microcrystalline cellulose.

[0028] In some embodiments, the tablet further comprises polyvinyl alcohol.

[0029] In some embodiments, the tablet further comprises iron oxide red.

[0030] In some embodiments, the tablet further comprises sodium lauryl sulfate.

[0031] In some embodiments, the tablet further comprises stearic acid.

[0032] In some embodiments, the tablet further comprises talc.

[0033] In some embodiments, the tablet further comprises titanium dioxide.

[0034] In some embodiments, the tablet further comprises iron oxide yellow.

[0035] In some embodiments, the tablet further comprises iron oxide yellow. In some embodiments, when the tablet is administered to a human patient twice a day for 8 days, the AUC of bupropion obtained after administering the tablet to a human patient who is a high CYP2D6 metabolizer or an ultra-rapid CYP2D6 metabolizer twice a day for 8 days 0-12 compared to, the human patient will have approximately the same AUC of bupropion 0-12 and will have.

[0036] In some embodiments, when a tablet is administered to a human patient twice a day for 8 days, the concentration of bupropion obtained after administering the tablet to a human patient who is in the high CYP2D6 metabolizer group or the ultra-rapid CYP2D6 metabolizer group twice a day for 8 days max is such that the human patient will have approximately the same concentration of bupropion max as compared to

[0037] The chemical name of dextromethorphan hydrobromide is morphinan, 3-methoxy-17-methyl-, (9α,13α,14α), hydrobromide monohydrate. The empirical formula of dextromethorphan hydrobromide is C 18 H 25 NO·HBr·H2O, and the molecular weight is 370.33 (the dextromethorphan base is 271.4). The structural formula is as follows. [Chemical formula]

[0038] Dextromethorphan hydrobromide powder is white or almost white, crystalline, and poorly soluble in water.

[0039] The chemical name of bupropion hydrochloride is (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The empirical formula of bupropion hydrochloride is C 13 H 18 ClNO·HCl, and the molecular weight is 276.2 (the bupropion base is 239.74). The structural formula is as follows. [Chemical formula] Bupropion hydrochloride powder is white and very soluble in water.

[0040] Cytochrome P450 2D6 (CYP2D6) is an enzyme encoded by the CYP2D6 gene in humans. The function of CYP2D6 in a specific subject can be described as one of the following: 1) poor metabolizer with little or no CYP2D6 function, 2) extensive metabolizer with normal CYP2D6 function, 3) intermediate metabolizer with a drug metabolism rate intermediate between poor and extensive metabolizers, and 4) ultra rapid metabolizer with multiple copies of the CYP2D6 gene that are expressed, resulting in CYP2D6 function higher than normal. See, for example, Bertilsson et al., "Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs", British Journal of Clinical Pharmacology, 53(2), 111-22, February 2002. Patients without a CYP2D6 poor metabolizer genotype or CYP2D6 poor metabolizer phenotype include intermediate metabolizers, extensive metabolizers, or ultra rapid metabolizers.

[0041] The present disclosure relates to the treatment of patients having a CYP2D6 poor metabolizer genotype or CYP2D6 poor metabolizer phenotype. An individual having a CYP2D6 poor metabolizer genotype can be identified by obtaining a biological sample such as a blood sample, a saliva sample, or other sample containing the individual's DNA and performing a genotyping assay. The CYP2D6 poor metabolizer phenotype can be obtained by comparing the plasma level of dextromethorphan in a patient administered only dextromethorphan to the level predicted based on the dosage of a combination of bupropion and dextromethorphan administered to the patient. Also, it can be determined by comparing the dextromethorphan / dextrorphan metabolic ratio in a patient, such as by administration of only dextromethorphan or as described in, for example, Julica. Clinical Pharmacology and Therapeutics Journal, 2012, 37, 486 - 490. Usually, a dextromethorphan / dextrorphan metabolic ratio of 0.3 or more indicates a poor metabolizer phenotype.

[0042] There are also a number of other genotyping tests that can be used to determine whether a person is in the CYP2D6 poor metabolizer group. See, for example, the following. "CYP2D6 Genotyping Strategy Based on Gene Copy Number Determination by TaqMan Real - Time PCR." by Schaeffeler et al., Human Mutation, 22, 476 - 485, (2003), "CYP2D6 allele frequency in European Caucasians, Asians, Africans, and their descendants." by Bradford L D., Pharmacogenomics, 2002, March, 3(2), 229 - 43, "Molecular genetics of CYP2D6, clinical relevance with focus on psychotropic drugs." by Bertilsson L, Dahl M L, Dalen P, Al-Shurbaji A., Br J Clin Pharmacol, 2002, February, 53(2), 111-22 "Protocol No. CILO522A2328. 22 Oct. 2001." by Bryan Campbell, Pharm. D., Jane Xu, Ph.D., Josephine Cucchiaro, Ph.D., Mila Etropolski, M. D., Mark Schmidt, M. D.; "Combined phenotypic assessment of cytochrome p450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the ”Cooperstown 5+1 cocktail.”" by Chainvuati S, Nafziger A N, Leeder J S, Gaedigk A, Kearns G L, Sellers E, Zhang Y, Kashuba A D, Rowland E, Bertino J S Jr., Clin. Pharmacol. Ther. 2003, November, 74(5), 437-47 "Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects." by Dahl M L, Yue Q Y, Roh H K, Johansson I, Sawe J, Sjoqvist F, Bertilsson L., Pharmacogenetics, 1995, June, 5(3), 159-64 "Identification of the primary gene defect at the cytochrome P450 CYP2D locus." by Gough A C, Miles J S, Spurr N K, Moss J E, Gaedigk A, Eichelbaum M, Wolf C R. Nature, October 5, 1990, 47(6295), 773 - 6 "The human CYP2D locus associated with a common genetic defect in drug oxidation, a G1934--A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3 splice recognition site." by Hanioka N, Kimura S, Meyer U A, Gonzalez F J. Am J Hum Genet., December 1990, 47(6), 994 - 1001 "Maintenance therapy with zuclopenthixol decanoate, associations between plasma concentrations, neurological side effects and CYP2D6 genotype." by Jaanson P, Marandi T, Kiivet R A, Vasar V, Vaan S, Svensson J O, Dahl M L. Psychopharmacology (Berl), June 2002, 162(1), 67 - 73 Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman-Sundberg M. "Genetic analysis of the Chinese cytochrome P4502D locus, characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation," Mol Pharmacol, 1994, September, 46(3), 452-9, Juif Jen, Sujata Vaidyanathan, Michael Hayes. "Clinical Pharmacology Report, ProtocoNo CILO5222328, 12, Jul. 2002, Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA. "Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes." J Biol Chem, 1990, Oct. 5, 265(28), 17209-14, Lyamichev V, Mast A L, Hall J G, Prudent J R, Kaiser M W, Takova T, Kwiatkowski R W, Sander T J, de Arruda M, Arco D A, Neri B P, Brow M A. "Polymorphism identification and quantitative detection of genomic DNA by invasive cleavage of oligonucleotide probes." Nat Biotechnol, 1999, March, 17(3), 292 - 6, McElroy S, Richmond J, Lira M, Friedman D, Silber B M, Milos P M, Sachse C, Brochmoller "Roots I. CYP2D5 genotyping as an alternative to phenotyping for determination of metabolic status in a clinical trial setting." AAPS Pharmsci 2000, 2(4), article 33, Nevilie M, SelzerR, Aizenstein B, Maguire M, Hogan K, Walton R, Welsh K, Neri B, de Arruda M. "Characterization of cytochrome P450 2D6 alleles using the Invader system." Biotechniques, 2002, June, Suppl, 34 - 8, 40 - 3, and, "Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism," by Yokota H, Tamura S, Furuya H, Kimura S, Watanabe M, Kanazawa I, Kondo I, Gonzalez F J., Pharmacogenetics, 1993, October, 3(5), 256-63.

[0043] In some embodiments, the patient has the CYP2D6 G1846 (AA) genotype. In some embodiments, the patient has the CYP2D6 G1846 (AG) genotype. In some embodiments, the patient has the CYP2D6 C100T (TT) genotype. In some embodiments, the patient has the CYP2D6 C100T (CT) genotype.

[0044] Patients having a CYP2D6 poor metabolizer genotype or CYP2D6 poor metabolizer phenotype can be administered an oral dosage form once a day that includes a combination of up to 105 mg of hydrochloric acid bupropion, or the molar equivalent amount of free base bupropion or other salt form thereof, and up to 45 mg of dextromethorphan hydrobromide, or the molar equivalent amount of free base dextromethorphan or other salt form thereof, to condition a neurological disorder or condition or a mental disorder or condition, where the molar ratio of bupropion to dextromethorphan is approximately equal to 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. Alternatively, a dosage of up to about 52.5 mg of hydrochloric acid bupropion, or the molar equivalent amount of free base form bupropion or other salt form thereof, and up to 22.5 mg of dextromethorphan hydrobromide, or the molar equivalent amount of free base form dextromethorphan or other salt form thereof, may be administered twice a day.

[0045] When bupropion is administered in combination with dextromethorphan to humans with a CYP2D6 poor metabolism phenotype or CYP2D6 poor metabolism genotype, it has been found that the plasma level of dextromethorphan is higher compared to patients with or without the poor metabolism genotype. As a result, since the risk of adverse events associated with the increase in the plasma level of dextromethorphan increases, there are concerns about safety for the poor metabolism group.

[0046] In some patients, potential adverse events due to increased dextromethorphan exposure may include dizziness, nausea, dry mouth, drowsiness, headache, excitation, hypomania, confusion, including mental confusion, hallucinations, lethargy, drowsiness shivering, hyperthermia, vasoconstriction, tachycardia, diarrhea, myoclonus (muscle twitching), increased reflexes (appearing as clonus), tremors, restlessness, insomnia, dissociation, vomiting, delusions of grandeur, blurred vision, diplopia, bloodshot eyes, mydriasis, sweating, fever, bruxism (teeth grinding), hypotension, hypertension, shallow breathing, respiratory depression, dysuria, urinary retention, muscle twitching, tremors, sedation, paresthesia, hypomanic state, incoherent speech, unsteady gait, fainting, inability to focus the eyes, skin rash, severe itching, spontaneous memory recall, acute psychosis, abnormal excitement, nervousness, irritability, constipation, abdominal pain, etc. Administration of a low dose, such as less than half the dose, may reduce the risk of any of these adverse events. For example, the dosage form can be administered once a day instead of twice a day. Alternatively, the amounts of bupropion and dextromethorphan can be reduced. For example, the amounts of bupropion and dextromethorphan can be reduced by 50%, 75%, 90% or more. Reducing the dosage or dosing frequency of bupropion and dextromethorphan (for example, administering a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide once a day) may reduce the risk of adverse events compared to administering to the patient a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide twice a day.

[0047] The dosage forms described herein may include any suitable form of bupropion, or be prepared therefrom, such as salt forms, e.g., bupropion hydrochloride, other salt forms, free base forms, hydrates, solvates, polymorphs, and other solid forms. In some embodiments, the pharmaceutical composition does not contain other active pharmaceutical agents other than bupropion and / or dextromethorphan.

[0048] Dosage forms for administration to patients having a CYP2D6 poor metabolizer genotype or CYP2D6 poor metabolizer phenotype include an amount of bupropion appropriate for once-daily administration, i.e., less than 105 mg, e.g., about 1-105 mg, about 1-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-105 mg, about 103-107 mg, about 105 mg, about 53 mg, about 26 mg, about 13 mg, or about 12 mg of bupropion hydrochloride, an equivalent molar amount of other salt forms of bupropion hydrochloride, or the free base form of bupropion.

[0049] Alternatively, dosage forms for administration to patients having a CYP2D6 poor metabolizer genotype or CYP2D6 poor metabolizer phenotype can be administered twice daily, and the daily dose is less than 105 mg, e.g., about 1-105 mg, about 1-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-105 mg, about 103-107 mg, about 105 mg, about 53 mg, about 26 mg, about 13 mg, or about 12 mg of bupropion hydrochloride, an equivalent molar amount of other salt forms of bupropion hydrochloride, bupropion, or the free base form of bupropion.

[0050] In some embodiments, the dosage form provides sustained release of bupropion.

[0051] The dosage forms described herein include or can be prepared from any suitable form of dextromethorphan, such as salt forms, e.g., dextromethorphan bromide, other salt forms, free base form, hydrates, solvates, polymorphs, and other solid forms.

[0052] Dosage forms for administration to patients having a CYP2D6 poor metabolizer genotype or CYP2D6 poor metabolizer phenotype can include an amount of dextromethorphan suitable for once-daily administration, i.e., less than 45 mg, such as about 1 - 45 mg, about 1 - 5 mg, about 5 - 10 mg, about 10 - 20 mg, about 20 - 30 mg, about 30 - 40 mg, about 40 - 45 mg, about 45 mg, about 34 mg, about 23 mg, about 11 mg, about 6 mg, or about 5 mg of dextromethorphan, e.g., a corresponding molar amount of dextromethorphan bromide, other salt forms of dextromethorphan, or the free base form of dextromethorphan.

[0053] Alternatively, dosage forms for administration to patients having a CYP2D6 poor metabolizer genotype or CYP2D6 poor metabolizer phenotype can be administered twice daily, and the daily dosage can be, e.g., about 1 - 45 mg, about 1 - 5 mg, about 5 - 10 mg, about 10 - 20 mg, about 20 - 30 mg, about 30 - 40 mg, about 40 - 45 mg, about 45 mg, about 34 mg, about 23 mg, about 11 mg, about 6 mg, or about 5 mg of dextromethorphan, e.g., a corresponding molar amount of dextromethorphan bromide, other salt forms of dextromethorphan, or the free base form of dextromethorphan.

[0054] In some embodiments, the dosage form provides immediate release of dextromethorphan.

[0055] In a pharmaceutical dosage form, the molar ratio of bupropion to dextromethorphan in the dosage form is approximately equal to 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. There is 0.38 mol of bupropion in 105 mg of bupropion hydrochloride (molecular weight: 276.2 g / mol), and 0.122 mol of dextromethorphan in 45 mg of dextromethorphan hydrobromide (molecular weight: 370.3 g / mol). Thus, this ratio is approximately 0.38 mol of bupropion to about 0.12 mol of dextromethorphan. In some embodiments, this ratio is about 0.37 - 0.39 mol of bupropion to about 0.11 - 0.13 mol of dextromethorphan, about 2.5 - 3.1 to 1, about 2.6 - 3.3 to 1, or about 2.5 - 3.3 to 1.

[0056] Pope reported that when CYP2D6 was inhibited by quinidine administration, the C of dextromethorphan was about 40% higher in poor metabolizers compared to other patients who were not CYP2D6 poor metabolizers, and the AUC of dextromethorphan was about 46% higher in CYP2D6 poor metabolizers. (Pope et al., J. Clin. Pharmacol 2004, 44, 1132 - 1142). Bupropion is also a CYP2D6 inhibitor. The inventor has found that, similar to quinidine, when bupropion and dextromethorphan are administered in combination, in poor metabolizers, the C and AUC of dextromethorphan are significantly higher compared to other patients who are not poor metabolizers (e.g., extensive metabolizers, intermediate metabolizers, or ultra - rapid metabolizers). max of dextromethorphan was about 40% higher, and the AUC of dextromethorphan was about 46% higher in CYP2D6 poor metabolizers. (Pope et al., J.ClinPharmacol2004, 44, 1132 - 1142). Bupropion is also a CYP2D6 inhibitor. The inventor has found that, similar to quinidine, when bupropion and dextromethorphan are administered in combination, in poor metabolizers, the C 0-12 and AUC of dextromethorphan are significantly higher compared to other patients who are not poor metabolizers (e.g., extensive metabolizers, intermediate metabolizers, or ultra - rapid metabolizers). max

[0057] When a combination of bupropion and dextromethorphan is administered to CYP2D6 poor metabolizers, the C of bupropion max ​There is no special reason to believe that the [[AUC]] is different from that of other patients who are not in the poor metabolizer group (e.g., the extensive metabolizer group, the intermediate metabolizer group, or the ultra-rapid metabolizer group). Thus, one of ordinary skill in the art would expect that when a combination of bupropion and dextromethorphan is administered to a CYP2D6 poor metabolizer group, the plasma level of bupropion in the CYP2D6 poor metabolizer group would be similar to that of other patients who are not in the poor metabolizer group (e.g., the extensive metabolizer group, the intermediate metabolizer group, or the ultra-rapid metabolizer group), but the plasma level of dextromethorphan would be significantly higher. The inventors discovered through clinical trials that this is indeed the case. The increased exposure of dextromethorphan in the CYP2D6 poor metabolizer group increases the risk of adverse events caused by dextromethorphan compared to patients who do not have the CYP2D6 poor metabolizer genotype or the CYP2D6 poor metabolizer phenotype.

[0058] The antidepressant effect of bupropion has been shown to be dose-dependent. (See, https: / / dailymed.nlm.nih.gov / dailymed / lookup.cfm?setid=a0fdfc21-165a-43fa-9b3c-e48f3b892250&version=3.) Thus, it is expected that reducing the dose of bupropion will result in the loss of the antidepressant effect of bupropion, particularly when the dose (e.g., 210 mg / day) is already below the dose of bupropion in the treatment of depression. To avoid losing the efficacy of bupropion, one of ordinary skill in the art would likely reduce the dose of dextromethorphan while keeping the dose of bupropion the same. For example, one of ordinary skill in the art might reduce the dose of dextromethorphan from 90 mg / day to 45 mg / day while maintaining the dose of bupropion at 210 mg / day. As a result, in the CYP2D6 poor metabolizer group, it is expected that the plasma concentrations of bupropion and dextromethorphan will be similar to those of bupropion and dextromethorphan in other patients who are not in the CYP2D6 poor metabolizer group (e.g., the extensive metabolizer group, the intermediate metabolizer group, or the ultra-rapid metabolizer group).

[0059] However, the inventor believes that in the treatment of depression, the dosages of both bupropion and dextromethorphan can be reduced at the same rate without reducing the combined therapeutic effect (for example, instead of administering a dosage form containing 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan twice a day, or a dosage form containing 210 mg of bupropion hydrochloride and 90 mg of dextromethorphan once a day, administer a dosage form containing 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan once a day).

[0060] In some embodiments, the dosage form can contain bupropion and dextromethorphan and no other active pharmaceutical ingredients. In some embodiments, bupropion and dextromethorphan are in two different layers or phases of the dosage form. For example, each layer contains only bupropion or dextromethorphan and nothing else.

[0061] The pharmaceutical composition or dosage form may contain cysteine (e.g., L-cysteine), for example, in an amount of about 30 - 100 mg, or about 50 - 100 mg. Cysteine can be, for example, L-cysteine hydrochloride, other salt forms of L-cysteine, or the neutral or zwitterionic form of L-cysteine. These amounts of cysteine can help stabilize bupropion in the presence of other excipients.

[0062] The pharmaceutical composition or dosage form may further comprise a sustained-release or controlled-release polymer, for example, a polymer for providing sustained release of bupropion, for example, a crosslinked or non-crosslinked acrylate polymer or copolymer (including poly(acrylic acid) or poly(alkacrylic acid), for example, poly(methacrylic acid), for example, Carbomer homopolymer type A such as Carbopol 971P), a cellulose derivative such as methylcellulose, and the like. In some embodiments, the controlled-release polymer (for example, Carbomer copolymer type A) is about 1 to 40%, about 1 to 5%, about 5 to 10%, about 10 to 15%, about 15 to 20%, about 20 to 30%, about 30 to 40%, about 11 to 13%, or about 12% of the weight of the pharmaceutical composition. In some embodiments, the controlled-release polymer is about 0.1 to 20%, about 0.1 to 2%, about 2 to 4%, about 4 to 6%, about 6 to 8%, about 8 to 10%, about 10 to 15%, about 15 to 20%, or about 7% of the weight of the dosage form.

[0063] The pharmaceutical composition or dosage form may further comprise a filler such as microcrystalline cellulose. In some embodiments, the filler may be about 20 to 60%, about 20 to 30%, about 30 to 40%, about 40 to 50%, or about 50 to 60% of the weight of the pharmaceutical composition or dosage form.

[0064] The pharmaceutical composition or dosage form may further comprise a lubricant such as magnesium stearate. In some embodiments, the lubricant is about 0.1 to 10%, about 0.1 to 2%, about 2 to 4%, about 4 to 6%, about 6 to 8%, or about 8 to 10% of the weight of the pharmaceutical composition or dosage form.

[0065] The dosage form may be formulated according to an appropriate route of administration such as oral administration.

[0066] Solid dosage forms such as capsules, tablets, or pills for oral administration may contain any one or more of excipients such as gum tragacanth, acacia, corn starch, gelatin, additives such as dicalcium phosphate, disintegrants such as corn starch, potato starch, alginic acid, sweeteners such as sucrose, lactose, saccharin, or flavoring forms such as peppermint, wintergreen oil, or cherry flavor. When the dosage form is a capsule, in addition to the above types of materials, it may also contain a liquid carrier. Various materials may be present as coatings, for example, tablets, pills, and capsules may be coated with shellac, sugar, or both. The materials in the dosage form or pharmaceutical composition may desirably be pharmaceutically pure and non-toxic in the amounts used. In some embodiments, the dosage form contains cysteine, carbopol 971P, microcrystalline cellulose, silicon dioxide, and magnesium. In some embodiments, the dosage form contains a first layer containing bupropion and cysteine, and a second layer containing dextromethorphan, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0067] Examples of bilayer dosage forms are shown below.

[0068]

Table 1

[0069]

Table 2

[0070] The pharmaceutical composition or dosage form described in this specification may be useful for the treatment of neurological disorders or mental diseases such as depression including major depressive disorder or treatment-resistant major depressive disorder in the genotype-based poor metabolizer group of dextromethorphan, excitement such as agitated excitement associated with Alzheimer's disease, and intoxication such as nicotine intoxication. For example, the pharmaceutical composition or dosage form may be administered once a day to a human suffering from a neurological disorder or mental disease. The treatment can be continued as necessary as long as the treatment is effective and safe, for example, for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year, from 1 week to 2 months, 1 to 3 months, 3 to 6 months, 6 to 12 months, 1 to 2 years, or longer.

[0071] The CYP2D6 gene is highly polymorphic, and more than 70 allelic variants have been reported so far. See, for example, http: / / www.imm.ki.se / CYPalleles / cyp2d6.htm. Two polymorphisms frequently found within the CYP2D6 gene in the white population are CYP2D6G1846A and CYP2D6P34S (also called CYP2D6C100T). These polymorphisms correspond to nucleotides 3465 and 1719 of the GenBank sequence M33388.1 (GI:181303), respectively. The CYP2D6P34S / CYP2D6C100T polymorphism also corresponds to nucleotide 100 of the GenBank mRNA sequence M20403.1 (GI:181349).

[0072] The CYP2D6 G1846A polymorphism (known as the CYP2D6*4 allele and including *4A, *4B, *4C, *4D, *4E, *4F, *4G, *4H, *4J, *4K, *4L) represents a G to A transition at the junction between intron 3 and exon 4, shifting the splice junction by one base pair and causing a frameshift and premature protein termination (Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer U A. "Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes." J Biol Chem, 1990, Oct. 5, 265(28), 17209-14. Gough A C, Miles J S, Spurr N K, Moss J E, Gaedigk A, Eichelbaum M, Wolf C R. "Identification of the primary gene defect at the cytochrome P450 CYP2D locus." Nature, 1990, Oct. 5, 47(6295), 773-6. Hanioka N, Kimura S, Meyer U A, Gonzalez F J. "The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934--A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3’s splice recognition site." Am J Hum Genet., 1990, December, 47(6), 994-1001).The CYP2D6P34S / CYP2D6C100T polymorphism (known as the CYP2D6*10 and CYP2D6*14 alleles) represents a change from C to T, resulting in the substitution of proline at position 34 with serine (Yokota H, Tamura S, Furuya H, Kimura S, Watanabe M, Kanazawa I, Kondo I, Gonzalez FJ. "Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism:", Pharmacogenetics, 1993, October, 3(5), 256 - 63. Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman - Sundberg M. "Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation:", Mol Pharmacol, 1994, September, 46(3), 452 - 9). Both of these polymorphisms are associated with a decrease in enzyme activity towards different substrates (Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman - Sundberg M. "Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation: ", Mol Pharmacol, 1994, Septembe, 46(3), 452 - 9).Dahl M L, Yue Q Y, Roh H K, Johansson I, Sawe J, Sjoqvist F, Bertilsson L. "Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects." Pharmacogenetics, 1995, June, 5(3), 159-64. Jaanson P, Marandi T, Kiivet R A, Vasar V, Vaan S, Svensson J O, Dahl M L. "Maintenance therapy with zuclopenthixol decanoate: associations between plasma concentrations, neurological side effects and CYP2D6 genotype." Psychopharmacology (Berl), 2002, June, 162(1), 67-73. Bertilsson L, Dahl M L, Dalen P, Al-Shurbaji A. "Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs." Br J Clin Pharmacol, 2002, February, 53(2), 111-22).

[0073] In one study, blood samples were collected from 128 individuals with patient consent according to a pharmacogenetic protocol. DNA was extracted from whole blood by Covance using the PUREGENE DNA isolation kit (D-50K). (US Pat. No. 8,586,610)

[0074] In this study, the genotypes of the CYP2D6 G1846A polymorphism were confirmed in 123 out of 128 consented individuals, and the genotypes of the CYP2D6 C100T polymorphism were determined in all 128 participants. Genotyping was performed on the amplified DNA fragments. The CYP2D6 genomic region was amplified using a Triplex PCR strategy (Neville 2002).

[0075] In this study, according to the manufacturer's recommendations, amplification of 40 - 100 ng of genomic DNA was performed using a GC-rich PCR kit (Roche Diagnostics, Mannheim, Germany). The thermocycling conditions were: initial denaturation (3 minutes at 95°C), 10 cycles of 30 seconds denaturation (30 seconds at 95°C), annealing (30 seconds at 66°C), extension (60 seconds at 72°C), followed by 22 cycles of 30 seconds at 95°C, 30 seconds at 66°C, 60 seconds + 5 seconds at 72°C, and a final extension (7 minutes at 72°C). (US Pat. No. 8,586,610)

[0076] In this study, Third Wave Technologies, Inc (Madison, Wisconsin) developed a probe set for genotyping. Genotyping of the PCR products was performed using the Invader® assay (Lyamichev 1999) (Third Wave Technologies, Inc) according to the manufacturer's recommendations. (US Pat. No. 8,586,610)

[0077] In this study, the genotyping results of 74 study subjects were reported. Among these subjects, 57 had the CC genotype, 14 had the CT genotype, and 3 had the TT genotype of the CYP2D6 C100T polymorphism. It was found that the TT and CT genotypes of the CYP2D6 C100T polymorphism included the CYP2D6 poor metabolizer group. For the CYP2D6 G1846A polymorphism, 2 subjects had the AA genotype, 14 subjects had the AG genotype, and 55 subjects had the GG phenotype. The AA and AG genotypes were determined to represent the CYP2D6 poor metabolizer group. (US Pat. No. 8,586,610)

[0078] The combination of the subject matter can be used for the adjuvant treatment of major depressive disorder or depression.

[0079] In addition to major depressive disorder, the combination of the subject matter can be used to treat other diseases of symptoms in the patient populations or situations described herein. For example, the combination of the subject matter can be used to treat pain and neuropathy. Examples of neurological diseases treated with the combination of the subject matter include, but are not limited to, mood disorders, mental disorders, brain function disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, headaches, etc.

[0080] The mood 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 cyclothymic 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 symptoms, obsessive-compulsive disorder, bulimia nervosa, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug intoxication or abuse, nicotine intoxication, psychotic dysfunction, emotional regulation disorder, and emotional instability.

[0081] Depression can be manifested by depressive symptoms. These symptoms may include, for example, mood changes, intense feelings of sadness, despair, reduced mental activity, decreased concentration, pessimistic worry, excitement, anxiety, hyperexcitability, guilt, anger, worthlessness, reckless behavior, suicidal thoughts or attempts, and / or inferiority. The physical symptoms of depression may include insomnia, anorexia nervosa, loss of appetite, weight loss, weight gain, decreased activity and libido, fatigue, restlessness, tingling, pain, headache, convulsions, digestive problems, and / or abnormal hormonal circadian rhythms.

[0082] The mental disorders treated with the combinations of subjects include, but are not limited to, anxiety disorders (including but not limited to anxiety disorders), phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, apathy, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD), mania, bipolar disorder, hypomania, unipolar depression, depression, stress disorder, somatic symptom disorder, personality disorder, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypal aggressive, aggression in Alzheimer's disease, agitation in Alzheimer's disease, and excitement, which may include but are not limited to these. Alzheimer's disease may also be referred to as Alzheimer's type dementia. Other neurobehavioral symptoms of Alzheimer's disease that may be treated may include disinhibition and apathy.

[0083] The agitation in Alzheimer's disease occurs as the disease progresses. The agitation may manifest as inappropriate words, emotions, and / or physical behaviors. Inappropriate actions may include incoherent babbling, inappropriate emotional responses, demands for attention, threats, hyper-excitability, frustration, whining, repeating questions, mood swings, cursing, curse words, physical outbursts, emotional distress, restlessness, breaking, sleep disorders, delusions, hallucinations, pacing, wandering, searching, incessant searching, repetitive body movements, brooding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and / or kicking, including but not limited to these.

[0084] Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and behavioral and psychological symptoms including agitation. AD is the most common form of dementia, affecting an estimated 6 million patients in the United States, and the number is expected to increase to approximately 14 million by 2050. Agitation is reported in up to 70% of AD patients and is characterized by emotional distress, aggressive behavior, disruptive hyper-excitability, and disinhibition. In AD, the management of agitation is a priority. The agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, early placement in a nursing facility, and increased mortality. Currently, there is no FDA-approved treatment for agitation in AD patients.

[0085] It is known that neurobehavioral symptoms appear during dementia and may be treated by this combination. Caregivers or family members may be overwhelmed by the patient's behavioral and psychological symptoms rather than the patient's cognitive impairment. The general forms of the syndrome are a group 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 of dementia patients are similar to those of mental disorders, but some are slightly different from each other. Neurobehavioral symptoms associated with dementia include depression, apathy, agitation, disinhibition, hallucinations, delusions, psychosis, impulsivity, aggression, compulsive impulsivity, hypersexuality, and personality disorders. Neurobehavioral symptoms such as disinhibition may also be seen in other symptoms such as brain damage.

[0086] Agitated excitement in Alzheimer's disease patients can be evaluated using the Cohen-Mansfield Agitation Inventory or CMAI. The CMAI evaluates various behaviors such as hitting (including self), kicking, grabbing at people, pushing, throwing objects, biting, scratching, spitting, hurting oneself or others, tearing or breaking objects, initiating physical sexual proximity, pacing, aimless wandering, inappropriate dressing or undressing, attempting to go to another place, deliberately falling, eating or drinking inappropriate substances, handling things inappropriately, hiding objects, hoarding objects, repeatedly performing tics, overall restlessness, shouting, sexual solicitation by words, verbal abuse or verbal aggression, repeating statements or questions, strange sounds (strange laughter or crying sounds), complaining, refusal, constantly seeking inappropriate attention or help, etc.

[0087] Schizophrenia can be treated in combinations that include positive and / or negative symptoms of schizophrenia, or residual symptoms of schizophrenia. Other treatable symptoms include intermittent explosive disorder.

[0088] Brain dysfunctions that can be treated by the combination of the subject matter include, but are not limited to, dysfunctions accompanied by intellectual disabilities such as senile dementia, Alzheimer's type dementia, memory loss, amnesia / amnesia syndrome, epilepsy, disturbance of consciousness, coma, decreased attention, language disorder, voice tremor, Parkinson's disease, Lennox-Gastaut syndrome, autism, attention deficit hyperactivity disorder, schizophrenia, etc. Brain dysfunctions also include dysfunctions caused by cerebrovascular disorders such as stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head trauma, etc., and their symptoms include disturbance of consciousness, senile dementia, coma, decreased attention, and language disorder.

[0089] Substance addictions and abuses that can be treated by the combination of the subject matter include drug dependence, cocaine intoxication, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, antianxiety drugs and hypnotics, marijuana (cannabis), amphetamines, hallucinogens, fenfluramine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction such as tobacco, cigars and / or pipes, e-cigarettes and vaping, and addiction to chewing tobacco.

[0090] Movement disorders that can be treated by the combination of the subject matter include, but are not limited to, akathisia, akinesia, associated movement, athetoid, ataxia, ballism, hemiballism, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's chorea, rheumatic chorea, Sydenham's 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.

[0091] 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, Pick's disease, etc.

[0092] 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.

[0093] Neurodegenerative 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), bulbar muscular atrophy, Friedreich'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 paraplegia, neurofibromatosis, olivopontine cerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, spastic paraplegia, etc.

[0094] 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 simple partial seizures - Jacksonian seizures - complex partial seizures - continuous partial epilepsy, generalized tonic-clonic seizures - absence seizures - atonic seizures - myoclonic seizures - juvenile myoclonic seizures - infantile spasms, and status epilepticus.

[0095] Types of headaches that can be treated by the combination of the subject matter include, but are not limited to, migraine, tension, and cluster headache.

[0096] Other neurological disorders that can be treated by the combination of the subject matter include Rett syndrome, autism, tinnitus, disturbances of consciousness disorders, sexual dysfunction, intractable cough, narcolepsy, cataplexy, vocal disorders due to uncontrollable laryngeal muscle spasms including abductor spastic dysphonia, adductor spastic dysphonia, muscle tension dysphonia, and vocal tremor, but not limited to these, diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity, incontinence including stress urinary incontinence, urge urinary incontinence, fecal incontinence, but not limited to these, and erectile dysfunction.

[0097] In some embodiments, the combination of the subject matter can be used for the treatment of pain, arthralgia, pain associated with sickle cell disease, mood regulation disorders, depression (including treatment-resistant depression), disorders related to memory and cognition, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), etc.

[0098] In some embodiments, the combination of the subject matter can be orally administered to reduce pain associated with musculoskeletal pain including low back pain, and joint rheumatism, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, perijoint disorders, axial spondyloarthritis including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient coxarthrosis, vertebral compression fractures, osteoporosis, etc.

[0099] In some embodiments, the combination of the subject matter can be administered to reduce inflammatory pain such as musculoskeletal pain, arthritis pain, complex regional pain syndrome, etc.

[0100] Arthritis refers to inflammatory joint diseases that may be accompanied by pain. Examples of arthritis pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, perijoint disorders, neuropathic arthropathy such as Charcot foot, axial spondyloarthritis such as ankylosing spondylitis, and pain associated with SAPHO syndrome.

[0101] In some embodiments, the combination of the subject is used to treat chronic musculoskeletal pain.

[0102] In some embodiments, the composition of the subject may be administered to reduce complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is a type of inflammatory pain. CRPS may also include elements of neuropathy. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the extremities that may be accompanied by edema and autonomic, motor, and sensory changes.

[0103] In some embodiments, the composition of the subject may be orally administered to reduce neuropathic pain.

[0104] 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, and the like. Other causes of neuropathic pain include cancer pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, radiation or chemotherapy-related neuropathy, and the like.

[0105] In some embodiments, the composition of the subject may be administered to reduce fibromyalgia.

[0106] In some embodiments, the symmetric composition may be co-administered with one or more potent CYP2D6 inhibitors. It has been found that co-administering the combination of the subject with one or more potent CYP2D6 inhibitors increases the plasma concentration of dextromethorphan. Therefore, it is recommended to monitor the patient for any possible side effects or adverse reactions due to dextromethorphan, such as drowsiness and dizziness.

[0107] When the subject composition is used in combination with one or more potent inhibitors of CYP2D6, dosage adjustment may be necessary. Adjusting the dosage of bupropion and / or dextromethorphan in the subject combination to a lower dose, or reducing the dosing frequency of the subject combination, can reduce side effects or adverse reactions, including but not limited to, drowsiness, dizziness, or a combination thereof, in the patient. For example, the recommended dosage of the subject combination when used in combination with one or more potent CYP2D6 inhibitors is one tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride, taken once a day, for example, once a day in the morning.

[0108] In some embodiments, the subject composition can be administered to patients who are members of the CYP2D6 poor metabolizer group. It has been found that when the subject composition is administered with a CYP2D6 inhibitor, the plasma concentration of dextromethorphan increases in patients who are not members of the CYP2D6 poor metabolizer group, compared to those who are. Therefore, it is recommended to monitor the patient for any side effects or adverse reactions that may be caused by dextromethorphan, such as drowsiness or dizziness.

[0109] If the patient is a member of the CYP2D6 poor metabolizer group, dosage adjustment may be necessary. Adjusting the dosage of bupropion and / or dextromethorphan in the subject combination to a lower dose, or reducing the dosing frequency of the subject combination, can reduce side effects or adverse reactions, including but not limited to, drowsiness, dizziness, or a combination thereof, in the patient. For example, the recommended dosage of the subject combination when co-administered to patients in the CYP2D6 poor metabolizer group is one tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride, administered once a day, for example, once a day in the morning.

[0110] When the subject combination is administered once a day to patients who are concomitantly using a strong CYP2D6 inhibitor or to patients in the CYP2D6 poor metabolizer group, side effects such as, but not limited to, drowsiness, dizziness, or a combination thereof may be reduced compared to when the subject combination is administered twice a day for the same number of days. In some embodiments, reducing the dosage or frequency of administration of the subject combination may reduce drowsiness. In some embodiments, reducing the dosage or frequency of administration may reduce dizziness. Since dizziness can lead to falls, adjusting to reduce the dosage or frequency of administration of the subject combination may reduce the risk of falls in patients taking the subject combination. For example, when the subject combination is taken once a day, the risk of falls in patients may be reduced compared to when the subject combination is taken twice a day for the same number of days. This can be important, for example, for elderly patients or patients suffering from dementia such as Alzheimer's disease.

[0111] The terms "treating" or "treatment" include the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals, or other activities that affect the structure or function of the body of humans or other animals.

[0112] The combination of the subject matter can be used for the treatment of any disease or condition identified as treatable by the combination of bupropion and dextromethorphan in any of the U.S. patents: U.S. Patent No. 8,569,328, U.S. Patent No. 9,168,234, U.S. Patent No. 9,189,905, U.S. Patent No. 9,205,083, U.S. Patent No. 9,238,032, U.S. Patent No. 9,278,095, U.S. Patent No. 9,314,462, U.S. Patent No. 9,370,513, U.S. Patent No. 9,375,429, U.S. Patent No. 9,408,815, U.S. Patent No. 9,421,176, U.S. Patent No. 9,457,023, U.S. Patent No. 9,457,025, U.S. Patent No. 9,474,731, U.S. Patent No. 9,486,450, U.S. Patent No. 9,700,528, U.S. Patent No. 9,700,553, U.S. Patent No. 9,707,191, U.S. Patent No. 9,763,932, U.S. Patent No. 9,861,595, U.S. Patent No. 9,867,819, U.S. Patent No. 9,968,568, U.S. Patent No. 10,058,518, U.S. Patent No. 10,064,857, U.S. Patent No. 10,080,727, U.S. Patent No. 10,092,560, U.S. Patent No. 10,092,561, U.S. Patent No. 10,105,327, U.S. Patent No. 10,105,361, U.S. Patent No. 10,251,879, U.S. Patent No. 10,463,634, U.S. Patent No. 10,512,643, U.S. Patent No. 10,548,857, U.S. Patent No. 10,596,167, U.S. Patent No. 10,772,850, U.S. Patent No. 10,780,064, U.S. Patent No. 10,780,066, U.S. Patent No. 10,786,469, U.S. Patent No. 10,786,496, U.S. Patent No. 10,799,497, U.S. Patent No. 10,806,710, U.S. Patent No. 10,864,209, U.S. Patent No. 10,874,663, U.S. Patent No. 10,874,664, U.S. Patent No. 10,874,665, U.S. Patent No. 10,881,624, U.S. Patent No. 10,881,657, U.S. Patent No. 10,894,046, U.S. Patent No. 10,894,047, U.S. Patent No. 10,898,453.All of these are hereby incorporated by reference in their entirety for the disclosure of diseases treatable by the combination of bupropion and dextromethorphan, including the specific embodiments and combinations described therein.

[0113] (Example 1) When 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide were administered twice a day to three subjects with low metabolism, the C max and AUC 0-12 of dextromethorphan increased by about 3-fold and 3.4-fold, respectively, compared to the high-metabolism group.

[0114] For comparison, Flesher (International Publication No. WO 2009 / 006194, page 86, Table IV) reported that when 30 mg of dextromethorphan and 30 mg of quinidine were administered twice a day for 7 days, the C max and AUC 0-12 in the low-metabolism group increased by only about 1.43-fold and 1.46-fold, respectively, compared to the high-metabolism group.

[0115] (Example 2) In an efficacy clinical trial, analysis of the steady-state pharmacokinetic data of 12 subjects with low metabolism treated twice a day with 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide showed that the plasma concentration of dextromethorphan was generally higher than the exposure in subjects who were not in the low-metabolism group.

[0116] (Example 3) The properties of tablets containing a combination of dextromethorphan hydrobromide, a non-competitive NMDA receptor antagonist and sigma-1 receptor agonist, and bupropion hydrochloride, an aminoketone and CYP450 2D6 inhibitor, were studied.

[0117] The tablets are for oral administration and are round bilayer tablets. Each tablet contains 45 mg of dextromethorphan hydrobromide (equivalent to 32.98 mg of dextromethorphan free base) as an immediate-release formulation and 105 mg of bupropion hydrochloride (equivalent to 91.14 mg of bupropion free base) as a sustained-release formulation. Each tablet contains inactive ingredients such as 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, yellow iron oxide, etc.

[0118] The effects of renal impairment, hepatic impairment, and CYP2D6 poor metabolizer status on exposure to tablets containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride are summarized in Figure 1.

[0119] 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 criteria used were healthy subjects who met the renal and hepatic impairment studies, and the high CYP2D6 metabolizer group or ultra-rapid CYP2D6 metabolizer group. AUC represents the area under the plasma concentration-time curve from 0 to 12 hours, BUP represents bupropion, and CI represents the confidence interval. C max represents the maximum plasma concentration, DM represents dextromethorphan, GMR represents the geometric mean ratio, and PK represents pharmacokinetics.

[0120] In the CYP2D6 poor metabolizer group, dextromethorphan AUC 0-12 was observed to increase 3.40-fold, and dextromethorphan C max was observed to increase 3.00-fold. No significant change was observed in bupropion AUC 0-12 or bupropion C max .

[0121] Based on these results, in patients known to be in the CYP2D6 poor metabolizer group, dextromethorphan concentrations are higher than in the CYP2D6 extensive metabolizer / intermediate metabolizer groups, and dose adjustment is recommended. The recommended dose for patients known to be in the CYP2D6 poor metabolizer group is 1 tablet once a day, such as in the morning.

[0122] Unless otherwise specified, all numerical values representing characteristics such as amounts, quantities, percentages, etc. of components used in the specification and claims are to be understood as indicating both the exact value shown and the value modified by the term "about" in all cases. Thus, unless otherwise specified, the numerical parameters set forth in the specification and the appended claims are approximate values and may vary depending on the desired characteristics to be obtained. At a minimum, and not as an attempt to limit the scope of the claims to the application of the doctrine of equivalents, each numerical parameter should be construed in accordance with the normal rounding-off method, taking into account the number of significant digits reported.

[0123] The use of the terms "comprising" or "comprises" in this specification is also contemplated to be the use of "consisting essentially of," "consists essentially of," "onsisting of," or "consists of" instead.

[0124] Any affirmative statement of an element anywhere in this specification should be understood to be intended to include both the inclusion and the exclusion of that element.

[0125] The terms "a", "an", "the", and similar referents used in the context of describing embodiments (particularly in the context of the following claims) are to be construed to include both the singular and the plural unless otherwise stated herein or clearly contradicted by the context. All methods described herein can be performed in any suitable order unless otherwise stated herein or clearly contradicted by the context. Any examples provided herein, or the use of exemplary language (such as "etc."), are intended only to clarify the embodiments and do not impose a limitation on any claims. The language of the specification should not be construed as indicating any non-claimed elements essential to the practice of the claims.

[0126] Groupings of alternative elements or embodiments disclosed herein should not be construed as limiting. Each group member can be referenced and claimed individually or in combination with other members of the group or other elements described herein. For reasons of convenience or to expedite prosecution, it is anticipated that one or more members of a group may be included in or deleted from the group. If such inclusion or deletion occurs, the specification is considered to include the modified group, thereby satisfying all descriptions of the markush groups used in the appended claims.

[0127] This specification describes certain embodiments that include the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations of these described embodiments will be apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to adopt such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited therein as permitted by applicable law. Further, unless otherwise stated herein or clearly contradicted by context, any combination of any possible variations of the above-described elements is contemplated.

[0128] 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, but are not limited thereto. Thus, the claims are not strictly limited to the embodiments as illustrated and described.

[0129] (Appendix) (Appendix 1) A method of treating a patient having a neurological disorder by administering a combination of dextromethorphan and bupropion, comprising orally administering to the patient, once a day, 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 equal to 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, comprising, The patient is selected for having 1) the symptoms of the nervous system and 2) being in the CYP2D6 poor metabolizer group. The patient is determined to be in the CYP2D6 poor metabolizer group by an assay on a biological sample from the patient. In the case of the patient who is in the CYP2D6 poor metabolizer group, the risk of drowsiness and dizziness after orally administering the dosage form containing the combination to the patient once a day 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 patient twice a day for the same number of days. Method.

[0130] (Appendix 2) A method for treating a patient experiencing symptoms of the nervous system 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 to determine whether the patient is in the CYP2D6 poor metabolizer group, or having performed it previously, a step of determining whether the patient is in the CYP2D6 poor metabolizer group, when the patient is in the CYP2D6 poor metabolizer group, orally administering to the patient once a day a dosage form containing a combination of bupropion hydrochloride of 105 mg or less, or a corresponding molar amount of free base of bupropion or other salt form, and dextromethorphan hydrobromide of 45 mg or less, or a corresponding molar amount of free base of dextromethorphan or other salt form, wherein the molar ratio of bupropion to dextromethorphan is approximately equal to 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 patient is not in the CYP2D6 poor metabolizer group, orally administering to the patient, twice a day, a dosage form comprising 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or other salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or other salt form of dextromethorphan; comprising For a patient who is in the CYP2D6 poor metabolizer group, the risk of drowsiness and dizziness after orally administering to the patient, once a day, the dosage form comprising the combination is lower than the risk that would occur if a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide were orally administered to the patient twice a day for the same number of days. Method.

[0131] (Appendix 3) A method for treating a patient experiencing symptoms of the nervous system, a) obtaining a biological sample from the patient, or having previously obtained it, and performing an assay on the biological sample to determine whether the patient is in the CYP2D6 poor metabolizer group, or having previously performed it, to determine whether there is a risk of adverse events associated with overexposure to dextromethorphan in the patient, wherein a result that the patient is in the CYP2D6 poor metabolizer group indicates that there is a risk of adverse events associated with overexposure to dextromethorphan in the patient; b) If there is a risk of adverse events related to excessive exposure of the patient to dextromethorphan, 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 the corresponding molar amount of free base or other salt form of bupropion, and not more than 45 mg of hydrobromide dextromethorphan, or the corresponding molar amount of free base or other salt form of dextromethorphan, wherein the molar ratio of bupropion to dextromethorphan is approximately equal to 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 hydrobromide dextromethorphan; c) If there is no risk of adverse events related to excessive exposure of the patient to dextromethorphan, orally administering to the patient twice a day a dosage form comprising a combination of 105 mg of hydrochloric acid bupropion, or the corresponding molar amount of free base or other salt form of bupropion, and 45 mg of hydrobromide dextromethorphan, or the corresponding molar amount of free base or other salt form of dextromethorphan; comprising: A method.

[0132] (Appendix 4) A method for treating symptoms of the nervous system by a combination of dextromethorphan and bupropion, comprising orally administering to a patient once a day a dosage form comprising a combination of not more than 105 mg of hydrochloric acid bupropion, or the corresponding molar amount of free base or other salt form of bupropion, and not more than 45 mg of hydrobromide dextromethorphan, or the 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 equal to 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 hydrobromide dextromethorphan. The patient is selected for having 1) symptoms of the nervous system and 2) being in the CYP2D6 poor metabolizer group, and the patient is determined to be in the CYP2D6 poor metabolizer group by an assay on a biological sample from the patient. 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. Method.

[0133] (Appendix 5) A method for treating a patient experiencing symptoms of the nervous system 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 to determine whether the patient is in the CYP2D6 poor metabolizer group or having previously performed it, a step of determining whether the patient is in the CYP2D6 poor metabolizer group; when the patient is in the CYP2D6 poor metabolizer group, orally administering once a day to the patient a dosage form comprising a combination of 105 mg or less of hydrochloric acid bupropion or a corresponding molar amount of the free base or other salt form of bupropion and 45 mg or less of hydrobromic acid dextromethorphan or a corresponding molar amount of the free base or other salt form of dextromethorphan, wherein the molar ratio of the bupropion to the dextromethorphan in the dosage form is approximately equal to 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 hydrobromic acid dextromethorphan; when the patient is not in the CYP2D6 poor metabolizer group, orally administering twice a day to the patient 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 hydrobromic acid dextromethorphan or a corresponding molar amount of the free base or other salt form of dextromethorphan; comprising, method.

[0134] (Appendix 6) A method for treating a patient having symptoms of the nervous system by administering a combination of dextromethorphan and bupropion, once a day, orally administering to the patient 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 equal to 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, the patient is selected for 1) having symptoms of the nervous system and 2) being a CYP2D6 poor metabolizer group, and the patient is determined to be a CYP2D6 poor metabolizer group by assay of a biological sample from the patient, in the case of the patient being a CYP2D6 poor metabolizer group, the risk of drowsiness or dizziness after orally administering the dosage form containing the combination to the 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 patient twice a day for the same number of days, method.

[0135] (Appendix 7) A method for treating a patient experiencing symptoms of the nervous system 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 to determine whether the patient is a CYP2D6 poor metabolizer group, or having previously performed it, A step of determining whether the patient is a CYP2D6 poor metabolizer group; When the patient is a CYP2D6 poor metabolizer group, an oral dosage form containing a combination of 105 mg or less of hydrochloric acid bupropion, or a molar amount of the free base or other salt form of bupropion corresponding thereto, and 45 mg or less of dextromethorphan hydrobromide, or a molar amount of the free base or other salt form of dextromethorphan corresponding thereto, is orally administered to the patient once a day, wherein the molar ratio of the bupropion to the dextromethorphan is approximately equal to 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; When the patient is not a CYP2D6 poor metabolizer group, an oral dosage form containing a combination of 105 mg of hydrochloric acid bupropion, or a molar amount of the free base or other salt form of bupropion corresponding thereto, and 45 mg of dextromethorphan hydrobromide, or a molar amount of the free base or other salt form of dextromethorphan corresponding thereto, is orally administered to the patient twice a day; comprising; In the case of the patient who is a CYP2D6 poor metabolizer group, the risk of drowsiness or dizziness after orally administering the dosage form containing the combination to the patient once a day is lower than the risk that would occur when a combination of 105 mg of hydrochloric acid bupropion and 45 mg of dextromethorphan hydrobromide is orally administered to the patient twice a day for the same number of days. Method.

[0136] (Appendix 8) The method according to Appendix 1, 4, or 6, wherein a combination of 105 mg of the hydrochloric acid bupropion and 45 mg of the dextromethorphan hydrobromide is orally administered to the patient once a day.

[0137] (Appendix 9) The method according to appendix 1, 4, or 6, wherein a combination of about 52.5 mg of said bupropion hydrochloride and about 22.5 mg of said dextromethorphan hydrobromide is orally administered to said patient twice a day.

[0138] (Appendix 10) When the patient is in the CYP2D6 poor metabolizer group, the dosage form containing a combination of 105 mg of said bupropion hydrochloride and 45 mg of said dextromethorphan hydrobromide is orally administered to said patient once a day, according to the method described in appendix 2, 3, 5, or 7.

[0139] (Appendix 11) When the patient is in the CYP2D6 poor metabolizer group, a dosage form containing a combination of about 52.5 mg of said bupropion hydrochloride and about 22.5 mg of said dextromethorphan hydrobromide is orally administered to said patient twice a day, according to the method described in appendix 2, 3, 5, or 7.

[0140] (Appendix 12) A method for treating symptoms of the nervous system in CYP2D6 poor metabolizer group, comprising administering once a day to a patient known to be in the CYP2D6 poor metabolizer group in need of treatment, a dosage form containing bupropion hydrochloride of 105 mg or less, or the free base or other salt form of bupropion in an equivalent molar amount, and dextromethorphan hydrobromide of 45 mg or less, or the free base or other salt form of dextromethorphan in an equivalent molar amount.

[0141] (Appendix 13) A method for treating symptoms of the nervous system in CYP2D6 poor metabolizer group, comprising administering once a day to a patient known to be in the CYP2D6 poor metabolizer group in need of treatment, a dosage form containing 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide.

[0142] (Appendix 14) The method according to appendix 12 or 13, wherein 105 mg of said bupropion hydrochloride and 45 mg of said dextromethorphan hydrobromide are present in said dosage form.

[0143] (Appendix 15) The method according to any one of appendices 1 to 14, wherein said dosage form provides immediate release of dextromethorphan.

[0144] (Appendix 16) The method according to any one of appendices 1 to 15, wherein said dosage form provides sustained release of bupropion.

[0145] (Appendix 17) By administering said dosage form once a day for 8 days, the AUC of dextromethorphan that would occur in patients who are in the high CYP2D6 metabolizer group or the ultra-rapid CYP2D6 metabolizer group, after administering said dosage form twice a day for 8 days 0-12 is avoided from increasing by about 3.4 times compared to the AUC of dextromethorphan in said patients. 0-12 The method according to any one of appendices 1 to 16.

[0146] (Appendix 18) By administering said dosage form once a day for 8 days, the C of dextromethorphan that would occur in patients who are in the high CYP2D6 metabolizer group or the ultra-rapid CYP2D6 metabolizer group, after administering said dosage form twice a day for 8 days max is avoided from increasing by about 3 times compared to the C of dextromethorphan in said patients. max The method according to any one of appendices 1 to 17.

[0147] (Appendix 19) The method according to any one of appendices 1 to 18, wherein said dosage form is administered orally in the morning.

[0148] (Appendix 20) The method according to any one of appendices 1 to 19, wherein said dosage form further contains L-cysteine hydrochloride monohydrate.

[0149] (Appendix 21) The dosage form further contains a carbomer homopolymer, and is the method according to any one of Appendices 1 to 20.

[0150] (Appendix 22) The dosage form further contains colloidal silicon dioxide, and is the method according to any one of Appendices 1 to 21.

[0151] (Appendix 23) The dosage form further contains crospovidone, and is the method according to any one of Appendices 1 to 22.

[0152] (Appendix 24) The dosage form further contains glyceryl monocaprylocaprate, and is the method according to any one of Appendices 1 to 23.

[0153] (Appendix 25) The dosage form further contains magnesium stearate, and is the method according to any one of Appendices 1 to 24.

[0154] (Appendix 26) The dosage form further contains microcrystalline cellulose, and is the method according to any one of Appendices 1 to 25.

[0155] (Appendix 27) The dosage form further contains polyvinyl alcohol, and is the method according to any one of Appendices 1 to 26.

[0156] (Appendix 28) The dosage form further contains red iron oxide, and is the method according to any one of Appendices 1 to 27.

[0157] (Appendix 29) The dosage form further contains sodium lauryl sulfate, and is the method according to any one of Appendices 1 to 28.

[0158] (Appendix 30) The dosage form further contains stearic acid, and is the method according to any one of Appendices 1 to 29.

[0159] (Supplementary Note 31) The dosage form further contains talc, and is the method described in any one of Supplementary Notes 1 to 30.

[0160] (Supplementary Note 32) The dosage form further contains titanium dioxide, and is the method described in any one of Supplementary Notes 1 to 31.

[0161] (Supplementary Note 33) The dosage form further contains yellow iron oxide, and is the method described in any one of Supplementary Notes 1 to 32.

[0162] (Supplementary Note 34) The dosage form is a solid dosage form, and is the method described in any one of Supplementary Notes 1 to 33.

[0163] (Supplementary Note 35) By administering the solid dosage form to human patients twice a day for 8 days, the AUC of bupropion that will occur after administering the solid dosage form twice a day for 8 days to human patients who are in the high CYP2D6 metabolism group or the ultra-rapid CYP2D6 metabolism group 0-12 Compared with, human patients will have approximately the same AUC of bupropion 0-12 and is the method described in any one of Supplementary Notes 1 to 34.

[0164] (Supplementary Note 36) By administering the solid dosage form to human patients twice a day for 8 days, the C of bupropion that will occur after administering the solid dosage form twice a day for 8 days to human patients who are in the high CYP2D6 metabolism group or the ultra-rapid CYP2D6 metabolism group max Compared with, human patients will have approximately the same C of bupropion max and is the method described in any one of Supplementary Notes 1 to 35.

[0165] (Supplementary Note 37) The neurological symptom is a major depressive disorder, and is the method described in any one of Supplementary Notes 1 to 36.

[0166] (Supplementary Note 38) The symptoms of the nervous system are excitability associated with Alzheimer's disease, the method according to any one of Appendices 1 to 37.

[0167] (Appendix 39) The patient has a risk of falling, the method according to any one of Appendices 1 to 38.

[0168] (Appendix 40) The symptoms of the nervous system are excitability associated with dementia, the method according to any one of Appendices 1 to 39.

[0169] (Appendix 41) The symptoms of the nervous system are neuropathic pain, the method according to any one of Appendices 1 to 40.

[0170] (Appendix 42) The symptoms of the nervous system are generalized anxiety disorder, the method according to any one of Appendices 1 to 41.

[0171] (Appendix 43) The patient has the CYP2D6 G1846(AA) genotype, the method according to any one of Appendices 1 to 42.

[0172] (Appendix 44) The patient has the CYP2D6 G1846(AG) genotype, the method according to any one of Appendices 1 to 43.

[0173] (Appendix 45) The patient has the CYP2D6 C100T(TT) genotype, the method according to any one of Appendices 1 to 44.

[0174] (Appendix 46) The patient has the CYP2D6 C100T(CT) genotype, the method according to any one of Appendices 1 to 45.

Claims

1. A method of treating a patient having a neurological disorder by administering a combination of dextromethorphan and bupropion, comprising: orally administering to the patient once a day 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 equal to 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; comprising: the patient being selected for having 1) the neurological disorder and 2) being a CYP2D6 poor metabolizer; the patient being determined to be a CYP2D6 poor metabolizer by an assay on a biological sample from the patient; in the case of a patient who is a CYP2D6 poor metabolizer, the risk of drowsiness and dizziness after once-daily oral administration of the dosage form comprising the combination to the 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 patient twice a day for the same number of days; a method.

2. A method of treating a patient experiencing a neurological disorder with a combination of dextromethorphan and bupropion, comprising: 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 is a CYP2D6 poor metabolizer, the step of determining whether the patient is a CYP2D6 poor metabolizer; When the patient is in the CYP2D6 poor metabolizer group, administering orally once a day to the patient a dosage form comprising propionylpropionyl hydrochloride of 105 mg or less, or a free base or other salt form of propionylpropionyl in a corresponding molar amount, and dextromethorphan hydrobromide of 45 mg or less, or a free base or other salt form of dextromethorphan in a corresponding molar amount, wherein the molar ratio of the propionylpropionyl to the dextromethorphan is substantially equal to the ratio of the molar amount of propionylpropionyl in 105 mg of propionylpropionyl hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide, step, When the patient is not in the CYP2D6 poor metabolizer group, orally administering to the patient twice a day a dosage form comprising 105 mg of propionylpropionyl hydrochloride, or a free base or other salt form of propionylpropionyl in a corresponding molar amount, and 45 mg of dextromethorphan hydrobromide, or a free base or other salt form of dextromethorphan in a corresponding molar amount, step, including, In the case of a patient who is in the CYP2D6 poor metabolizer group, the risk of drowsiness and dizziness after orally administering once a day to the patient the dosage form comprising the combination is lower than the risk that would occur when a combination of 105 mg of propionylpropionyl hydrochloride and 45 mg of dextromethorphan hydrobromide is administered twice a day to the patient over the same number of days. Method.

3. A method for treating a patient experiencing symptoms of the nervous system, a) obtaining a biological sample from the patient, or having previously obtained it, and performing an assay on the biological sample to determine whether the patient is in the CYP2D6 poor metabolizer group, or having previously performed it, to determine whether there is a risk of adverse events associated with overexposure to dextromethorphan in the patient, wherein the result that the patient is in the CYP2D6 poor metabolizer group indicates that there is a risk of adverse events associated with overexposure to dextromethorphan in the patient, step, b) If there is a risk of adverse events associated with excessive exposure to dextromethorphan in the patient, administering orally once a day to the patient a dosage form comprising a combination of 105 mg or less of hydrochloric acid bupropion, 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 is approximately equal to 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 there is no risk of adverse events associated with excessive exposure to dextromethorphan in the patient, administering orally twice a day to the patient a dosage form comprising a combination of 105 mg of hydrochloric acid bupropion, 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. **Claim 4** A method for treating symptoms of the nervous system with a combination of dextromethorphan and bupropion, comprising the step of orally administering once a day to a patient a dosage form comprising a combination of 105 mg or less of hydrochloric acid bupropion, 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 equal to 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, wherein the patient is selected for having 1) symptoms of the nervous system and 2) being a CYP2D6 poor metabolizer group, and the patient is determined to be a CYP2D6 poor metabolizer group by an assay on a biological sample from the patient, wherein the risk of adverse events in the patient is reduced compared to the risk of adverse events the patient would have if the dosage form were administered twice a day to the patient. Method

5. A method for treating a patient experiencing symptoms of the nervous system 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 patient is a CYP2D6 poor metabolizer, a step of determining whether the patient is a CYP2D6 poor metabolizer, wherein when the patient is a CYP2D6 poor metabolizer, administering orally once a day to the patient 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, and the molar ratio of bupropion to dextromethorphan in the dosage form is approximately equal to 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, a step, wherein when the patient is not a CYP2D6 poor metabolizer, administering orally twice a day to the patient 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, Method

6. A method for treating a patient having symptoms of the nervous system by administering a combination of dextromethorphan and bupropion, Administering orally to the patient once a day a dosage form comprising 105 mg or less of bupropion hydrochloride, or the free base or other salt form of bupropion in an equivalent molar amount, and 45 mg or less of dextromethorphan hydrobromide, or the free base or other salt form of dextromethorphan in an equivalent molar amount, wherein the molar ratio of the bupropion to the dextromethorphan in the dosage form is approximately equal to the ratio of the molar amount of the bupropion in 105 mg of bupropion hydrochloride to the molar amount of the dextromethorphan in 45 mg of dextromethorphan hydrobromide, wherein the patient is selected for having 1) neurological symptoms and 2) being a CYP2D6 poor metabolizer, and the patient is determined to be a CYP2D6 poor metabolizer by assay of a biological sample from the patient, in the case of the patient being a CYP2D6 poor metabolizer, the risk of drowsiness or dizziness after orally administering the dosage form comprising the combination to the 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 patient twice a day for the same number of days, Method.

7. A method of treating a patient experiencing neurological 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 patient is a CYP2D6 poor metabolizer, the step of determining whether the patient is a CYP2D6 poor metabolizer, When the patient belongs to the CYP2D6 poor metabolizer group, a dosage form containing a combination of not more than 105 mg of hydrochloric acid bupropion, or the free base or other salt form of bupropion in an equivalent molar amount, and not more than 45 mg of dextromethorphan hydrobromide, or the free base or other salt form of dextromethorphan in an equivalent molar amount, is orally administered to the patient once a day, wherein the molar ratio of bupropion to dextromethorphan is approximately equal to 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 step of When the patient does not belong to the CYP2D6 poor metabolizer group, a dosage form containing a combination of 105 mg of hydrochloric acid bupropion, or the free base or other salt form of bupropion in an equivalent molar amount, and 45 mg of dextromethorphan hydrobromide, or the free base or other salt form of dextromethorphan in an equivalent molar amount, is orally administered to the patient twice a day, the step of comprising In the case of the patient belonging to the CYP2D6 poor metabolizer group, the risk of drowsiness or dizziness after orally administering the dosage form containing the combination to the patient once a day is lower than the risk that would occur when a combination of 105 mg of hydrochloric acid bupropion and 45 mg of dextromethorphan hydrobromide is administered to the patient twice a day over the same number of days. Method.

8. The method according to claim 1, 4, or 6, wherein a combination of 105 mg of the hydrochloric acid bupropion and 45 mg of the dextromethorphan hydrobromide is orally administered to the patient once a day.

9. The method according to claim 1, 4, or 6, wherein a combination of about 52.5 mg of the hydrochloric acid bupropion and about 22.5 mg of the dextromethorphan hydrobromide is orally administered to the patient twice a day.

10. The method according to claim 2, 3, 5, or 7, wherein when the patient belongs to the CYP2D6 poor metabolizer group, a dosage form containing a combination of 105 mg of the hydrochloric acid bupropion and 45 mg of the dextromethorphan hydrobromide is orally administered to the patient once a day.

11. When the patient is in the CYP2D6 poor metabolizer group, the method according to claim 2, 3, 5, or 7, wherein a dosage form comprising a combination of about 52.5 mg of the bupropion hydrochloride and about 22.5 mg of the dextromethorphan hydrobromide is orally administered to the patient twice a day.

12. A method for treating symptoms of the nervous system in the CYP2D6 poor metabolizer group, comprising administering once a day to a patient known to be in the CYP2D6 poor metabolizer group in need of treatment, 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.

13. A method for treating symptoms of the nervous system in the CYP2D6 poor metabolizer group, comprising administering once a day to a patient known to be in the CYP2D6 poor metabolizer group in need of treatment, a dosage form comprising 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide.

14. The method according to claim 12 or 13, wherein 105 mg of the bupropion hydrochloride and 45 mg of the dextromethorphan hydrobromide are present in the dosage form.

15. The method according to any one of claims 1 to 14, wherein the dosage form provides immediate release of dextromethorphan.

16. The method according to any one of claims 1 to 15, wherein the dosage form provides sustained release of bupropion.

17. By administering the dosage form once a day for 8 days, the AUC of dextromethorphan that would occur after administering the dosage form twice a day for 8 days in patients who are in the high CYP2D6 metabolizer group or the ultra-rapid CYP2D6 metabolizer group ０－１２ Compared with the AUC of dextromethorphan in the patient ０－１２ The method according to any one of claims 1 to 16, wherein an increase of about 3.4 times is avoided

18. By administering the dosage form once a day for 8 days, in patients who are in the high CYP2D6 metabolism group or the ultra-rapid CYP2D6 metabolism group, the C of dextromethorphan that would occur after administering the dosage form twice a day for 8 days ｍａｘ Compared with, the C of dextromethorphan in the patient ｍａｘ is increased by about 3 times is avoided, The method according to any one of claims 1 to 17.

19. The method according to any one of claims 1 to 18, wherein the dosage form is orally administered in the morning.

20. The method according to any one of claims 1 to 19, wherein the dosage form further comprises L-cysteine hydrochloride monohydrate.

21. The method according to any one of claims 1 to 20, wherein the dosage form further comprises a carbomer homopolymer.

22. The method according to any one of claims 1 to 21, wherein the dosage form further comprises colloidal silicon dioxide.

23. The method according to any one of claims 1 to 22, wherein the dosage form further comprises crospovidone.

24. The method according to any one of claims 1 to 23, wherein the dosage form further comprises glyceryl monocaprylocaprate.

25. The method according to any one of claims 1 to 24, wherein the dosage form further comprises magnesium stearate.

26. The method according to any one of claims 1 to 25, wherein the dosage form further comprises microcrystalline cellulose.

27. The method according to any one of claims 1 to 26, wherein the dosage form further comprises polyvinyl alcohol.

28. The method according to any one of claims 1 to 27, wherein the dosage form further comprises red iron oxide.

29. The method according to any one of claims 1 to 28, wherein the dosage form further comprises sodium lauryl sulfate.

30. The method according to any one of claims 1 to 29, wherein the dosage form further comprises stearic acid.

31. The method according to any one of claims 1 to 30, wherein the dosage form further comprises talc.

32. The method according to any one of claims 1 to 31, wherein the dosage form further comprises titanium dioxide.

33. The method according to any one of claims 1 to 32, wherein the dosage form further comprises yellow iron oxide.

34. The method according to any one of claims 1 to 33, wherein the dosage form is a solid dosage form.

35. By administering the solid dosage form to a human patient twice a day for 8 days, the AUC of bupropion that would occur after administering the solid dosage form to a human patient twice a day for 8 days, who is in the high CYP2D6 metabolizer group or the ultra-rapid CYP2D6 metabolizer group ０－１２ Compared to, the human patient will have approximately the same AUC of bupropion ０－１２ The method according to any one of claims 1 to 34, which will result in.

36. By administering the solid dosage form to a human patient twice a day for 8 days, the concentration of bupropion that would occur after administering the solid dosage form twice a day for 8 days to a human patient who is in the high CYP2D6 metabolizer group or the ultra-rapid CYP2D6 metabolizer group is ｍａｘ compared to, the human patient has approximately the same concentration of bupropion ｍａｘ The method according to any one of claims 1 to 35, which will result in having.

37. The method according to any one of claims 1 to 36, wherein the neurological symptom is a major depressive disorder.

38. The method according to any one of claims 1 to 37, wherein the neurological symptom is excitation associated with Alzheimer's disease.

39. The method according to any one of claims 1 to 38, wherein the patient has a risk of falling.

40. The method according to any one of claims 1 to 39, wherein the neurological symptom is excitation associated with dementia.

41. The method according to any one of claims 1 to 40, wherein the neurological symptom is neuropathic pain.

42. The method according to any one of claims 1 to 41, wherein the neurological symptom is generalized anxiety disorder.

43. The method according to any one of claims 1 to 42, wherein the patient has a CYP2D6 G1846(AA) genotype.

44. The method according to any one of claims 1 to 43, wherein the patient has a CYP2D6 G1846(AG) genotype.

45. The method according to any one of claims 1 to 44, wherein the patient has a CYP2D6 C100T(TT) genotype.

46. The method according to any one of claims 1 to 45, wherein the patient has a CYP2D6 C100T (CT) genotype.

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