Treatment of weak metabolites of dextromethorphan using combination of bupropion and dextromethorphan

Abstract

Disclosed herein is a method of treating a neurological condition with a combination of dextromethorphan and bupropion. The method is intended for patients suffering from a neurological or psychiatric condition, such as major depression and being a CYP2D6 weak metabolizer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of 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; all of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to treating various neurological and psychiatric disorders or conditions with a combination of bupropion and dextromethorphan in patients having a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype. Summary of the invention

[0004] Disclosed herein is a method for treating a neurological condition (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 diabetic peripheral neuropathic pain) in a CYP2D6 poor metabolizer, comprising administering a daily dose (e.g., a once-daily dose) of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide to a human patient in need thereof, wherein the human patient is known to be a CYP2D6 poor metabolizer.

[0005] Disclosed herein is a method for treating a patient with major depressive disorder by administering a combination of dextromethorphan and bupropion. This method is intended for patients with neurological disorders or conditions or psychiatric disorders or conditions (such as major depressive disorder) and with a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype. Typically, the CYP2D6 genotype or phenotype is determined by assaying a biological sample from the patient. In this method, the dosage form is orally administered to the patient, for example, once a day. The dosage form comprises 105 mg or less of bupropion hydrochloride or a molar equivalent of bupropion in the form of a free base or another salt and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent of bupropion in the form of a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide. Alternatively, a dosage of about 52.5 mg or less of bupropion hydrochloride or a molar equivalent amount of bupropion in free base form or another salt form and 22.5 mg or less of dextromethorphan hydrobromide or a molar equivalent amount of dextromethorphan in free base form or another salt form may be orally administered twice daily. Thus, for patients with a CYP2D6 poor metabolizer genotype, the risk of dizziness (a potential side effect of dextromethorphan exposure) following oral administration of a dosage form containing the combination to the patient once daily is lower than the risk if the patient is administered a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide twice daily for the same number of days.

[0006] In some embodiments, if the patient does not have a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype, a dosage form is orally administered to the patient twice daily, wherein the dosage form contains a combination of 105 mg or more of bupropion hydrochloride or a molar equivalent amount of bupropion as a free base or another salt form and 45 mg or more of dextromethorphan hydrobromide or a molar equivalent amount of bupropion as a free base or another salt form.

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

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

[0009] wherein the patient is selected based on: 1) suffering from the neurological condition, and 2) being a CYP2D6 poor metabolizer, wherein the patient is determined to be a CYP2D6 poor metabolizer by assay of a biological sample from the patient; and

[0010] wherein for said patient who is a poor metabolizer of CYP2D6, the risk of somnolence or dizziness following administration of said dosage form containing said combination to said patient once daily is lower than the risk following administration of a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide to said patient twice daily for the same number of days.

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

[0012] Determine whether the patient is a CYP2D6 poor metabolizer by:

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

[0014] The biological sample is or has been assayed to determine that the patient is a CYP2D6 poor metabolizer; and

[0015] if the patient is a CYP2D6 poor metabolizer, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of bupropion as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;

[0016] If the patient is not a CYP2D6 poor metabolizer, a dosage form containing a combination of 105 mg bupropion hydrochloride or a molar equivalent amount of bupropion as a free base or another salt and 45 mg dextromethorphan hydrobromide or a molar equivalent amount of bupropion as a free base or another salt is orally administered to the patient twice daily;

[0017] wherein for a patient who is a poor metabolizer of CYP2D6, the risk of somnolence or dizziness following administration of said dosage form containing said combination to said patient once daily is lower than the risk following administration of said combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide to said patient twice daily for the same number of days.

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

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

[0020] obtaining or having obtained a biological sample from the patient; and performing or having performed an assay on the biological sample to determine that the patient is a CYP2D6 poor metabolizer, wherein a result that the patient is a CYP2D6 poor metabolizer indicates that the patient is at risk for an adverse event associated with dextromethorphan overexposure; and

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

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

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

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

[0025] wherein the patient is selected based on: 1) suffering from the neurological condition, and 2) being a CYP2D6 poor metabolizer, wherein the patient is determined to be a CYP2D6 poor metabolizer by assay of a biological sample from the patient; and

[0026] wherein the patient's risk of an adverse event is reduced compared to the patient's risk of an adverse event if the dosage form is administered to the patient twice daily.

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

[0028] Determine whether the patient is a CYP2D6 poor metabolizer by:

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

[0030] The biological sample is or has been assayed to determine that the patient is a CYP2D6 poor metabolizer; and

[0031] If the patient is a CYP2D6 poor metabolizer, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of bupropion as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and

[0032] If the patient is not a CYP2D6 poor metabolizer, a dosage form containing a combination of 105 mg bupropion hydrochloride or a molar equivalent amount of bupropion as a free base or another salt form and 45 mg dextromethorphan hydrobromide or a molar equivalent amount of bupropion as a free base or another salt form is orally administered to the patient twice daily.

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

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

[0035] wherein the patient is selected based on: 1) suffering from the neurological condition, and 2) being a CYP2D6 poor metabolizer, wherein the patient is determined to be a CYP2D6 poor metabolizer by assay of a biological sample from the patient; and

[0036] wherein for said patient who is a poor metabolizer of CYP2D6, the risk of somnolence and dizziness following administration of said dosage form containing said combination to said patient once daily is lower than the risk following administration of a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide to said patient twice daily for the same number of days.

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

[0038] Determine whether the patient is a CYP2D6 poor metabolizer by:

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

[0040] The biological sample is or has been assayed to determine that the patient is a CYP2D6 poor metabolizer; and

[0041] if the patient is a CYP2D6 poor metabolizer, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of bupropion as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;

[0042] If the patient is not a CYP2D6 poor metabolizer, a dosage form containing a combination of 105 mg bupropion hydrochloride or a molar equivalent amount of bupropion as a free base or another salt and 45 mg dextromethorphan hydrobromide or a molar equivalent amount of bupropion as a free base or another salt is orally administered to the patient twice daily;

[0043] wherein for a patient who is a poor metabolizer of CYP2D6, the risk of somnolence and dizziness following administration of the dosage form containing the combination to the patient once daily is lower than the risk following administration of the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide to the patient twice daily for the same number of days. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1The effects of renal impairment, hepatic impairment, and CYP2D6 poor metabolizer status on the pharmacokinetics of a tablet containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride are depicted. DETAILED DESCRIPTION

[0045] Disclosed herein is a method for treating a neurological condition (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 diabetic peripheral neuropathic pain) in a CYP2D6 poor metabolizer, comprising administering a daily dose (e.g., a once-daily dose) of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide to a human patient in need thereof, wherein the human patient is known to be a CYP2D6 poor metabolizer.

[0046] In some embodiments, there is a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide in the tablet.

[0047] In some embodiments, once daily administration avoids an AUC of dextromethorphan in the human patient of 0-12 AUC of dextromethorphan resulting from twice daily administration of the tablets for 8 days to human patients who are extensive or extreme metabolizers of CYP2D6 0-12 Compared with the previous study, the results showed that the growth rate of 4.5% and 2.5% of the control group was

[0048] In some embodiments, once daily administration avoids the patient's C max C of dextromethorphan resulting from 8 days of twice daily administration of the tablets to human patients who are extensive or ultra-extensive metabolizers of CYP2D6 max Compared to the previous study, the increase was about 3 times.

[0049] In some embodiments, the tablet is administered orally in the morning.

[0050] In some embodiments, the dextromethorphan is in an immediate release formulation.

[0051] In some embodiments, bupropion is in an extended release formulation.

[0052] In some embodiments, the tablet further contains a carbomer homopolymer.

[0053] In some embodiments, the tablet further contains colloidal silicon dioxide.

[0054] In some embodiments, the tablet further contains crospovidone.

[0055] In some embodiments, the tablet further contains caprylic / decanoic acid glyceryl.

[0056] In some embodiments, the tablet further contains l-cysteine ​​hydrochloride monohydrate.

[0057] In some embodiments, the tablet further contains magnesium stearate.

[0058] In some embodiments, the tablet further contains microcrystalline cellulose.

[0059] In some embodiments, the tablet further contains polyvinyl alcohol.

[0060] In some embodiments, the tablet further contains red iron oxide.

[0061] In some embodiments, the tablet further contains sodium lauryl sulfate.

[0062] In some embodiments, the tablet further contains stearic acid.

[0063] In some embodiments, the tablet further contains talc.

[0064] In some embodiments, the tablet further contains titanium dioxide.

[0065] In some embodiments, the tablet further contains yellow iron oxide.

[0066] In some embodiments, administration of the tablets twice daily to a human patient for 8 days results in an AUC of bupropion in the human patient of 0-12 The AUC of bupropion resulting from twice daily administration of the tablets for 8 days to human patients who are extensive or ultra-extensive metabolizers of CYP2D6 is 0-12 Compared to about the same.

[0067] In some embodiments, administering the tablet twice daily to a human patient for 8 days results in a C of bupropion in the human patient of max The C of bupropion resulting from twice daily administration of the tablets for 8 days to human patients who are extensive or ultra-extensive metabolizers of CYP2D6 was max Compared to about the same.

[0068] 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 (271.4 dextromethorphan base). The structural formula is:

[0069]

[0070] Dextromethorphan hydrobromide powder is white or almost white crystals and is slightly soluble in water.

[0071] 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 (239.74 bupropion base). The structural formula is:

[0072]

[0073] Bupropion hydrochloride powder is white and readily soluble in water.

[0074] Cytochrome P450 2D6 (CYP2D6) is an enzyme encoded by the CYP2D6 gene in humans. The CYP2D6 function in any particular subject can be described as one of the following: 1) a poor metabolizer, which has little or no CYP2D6 function; 2) an extensive metabolizer, which has normal CYP2D6 function; 3) an intermediate metabolizer, whose rate of metabolizing drugs is between that of a poor metabolizer and an extensive metabolizer; and 4) an ultrafast metabolizer, which has multiple copies of the CYP2D6 gene expressed, so that the CYP2D6 function is 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 who do not have a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype include intermediate metabolizers, extensive metabolizers, or ultrafast metabolizers.

[0075] The present disclosure relates to treating patients with CYP2D6 poor metabolizer genotype or CYP2D6 poor metabolizer phenotype. Individuals with CYP2D6 poor metabolizer genotype can be identified by obtaining biological samples (such as blood samples, saliva samples or any other samples containing individual DNA) and performing genotyping assays. The CYP2D6 poor metabolizer phenotype can be obtained by comparing the plasma dextromethorphan level of the patient using dextromethorphan alone with the level expected based on the dose of the combination of bupropion and dextromethorphan administered to the patient. It can also be determined by using dextromethorphan alone and comparing the dextromethorphan / dextrphan metabolism ratio of the patient, as described in Jurica et al., Journal of Clinical Pharmacology and Therapeutics, 2012, 37, 486-490. Typically, the metabolism ratio of dextromethorphan / dextrphan is 0.3 or higher indicating a poor metabolizer phenotype.

[0076] There are many other typing tests that can be used to determine if a person is a CYP2D6 poor metabolizer. See, e.g., Schaeffeler et al., CYP2D6 Genotyping Strategy Based on Gene Copy Number Determination by TaqMan Real-Time PCR. Human Mutation 22, 476-485 (2003); Bradford L D. CYP2D6 allele frequency in European Caucasians, Asians, Africans, and their descendants. Pharmacogenomics 2002 Mar;3(2):229-43; Bertilsson L, Dahl ML, Dalen P, Al-Shurbaji A. Molecular genetics of CYP2D6: clinicalrelevance with focus on psychotropic drugs. Br J Clin Pharmacol 2002 Feb;53(2):111-22; Bryan Campbell, Pharm.D., Jane Xu, Ph.D., Josephine Cucchiaro,Ph.D.,Mila Etropolski,MD,Mark Schmidt, MDProtocol No. CILO522A2328. October 22, 2001; Chainvuati S, Nafziger AN, Leeder JS, Gaedigk A, Kearns GL, Sellers E, ZhangY, Kashuba AD, Rowland E, Bertino JS Jr. Combined phenotypic assessment of cytochrome p450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthineoxidase activities with the “Cooperstown 5+1 cocktail.” Clin. Pharmacol. Ther. 2003 Nov;74(5):437-47; Dahl ML, Yue QY, RohHK, Johansson I, Sawe J,Sjoqvist F,Bertilsson L.Pharmacogenetics 1995 / 6 / 15(3):159-64: Gough AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, Eichelbaum M, Wolf C. Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects R.Identification of the primary genedefect at the cytochrome P450 CYP2D locus.Nature 1990October 547(6295):773-6;Hanioka N,Kimura S,Meyer UA,Gonzalez FJ G1934--A base change in intron 3of a mutant CYP2D6 allele results in an aberrant 3'splice recognitionsite.Am J Hum Genet.1990–12 / 47(6):994-1001; JO,Dahl M L.Maintenance therapy with zuclopenthixoldecanoate: associations between plasma concentrations, neurological side effects and CYP2D6 genotype F,Ingelman-SundbergM.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: Protocol No CILO522A 2328: 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 Chern 1990 October 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, BrowMA. 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.CYP2D6 genotyping as an alternative to phenotyping fordetermination of metabolic status in a clinical trial setting.AAPS Pharmsci2000;2(4):article 33;Nevilie M,Selzer R,Aizenstein B,Maguire M,Hogan K,WaltonR,Welsh K,Neri B,de Arruda M.Characterization of cytochrome P450 2D6 allelesusing the Invader system.Biotechniques June 2002; Suppl:34-8,40-3; and 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:Pharmacogenetics1993Oct;3(5):256-63. .

[0077] In some embodiments, the patient has a CYP2D6G1846 (AA) genotype. In some embodiments, the patient has a CYP2D6G1846 (AG) genotype. In some embodiments, the patient has a CYP2D6C100T (TT) genotype. In some embodiments, the patient has a CYP2D6C100T (CT) genotype.

[0078] Patients with a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype can be treated for a neurological disorder or condition or a psychiatric disorder or condition by orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride or a molar equivalent amount of bupropion in free base or another salt form and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent amount of bupropion in free base or another salt form, wherein the molar ratio of bupropion to dextromethorphan is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide. Alternatively, a dosage of about 52.5 mg or less of bupropion hydrochloride or a molar equivalent amount of bupropion in free base or another salt form and 22.5 mg or less of dextromethorphan hydrobromide or a molar equivalent amount of dextromethorphan in free base or another salt form can be administered twice daily.

[0079] It has been found that administration of a combination of bupropion and dextromethorphan to a person with a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype results in higher plasma dextromethorphan levels compared to patients who do not have the poor metabolizer genotype or phenotype. This raises safety concerns for poor metabolizers, as an increased risk of adverse events is associated with high plasma dextromethorphan levels.

[0080] For some patients, potential adverse events due to increased dextromethorphan exposure may include dizziness, nausea, dry mouth, somnolence, headache, agitation, hypomania, confusion (including mental confusion), hallucinations, coma, drowsiness, shivering, hyperthermia, vasoconstriction, tachycardia, diarrhea, myoclonus (muscle twitching), hyperreflexia (manifesting as clonus), tremor, restlessness, insomnia, dissociation, vomiting, grandiose delusions, blurred vision, diplopia, bloodshot eyes, dilated pupils, sweating, fever, bruxia (teeth grinding), hypotension, hypertension, shallow breathing, slowed breathing, dysuria, urinary retention, muscle cramps, shakiness, sedation, paresthesias, hypomania, slurred speech, unsteady gait, blackouts, inability to focus eyes, rash, severe itching, spontaneous memory recall, acute psychosis, unusual excitement (unusual irritability), and nausea, vomiting. Excitement), nervousness, irritability, constipation, stomach pain, etc. The administration of a lower dose, such as half the dose or less, 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 or in addition, the amount of bupropion and dextromethorphan can be reduced. For example, the amount of bupropion and dextromethorphan can be reduced by 50%, 75%, 90% or more. Compared with the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide administered to patients twice a day, the risk of adverse events of administering reduced and / or less frequent doses of bupropion and dextromethorphan (e.g., a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide administered once a day) may be reduced.

[0081] The dosage forms described herein can contain or be prepared from bupropion in any suitable form, such as a salt form (e.g., bupropion hydrochloride), other salt forms, free base form, hydrates, solvates, polymorphs, other solid forms, etc. In some embodiments, the pharmaceutical composition does not contain any other active pharmaceutical agents other than bupropion and / or dextromethorphan.

[0082] Dosage forms for administration to patients having a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype may include any suitable amount of bupropion for once daily administration, i.e., less than 105 mg, such as 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, a molar equivalent amount of another salt form of bupropion salt, or bupropion in free base form.

[0083] Alternatively, a dosage form for administration to a patient having a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype can be administered twice daily, and the daily dose can be less than 105 mg, such as 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, a molar equivalent amount of bupropion in another salt form, or bupropion in free base form.

[0084] In some embodiments, the dosage form provides sustained release of bupropion.

[0085] The dosage forms described herein can contain or be prepared from any suitable form of dextromethorphan, such as a salt form (e.g., dextromethorphan bromide), other salt forms, free base form, hydrates, solvates, polymorphs, other solid forms, and the like.

[0086] Dosage forms for administration to patients having a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype can include any suitable amount of dextromethorphan 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, such as dextromethorphan bromide, a molar equivalent amount of dextromethorphan in the form of another salt, or dextromethorphan in the form of the free base.

[0087] Alternatively, a dosage form for administration to a patient having a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype can be administered twice daily, and the daily dose can be, for example, 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, such as dextromethorphan bromide, a molar equivalent amount of dextromethorphan in the form of another salt, or dextromethorphan in the form of the free base.

[0088] In some embodiments, the dosage form provides immediate release of dextromethorphan.

[0089] The pharmaceutical dosage form has a molar ratio of bupropion to dextromethorphan in the dosage form of about the ratio of the moles of bupropion in 105 mg of bupropion hydrochloride to the moles of dextromethorphan in 45 mg of dextromethorphan hydrobromide. There are 0.38 moles of bupropion (molecular weight: 276.2 g / mol) in 105 mg of bupropion hydrochloride; and there are 0.122 moles of dextromethorphan (molecular weight: 370.3 g / mol) in 45 mg of dextromethorphan hydrobromide. Thus, this ratio is about 0.38 moles of bupropion to about 0.12 moles of dextromethorphan. In some embodiments, the ratio is about 0.37-0.39 moles of bupropion to about 0.11-0.13 moles of dextromethorphan, about 2.5-3.1 to 1, about 2.6-3.3 to 1, or about 2.5-3.3 to 1.

[0090] Pope reported that when CYP2D6 was inhibited by administration of quinidine, the C of dextromethorphan in poor metabolizers was increased compared with that in other patients who were not poor metabolizers of CYP2D6. max The AUC of dextromethorphan in CYP2D6 poor metabolizers was approximately 40% higher. 0-12 Bupropion is also a CYP2D6 inhibitor. The inventors found that, similar to quinidine, administration of a combination of bupropion and dextromethorphan resulted in a decrease in the C of dextromethorphan in poor metabolizers. max and AUC were significantly higher than in other patients who were not poor metabolizers (e.g., extensive, intermediate, or ultra-rapid metabolizers).

[0091] When the combination of bupropion and dextromethorphan is administered to a CYP2D6 poor metabolizer, there is no particular reason to believe that the C maxThe AUC and AUC of bupropion are different from those of other patients who are not poor metabolizers (e.g., extensive, intermediate or ultra-rapid metabolizers). Therefore, one of ordinary skill in the art would expect that when the combination of bupropion and dextromethorphan is administered to a CYP2D6 poor metabolizer, the plasma bupropion level of the CYP2D6 poor metabolizer is similar to that of other patients who are not poor metabolizers (e.g., extensive, intermediate or ultra-rapid metabolizers), but the plasma dextromethorphan level is significantly higher. The inventors found this to be the case in clinical trials. Compared with patients who do not have a CYP2D6 poor metabolizer genotype or a CYP2D6 poor metabolizer phenotype, the increase in dextromethorphan exposure of CYP2D6 poor metabolizers increases the risk of adverse events caused by dextromethorphan.

[0092] The antidepressant efficacy of bupropion has been shown to be dose-dependent. (See https: / / dailymed.nlm.nih.gov / dailymed / lookup.cfm?setid=a0fdfc21-165a-43fa-9b3c-e48f3b892250&versio n=3.) Therefore, it is expected that reducing the dose of bupropion will result in a loss of the antidepressant effect of bupropion, especially when the dose (e.g., 210 mg / day) is already below the target dose of bupropion for treating depression. In order to avoid losing the efficacy of bupropion, a person of ordinary skill in the art may reduce the dose of dextromethorphan while keeping the dose of bupropion the same. For example, a person of ordinary skill in the art may reduce the dose of dextromethorphan from 90 mg / day to 45 mg / day while maintaining a bupropion dose of 210 mg / day. This is expected to result in plasma bupropion and dextromethorphan levels in CYP2D6 poor metabolizers that are similar to those in other patients who are not poor metabolizers of CYP2D6 (e.g., extensive, intermediate, or ultra-rapid metabolizers).

[0093] However, the inventors believe that the doses of bupropion and dextromethorphan can be reduced by the same proportion (e.g., by administering a dosage form containing 105 mg bupropion hydrochloride and 45 mg dextromethorphan once daily, rather than administering a dosage form having 105 mg bupropion hydrochloride and 45 mg dextromethorphan twice daily or a dosage form having 210 mg bupropion hydrochloride and 90 mg dextromethorphan once daily) without reducing the therapeutic efficacy of the combination in treating depression.

[0094] 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 does not contain the other.

[0095] The pharmaceutical composition or dosage form may include cysteine ​​(e.g., L-cysteine), such as about 30-100 mg or about 50-100 mg cysteine, such as L-cysteine ​​hydrochloride, another salt form of L-cysteine, or neutral or zwitterionic form of L-cysteine. These amounts of cysteine ​​may help stabilize bupropion in the presence of other excipients.

[0096] The pharmaceutical composition or dosage form may also include a sustained release or controlled release polymer, for example, a polymer for providing sustained release of bupropion, such as a cross-linked or uncross-linked acrylate polymer or copolymer (including poly (acrylic acid) or poly (alkyl acrylic acid), such as poly (methacrylic acid), for example, carbomer homopolymer type A, such as Carbopol 971P), a cellulose derivative such as methylcellulose, etc. In some embodiments, the controlled release polymer (e.g., carbomer copolymer type A) is about 1-40%, about 1-5%, about 5-10%, about 10-15%, about 15-20%, about 20-30%, about 30-40%, about 11-13%, or about 12% by weight of the pharmaceutical composition. In some embodiments, the controlled release polymer is about 0.1-20%, about 0.1-2%, about 2-4%, about 4-6%, about 6-8%, about 8-10%, about 10-15%, about 15-20%, or about 7% by weight of the dosage form.

[0097] The pharmaceutical composition or dosage form may also include a filler, such as microcrystalline cellulose. In some embodiments, the filler may be about 20-60%, about 20-30%, about 30-40%, about 40-50%, or about 50-60% by weight of the pharmaceutical composition or dosage form.

[0098] The pharmaceutical composition or dosage form may also include a lubricant, such as magnesium stearate. In some embodiments, the lubricant is about 0.1-10%, about 0.1-2%, about 2-4%, about 4-6%, about 6-8%, or about 8-10% by weight of the pharmaceutical composition or dosage form.

[0099] Dosage forms can be formulated for any suitable route of administration, such as oral administration.

[0100] Dosage forms for oral administration, such as solid dosage forms (e.g., capsules, tablets, or pills), may also contain one or more of the following: a binder such as gum tragacanth, gum arabic, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, alginic acid, etc.; a sweetener such as sucrose, lactose, or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage form is a capsule, it may contain a liquid carrier in addition to the above types of materials. Various other materials may be present as coatings, for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. It may be desirable that the materials in the dosage form or pharmaceutical composition be pharmaceutically pure and nontoxic in the amounts employed. In some embodiments, the dosage form contains cysteine, Carbopol 971P, microcrystalline cellulose, silicon dioxide, and magnesium. In some embodiments, the dosage form comprises: a first layer comprising bupropion and cysteine; and a second layer comprising dextromethorphan, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0101] An example of a two-layer dosage form is shown below:

[0102] Tier 1

[0103] Element Amount (mg) Bupropion Hydrochloride 105 Cysteine 10-100 Carbopol 971P 20-60 Microcrystalline Cellulose 200-300 Colloidal Silica 1-10 Magnesium Stearate 1-10

[0104] Tier 2

[0105] Element Amount (mg) Dextromethorphan Hydrobromide 45 Microcrystalline Cellulose 100-150 Croscarmellose Sodium 1-20 Magnesium Stearate 1-10

[0106] The pharmaceutical compositions or dosage forms described herein can be used to treat neurological or psychiatric conditions, such as depression (including major depressive disorder or refractory major depressive disorder), agitation (such as agitation associated with Alzheimer's disease), addiction (such as nicotine addiction), etc., in genetically poor metabolizers of dextromethorphan. For example, the pharmaceutical composition or dosage form can be administered once a day to a person suffering from a neurological or psychiatric condition. Treatment can be continued as needed, 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, 1 week to 2 months, 1-3 months, 3-6 months, 6-12 months, 1-2 years, or possibly longer, while the treatment is effective and safe.

[0107] The CYP2D6 gene is highly polymorphic, with more than 70 allelic variants described to date. See, e.g., http: / / www.imm.ki.se / CYPalleles / cyp2d6.htm. Two common polymorphisms within the CYP2D6 gene in the Caucasian population are CYP2D6G1846A and CYP2D6P34S (also known as CYP2D6C100T). These polymorphisms correspond to nucleotides 3465 and 1719, respectively, in the GenBank sequence M33388.1 (GI: 181303). The CYP2D6P34S / CYP2D6C100T polymorphism also corresponds to nucleotide 100 in the GenBank mRNA sequence M20403.1 (GI: 181349).

[0108] The CYP2D6G1846A polymorphism (called CYP2D6*4 alleles, including *4A, *4B, *4C, *4D, *4E, *4F, *4G, *4H, *4J, *4K and *4L) represents a transition from G to A at the junction between intron 3 and exon 4, which moves the splice junction by one base pair, resulting in a frameshift and premature termination of the protein (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 AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, Eichelbaum M, Wolf C R. Identification of the primary gene defect at the cytochrome P450CYP2D locus. Nature 1990 Oct 5;47(6295):773-6; Hanioka N, Kimura S, Meyer UA, Gonzalez F J. The human CYP2D locus associated with a common genetic defect indrug oxidation:a G1934--A base change in intron 3of a mutant CYP2D6 alleleresults in an aberrant 3'splice recognition site. Am J Hum Genet. 1990 Dec;47(6):994-1001).The CYP2D6P34S / CYP2D6C100T polymorphism (referred to as the CYP2D6*10 and CYP2D6*14 alleles) represents a C to T change that results in a proline to serine substitution at position 34 (Yokota H, Tamura S, Furuya H, Kimura S, Watanabe M, Kanazawa I, Kondo I, Gonzalez F J. Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine ​​metabolism: Pharmacogenetics 1993 Oct;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 fordebrisoquine hydroxylation: Mol Pharmacol 1994 Sep;46(3):452-9).Two of these polymorphisms were associated with reduced enzyme activities for 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 Sep;46(3):452-9; Dahl ML, Yue QY, Roh HK, 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 Jun;5(3):159-64; Jaanson P, Marandi T, Kiivet RA, Vasar V, Vaan S, Svensson JO, Dahl M L. Maintenance therapy with zuclopenthixol decanoate: associations between plasma concentrations, neurological side effects and CYP2D6 genotype. Psychopharmacology (Berl) 2002 Jun;162(1):67-73; Bertilsson L, Dahl ML, Dalen P, Al-Shurbaji A. Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br JClin Pharmacol 2002 Feb;53(2):111-22).

[0109] In one study, blood samples were collected from 128 individuals following a pharmacogenetic protocol and after patient consent. DNA was extracted from whole blood using the PUREGENE DNA Isolation Kit (D-50K) by Covance. (U.S. Patent No. 8,586,610)

[0110] In this study, the genotypes of the CYP2D6G1846A polymorphism were determined in 123 of the 128 consenting individuals, while the genotypes of the CYP2D6C100T polymorphism were identified 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).

[0111] In this study, 40-100 ng of genomic DNA was amplified using a GC-enriched PCR kit (Roche Diagnostics, Mannheim, Germany) according to the manufacturer's recommendations. The thermal cycling conditions were as follows: initial denaturation (3 min at 95°C), 10 cycles of 30 s denaturation (30 s at 95°C), annealing (30 s at 66°C), and extension (60 s at 72°C), followed by 22 cycles of 30 s at 95°C, 30 s at 66°C, 60 s + 5 s / cycle at 72°C, followed by a final extension (7 min at 72°C). (U.S. Patent No. 8,586,610)

[0112] In this study, the probe sets used for genotyping were developed by Third Wave Technologies, Inc (Madison, Wis.). Assay (Lyamichev 1999) (Third Wave Technologies, Inc) genotypes PCR products. (U.S. Patent No. 8,586,610)

[0113] This study reported the genotyping results of 74 study participants. Of these participants, 57 had the CC genotype, 14 had the CT genotype, and 3 had the TT genotype for the CYP2D6C100T polymorphism. The TT and CT genotypes for the CYP2D6C100T polymorphism were determined to include CYP2D6 poor metabolizers. For the CYP2D6G1846A polymorphism, 2 participants were of the AA genotype, 14 participants were of the AG genotype, and 55 participants were of the GG genotype. The AA and AG genotypes were determined to indicate CYP2D6 poor metabolizers. (U.S. Patent No. 8,586,610)

[0114] The topic combination can be used as an adjunctive treatment for major depressive disorder or depression.

[0115] In addition to major depressive disorder, the subject combinations can also be used to treat other diseases of the condition in the patient population or situation described herein. For example, the subject combinations can be used to treat pain or neurological disorders. Examples of neurological disorders that can be treated with the subject combinations include, but are not limited to, affective disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, epilepsy, and headaches.

[0116] Affective disorders that may be treated by the subject combinations include, but are not limited to, depression, major depression, refractory depression, refractory bipolar depression, bipolar disorder including cyclothymia, seasonal affective disorder, mood disorders, chronic depressive disorder (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH) and attention deficit / hyperactivity disorder (AD / HD), bipolar disorder and mania, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychotic dysfunction, pseudobulbar mood, and mood lability.

[0117] Depression can be manifested by depressive symptoms. These symptoms can include psychological changes (such as mood changes), feelings of extreme sadness, despair, mental dullness, difficulty concentrating, pessimistic worries, agitation, anxiety, irritability, guilt, anger, worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-depreciation. The physical symptoms of depression can include insomnia, anorexia, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, irritability, aches, pains, headaches, cramps, digestive problems, and / or abnormal hormonal circadian rhythms.

[0118] Mental disorders that can be treated by the subject combination include, but are not limited to: anxiety disorders, including, but not limited to, phobia, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic-depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, paranoia, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease. Alzheimer's disease can also be referred to as Alzheimer's dementia. Other neurobehavioral symptoms of Alzheimer's disease that can be treated include disinhibition and emotional indifference.

[0119] Agitation may occur in Alzheimer's disease as the disease progresses. Agitation may present itself as inappropriate verbal, emotional, and / or physical behavior. Inappropriate behavior may include, but is not limited to, incoherent babbling, inappropriate emotional responses, demands for attention, threats, irritability, frustration, screaming, repetitive questioning, mood swings, swearing, abusive language, physical outbursts, emotional distress, restlessness, tearing, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body movements, hoarding, stalking, hitting, scratching, biting, aggressiveness, hyperactivity, and / or kicking.

[0120] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral and psychological symptoms (including agitation). AD is the most common form of dementia and affects approximately 6 million individuals in the United States, a figure that is expected to increase to approximately 14 million by 2050. It is reported that up to 70% of AD patients suffer from agitation and are characterized by emotional distress, aggressive behavior, destructive irritability, and disinhibition. Managing agitation is a priority for AD. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, premature nursing home placement, and increased mortality. Currently, the FDA has not approved a therapy for the treatment of agitation in AD patients.

[0121] It is known that neurobehavioral symptoms may occur during dementia, and it can be treated by combination therapy. Compared to the patient's cognitive impairment, caregivers or family members may feel more unbearable due to the patient's behavior / psychological symptoms. The common form of syndrome includes Alzheimer's disease, vascular dementia, Lewy body (abnormal protein aggregates formed in nerve cells) dementia and a group of diseases causing frontotemporal dementia (degeneration of the frontal lobe of the brain). The symptoms of dementia patients are similar to those of mental disorders, but slightly different from each other. The neurobehavioral symptoms associated with dementia include depression, apathy, agitation, disinhibition, hallucinations, delusions, psychosis, impulse, aggressiveness, compulsion, hypersexuality and personality disorders. Neurobehavioral symptoms may also be found in other conditions (such as traumatic brain injury), such as disinhibition.

[0122] Agitation in patients with Alzheimer's disease can be assessed using the Cohen Mansfield Agitation Inventory or (CMAI). The CMAI assesses a variety of behaviors, including hitting (including self), kicking, grabbing, pushing, throwing, biting, scratching, spitting, hurting self or others, tearing objects or destroying property, making physical advances, pacing, wandering aimlessly, dressing inappropriately or undressing, trying to go to different places, intentionally falling down, eating / drinking inappropriate substances, handling things inappropriately, hiding things, hoarding things, repetitive quirks, general irritability, screaming, making verbal advances, swearing or verbally aggression, repeating sentences or questions, strange noises (weird laughter or crying), complaining, whining, and constant and unprovoked requests for attention or help.

[0123] Schizophrenia may be treated by a combination of positive and / or negative symptoms of schizophrenia or residual symptoms of schizophrenia.Other conditions that may be treated include intermittent explosive disorder.

[0124] The brain dysfunction that the subject combination can treat includes, but is not limited to, disorders involving intellectual impairment, such as Alzheimer's disease, Alzheimer's dementia, amnesia, amnesia / amnestic syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperactivity syndrome and schizophrenia. Brain dysfunction also includes disorders caused by cerebrovascular disease, including but not limited to stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head injury, etc., wherein symptoms include impaired consciousness, Alzheimer's disease, coma, decreased attention and speech disorders.

[0125] Substance addictions that can be treated by the subject combination include, but are not limited to, drug dependence, cocaine addiction, psychostimulants (e.g., crack, cocaine, speed, methamphetamine), nicotine, alcohol, opioids, antianxiety and hypnotic drugs, cannabis, marijuana, amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking, cigars and / or pipes, e-cigarettes or vaping, and chewing cigarette addiction.

[0126] Movement disorders that may be treated by the subject combinations include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's disease chorea, chorea rheumatica, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette's syndrome and Wilson's disease.

[0127] Dementias that may be treated by the subject combinations include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff Syndrome, and Pick's disease.

[0128] Motor neuron diseases that may be treated by the subject combinations include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sachs disease, Sandoff disease, and hereditary spastic paraplegia.

[0129] Neurodegenerative diseases that may be treated by the subject combinations include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CHD), and schizophrenia. disease, CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0130] Epileptic disorders that may be treated by the subject combinations include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile convulsions; partial seizures, including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsy continua partial; generalized seizures, including, but not limited to, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0131] Headache types that may be treated by the subject combination include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0132] Other neurological conditions that may be treated by the subject combinations include Rett Syndrome, autism, tinnitus, impaired consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; voice disorders caused by uncontrolled laryngeal muscle spasms, including but not limited to abductor spasmodic dysphonia, adductor spasmodic dysphonia, musculartension dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence, including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0133] In some embodiments, the subject combinations can be used to treat pain, joint pain, pain associated with sickle cell disease, pseudobulbar mood, depression (including refractory depression), disorders related to memory and cognition, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rhett syndrome, seizures, cough (including chronic cough), and the like.

[0134] In some embodiments, the subject combinations may be administered orally to relieve musculoskeletal pain, including low back pain, and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, periarticular disorders, axial spondyloarthritis (including ankylosing spondylitis), Paget's disease, fibrous dysplasia, SAPHO syndrome, transient hip osteoarthritis, vertebral compression fractures, osteoporosis, and the like.

[0135] In some embodiments, the subject combinations may be administered to relieve inflammatory pain, including musculoskeletal pain, arthritic pain, and complex regional pain syndrome.

[0136] Arthritis refers to inflammatory joint diseases that may be associated with pain. Examples of arthritis pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, periarticular disease, neuropathic arthropathy (including Charcot foot), axial spondyloarthritis (including ankylosing spondylitis), and SAPHO syndrome.

[0137] In some embodiments, the subject combinations are used to treat chronic musculoskeletal pain.

[0138] In some embodiments, the subject compositions can be administered to relieve complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is a type of inflammatory pain. CRPS can also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the limbs, which may be accompanied by edema and autonomic, motor and sensory changes.

[0139] In some embodiments, the subject compositions may be administered orally to relieve neuropathic pain.

[0140] Examples of neuropathic pain include pain caused by diabetic peripheral neuropathy or diabetic peripheral neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, central pain, pain caused by multiple sclerosis, etc. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and radiation or chemotherapy-related neuropathy, etc.

[0141] In some embodiments, the subject compositions may be administered to relieve fibromyalgia.

[0142] In some embodiments, the subject compositions can be co-administered with one or more strong CYP2D6 inhibitors. It has been found that concomitant use of the subject compounds with one or more strong CYP2D6 inhibitors increases plasma dextromethorphan concentrations. Therefore, it is recommended to monitor patients for adverse effects or reactions that may be caused by dextromethorphan, such as drowsiness and dizziness.

[0143] When the subject combination is co-administered with one or more strong CYP2D6 inhibitors, it may be necessary to adjust the dosage. Adjusting the dosing frequency of the subject combination to a lower dose of bupropion and / or dextromethorphan in the subject combination or a smaller dose can reduce adverse effects or reactions in the patient, such as, but not limited to, drowsiness, dizziness, or a combination thereof. For example, when co-administered with one or more strong CYP2D6 inhibitors, the recommended dosage of the subject combination is one tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride once a day (such as once a day in the morning).

[0144] In some embodiments, the subject compositions can be administered to patients who are poor metabolizers of CYP2D6. It has been found that administration of the subject compositions to CYP2D6 inhibitors increases plasma dextromethorphan concentrations compared to patients who are not poor metabolizers of CYP2D6. Therefore, it is recommended to monitor patients for adverse effects or reactions that may be caused by dextromethorphan, such as drowsiness and dizziness.

[0145] When the patient is a CYP2D6 poor metabolizer, it may be necessary to adjust the dosage. Adjusting the dosing frequency of the subject combination to a lower dose of bupropion and / or dextromethorphan or a smaller dose of the subject combination can reduce adverse effects or reactions in the patient, such as but not limited to drowsiness, dizziness, or a combination thereof. For example, when co-administered to a patient who is a CYP2D6 poor metabolizer, the recommended dosage of the subject combination is one tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride once a day (such as once a day in the morning).

[0146] Compared with twice daily administration of the same number of days of the subject combination, once daily administration of the subject combination to a patient receiving a strong CYP2D6 of companionship or a patient as a CYP2D6 poor metabolizer can reduce adverse effects, such as but not limited to drowsiness, dizziness or a combination thereof. In some embodiments, reducing the dosage or administration frequency of the subject combination may reduce drowsiness. In some embodiments, reducing the dosage or administration frequency may alleviate dizziness. Since dizziness may be relevant to falling, adjusting the dosage of the subject combination to a lower amount or a lower administration frequency may reduce the risk of falling in the patient taking the subject combination. For example, taking the subject combination once a day may reduce the risk of falling in the patient compared to taking the subject combination twice daily for the same number of days. For example, for elderly patients or patients suffering from dementia (such as Alzheimer's disease), this may be very important.

[0147] The terms "treating" or "treatment" include any activity that affects the structure or any function of the human or other animal body, including the diagnosis, cure, mitigation, treatment, or prevention of disease.

[0148] The subject combination may be used to treat any disease or condition identified in the following U.S. Patents as treatable by a combination of bupropion and dextromethorphan: 8,569,328, 9,168,234, 9,189,905, 9,205,083, 9,238,032, 9,278,095, 9,314,462, 9,370,513, 9,375,429, 9,408,815, 9,421,176, 9, 457,023、9,457,025、9,474,731、9,486,450、9,700,528、9,700,553、9,707,191、9,763,932、9,861,595、9,867,819、9,968,568、10,058,518、10,064,857、10,080,727、10,092,560、10,092,56 1, 10,105,327, 10,105,361, 10,251,879, 10,463,634, 10,512,643, 10,548,857, 10,596,167, 10,772,850, 10,780,064, 10,780,066, 10,786,469, 10,786,496, 10,799,497, 10,806,710, 10,8 64,209, 10,874,663, 10,874,664, 10,874,665, 10,881,624, 10,881,657, 10,894,046, 10,894,047, 10,898,453, all of which are incorporated herein by reference in their entirety for their disclosure of diseases that may be treated by a combination of bupropion and dextromethorphan, including the specific embodiments and combinations described therein.

[0149] Example 1

[0150] In 3 poor metabolizers, twice-daily administration of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide resulted in a significantly lower dextromethorphan C compared with extensive metabolizers. max and AUC 0-12 An increase of approximately 3 times and 3.4 times respectively.

[0151] In contrast, Flesher (WO 2009 / 006194, p. 86, Table IV) reported that twice daily administration of 30 mg dextromethorphan and 30 mg quinidine for 7 days resulted in a decrease in C in poor metabolizers compared with extensive metabolizers. max and AUC 0-12 The increase was only about 1.43 times and 1.46 times respectively.

[0152] Example 2

[0153] Analysis of steady-state kinetic data in 12 poor metabolizers treated with 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide twice daily in an efficacy clinical trial showed that plasma dextromethorphan concentrations were generally greater than the exposure of non-poor metabolizers.

[0154] Example 3

[0155] The properties of tablets containing a combination of dextromethorphan hydrobromide, which is a noncompetitive NMDA receptor antagonist and sigma-1 receptor agonist, and bupropion hydrochloride, which is an aminoketone and CYP450 2D6 inhibitor, were investigated.

[0156] 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) in an immediate release formulation and 105 mg of bupropion hydrochloride (equivalent to 91.14 mg of bupropion free base) in an extended release formulation. Each tablet contains the following inactive ingredients: carbomer homopolymer, colloidal silicon dioxide, crospovidone, monocaprylic and capric glyceride, L-cysteine ​​hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide, and yellow iron oxide.

[0157] The effects of renal impairment, hepatic impairment, and CYP2D6 poor metabolizer status on the exposure of tablets containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride are summarized in Figure 1 middle.

[0158] Figure 1 The results depicted in are based on plasma concentrations in human patients following 8 days of twice daily dosing with tablets containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride. Data are GMRs and 90% CIs. The reference used was matched healthy subjects studied for renal and hepatic impairment, and CYP2D6 extensive or super metabolizers. AUC denotes area under the plasma concentration-time curve from zero to 12 hours; BUP denotes bupropion; CI denotes confidence interval; C max is maximum plasma concentration; DM, dextromethorphan; GMR, geometric mean ratio; PK, pharmacokinetics.

[0159] For CYP2D6 poor metabolizers, dextromethorphan AUC was observed 0-12 Increased 3.40 times and dextromethorphan C max AUC of bupropion was not observed. 0-12 or bupropion C max significant changes.

[0160] Based on these results, a dose adjustment is recommended for patients known to be poor CYP2D6 metabolizers, as these patients have higher dextromethorphan concentrations than strong / intermediate CYP2D6 metabolizers. The recommended dose for patients known to be poor CYP2D6 metabolizers is one tablet once daily (such as in the morning).

[0161] Unless otherwise indicated, all numbers used in the specification and claims to indicate quantities of components, properties such as amounts, percentages, etc. should be understood in all cases to indicate the exact value shown and to be modified by the term "about". Therefore, unless otherwise indicated, the numerical parameters listed in the specification and the attached claims are approximate values, which may vary depending on the desired properties to be obtained. At the very least, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be interpreted in accordance with the number of reported significant digits and applying customary rounding techniques.

[0162] The use of the terms "comprising" or "comprises" herein also encompasses the use of "consisting essentially of" or "consists essentially of" or "consisting of" in its place.

[0163] The affirmative recitation of elements anywhere herein should be understood to contemplate both the inclusion of the elements and the exclusion of the elements.

[0164] Unless otherwise indicated herein or clearly contradicted by the context, the terms "one", "a", "said" and similar references used in the context of describing the embodiments (especially in the context of the following claims) should be interpreted as covering singular and plural references. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein can be performed in any suitable order. The use of any and all embodiments or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the embodiments and does not limit the scope of any claim. Any language in this specification should not be interpreted as indicating that any unclaimed element is necessary to practice the claims.

[0165] The grouping of alternative elements or embodiments disclosed herein should not be interpreted as limiting. Each group member may be mentioned and claimed individually, or mentioned and claimed in any combination with other members of the group or other elements found herein. For reasons of convenience and / or accelerating the application process, it is contemplated that one or more members of the group may be included in the group or deleted from the group. When any such inclusion or deletion occurs, this specification is deemed to include the modified group, and therefore satisfies the written description of all Markush groups used in the appended claims.

[0166] Certain embodiments are described herein, including the best mode known to the inventors for implementing the claimed embodiments. Of course, variations of these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect that the skilled person will adopt such variations as appropriate, and the inventors expect that the claimed embodiments can be practiced in ways other than those specifically described herein. Therefore, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. In addition, any combination of the above elements in all possible variations is covered unless otherwise indicated herein or clearly contradicted by the context.

[0167] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Therefore, by way of example and not limitation, alternative embodiments may be used in accordance with the teachings herein. Therefore, the claims are not limited to the embodiments exactly shown and described.

Claims

1. A method of treating a patient suffering from a neurological condition by administering a combination of dextromethorphan and bupropion, the method comprising: orally administering to the patient once daily a dosage form comprising: 105 mg or less of bupropion hydrochloride or a molar equivalent amount of bupropion as a free base or another salt form, and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent amount of dextromethorphan as a free base or another salt form, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; wherein the patient is selected based on: 1) suffering from the neurological condition, and 2) being a CYP2D6 poor metabolizer, wherein the patient is determined to be a CYP2D6 poor metabolizer by assay of a biological sample from the patient; and wherein for said patient who is a poor metabolizer of CYP2D6, the risk of somnolence and dizziness following administration of said dosage form containing said combination to said patient once daily is lower than the risk following administration of a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide to said patient twice daily for the same number of days.

2. A method of treating a patient experiencing a neurological condition using a combination of dextromethorphan and bupropion, the method comprising the steps of: Determine whether the patient is a CYP2D6 poor metabolizer by: obtaining or having obtained a biological sample from the patient; and performing or having performed an assay on the biological sample to determine that the patient is a CYP2D6 poor metabolizer; and if the patient is a CYP2D6 poor metabolizer, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of bupropion as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; If the patient is not a CYP2D6 poor metabolizer, orally administering to the patient twice daily a dosage form containing a combination of 105 mg bupropion hydrochloride, or a molar equivalent amount of bupropion as a free base or another salt, and 45 mg dextromethorphan hydrobromide, or a molar equivalent amount of bupropion as a free base or another salt; and wherein for a patient who is a poor metabolizer of CYP2D6, the risk of somnolence and dizziness following administration of the dosage form containing the combination to the patient once daily is lower than the risk following administration of the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide to the patient twice daily for the same number of days.

3. A method of treating a patient experiencing a neurological condition, the method comprising the steps of: a) determining whether the patient is at risk for an adverse event associated with dextromethorphan overexposure by: obtaining or having obtained a biological sample from the patient; and performing or having performed an assay on the biological sample to determine that the patient is a CYP2D6 poor metabolizer, wherein a result that the patient is a CYP2D6 poor metabolizer indicates that the patient is at risk for an adverse event associated with dextromethorphan overexposure; and b) if the patient is at risk for an adverse event associated with overexposure to dextromethorphan, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of bupropion as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and c) if the patient is not at risk for an adverse event associated with overexposure to dextromethorphan, orally administering to the patient twice daily a dosage form containing a combination of 105 mg bupropion hydrochloride, or a molar equivalent amount of bupropion as the free base or another salt form, and 45 mg dextromethorphan hydrobromide, or a molar equivalent amount of bupropion as the free base or another salt form.

4. A method of treating a neurological condition using a combination of dextromethorphan and bupropion, comprising: orally administering to a patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of bupropion as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and wherein the patient is selected based on: 1) suffering from the neurological condition, and 2) being a CYP2D6 poor metabolizer, wherein the patient is determined to be a CYP2D6 poor metabolizer by assay of a biological sample from the patient; and wherein the patient's risk of an adverse event is reduced compared to the patient's risk of an adverse event if the dosage form is administered to the patient twice daily.

5. A method of treating a patient experiencing a neurological condition using a combination of dextromethorphan and bupropion, the method comprising the steps of: Determine whether the patient is a CYP2D6 poor metabolizer by: obtaining or having obtained a biological sample from said patient; as well as The biological sample is or has been assayed to determine that the patient is a CYP2D6 poor metabolizer; and If the patient is a CYP2D6 poor metabolizer, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of bupropion as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and If the patient is not a CYP2D6 poor metabolizer, a dosage form containing a combination of 105 mg bupropion hydrochloride or a molar equivalent amount of bupropion as a free base or another salt form and 45 mg dextromethorphan hydrobromide or a molar equivalent amount of bupropion as a free base or another salt form is orally administered to the patient twice daily.

6. A method of treating a patient suffering from a neurological condition by administering a combination of dextromethorphan and bupropion, the method comprising: orally administering to the patient once daily a dosage form comprising: 105 mg or less of bupropion hydrochloride or a molar equivalent amount of bupropion as a free base or another salt form, and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent amount of dextromethorphan as a free base or another salt form, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; wherein the patient is selected based on: 1) suffering from the neurological condition, and 2) being a CYP2D6 poor metabolizer, wherein the patient is determined to be a CYP2D6 poor metabolizer by assay of a biological sample from the patient; and wherein for said patient who is a poor metabolizer of CYP2D6, the risk of somnolence or dizziness following administration of said dosage form containing said combination to said patient once daily is lower than the risk following administration of a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide to said patient twice daily for the same number of days.

7. A method of treating a patient experiencing a neurological condition using a combination of dextromethorphan and bupropion, the method comprising the steps of: Determine whether the patient is a CYP2D6 poor metabolizer by: obtaining or having obtained a biological sample from said patient; as well as The biological sample is or has been assayed to determine that the patient is a CYP2D6 poor metabolizer; and if the patient is a CYP2D6 poor metabolizer, orally administering to the patient once daily a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of bupropion as a free base or another salt, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; If the patient is not a CYP2D6 poor metabolizer, orally administering to the patient twice daily a dosage form containing a combination of 105 mg bupropion hydrochloride, or a molar equivalent amount of bupropion as a free base or another salt, and 45 mg dextromethorphan hydrobromide, or a molar equivalent amount of bupropion as a free base or another salt; and wherein for a patient who is a poor metabolizer of CYP2D6, the risk of somnolence or dizziness following administration of said dosage form containing said combination to said patient once daily is lower than the risk following administration of said combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide to said patient twice daily for the same number of days.

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

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

10. The method of claim 2, 3, 5 or 7, wherein if the patient is a CYP2D6 poor metabolizer, a dosage form containing a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is orally administered to the patient once daily.

11. The method of claim 2, 3, 5 or 7, wherein if the patient is a CYP2D6 poor metabolizer, a dosage form containing a combination of about 52.5 mg bupropion hydrochloride and about 22.5 mg dextromethorphan hydrobromide is orally administered to the patient twice daily.

12. A method of treating a neurological condition in a CYP2D6 poor metabolizer comprising administering once daily to a patient in need thereof a dosage form containing 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of bupropion as a free base or another salt, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of dextromethorphan as a free base or another salt, wherein the patient is known to be a CYP2D6 poor metabolizer.

13. A method of treating a neurological condition in a CYP2D6 poor metabolizer comprising administering once daily to a patient in need thereof a dosage form comprising 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide, wherein the patient is known to be a CYP2D6 poor metabolizer.

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

15. The method of any preceding claim, wherein the dosage form provides immediate release of dextromethorphan.

16. The method of any preceding claim, wherein the dosage form provides sustained release of bupropion.

17. The method of any preceding claim, wherein administering the dosage form once daily for 8 days avoids an AUC of dextromethorphan in the patient 0-12 The AUC of dextromethorphan resulting from twice daily administration of the dosage form for 8 days to patients who are extensive or ultra-extensive metabolizers of CYP2D6 is 0-12 Compared with the previous study, the results showed that the growth rate of 4.5% and 2.5% of the control group was 18. The method of any preceding claim, wherein once daily administration of the dosage form for 8 days avoids C max The C of dextromethorphan resulting from twice daily administration of the dosage form for 8 days to patients who are extensive or ultra-extensive metabolizers of CYP2D6 is max An increase of about 3 times.

19. The method according to any preceding claim, wherein the dosage form is administered orally in the morning.

20. The method according to any preceding claim, wherein the dosage form further comprises L-cysteine ​​hydrochloride monohydrate.

21. The method according to any preceding claim, wherein the dosage form further comprises a carbomer homopolymer.

22. The method of any preceding claim, wherein the dosage form further comprises colloidal silicon dioxide.

23. The method of any preceding claim, wherein the dosage form further comprises crospovidone.

24. The method of any preceding claim, wherein the dosage form further comprises caprylic / decanoic acid monoglyceride.

25. The method of any preceding claim, wherein the dosage form further comprises magnesium stearate.

26. The method of any preceding claim, wherein the dosage form further comprises microcrystalline cellulose.

27. The method according to any preceding claim, wherein the dosage form further comprises polyvinyl alcohol.

28. A method according to any preceding claim, wherein the dosage form further comprises red iron oxide.

29. The method of any preceding claim, wherein the dosage form further comprises sodium lauryl sulfate.

30. The method of any preceding claim, wherein the dosage form further comprises stearic acid.

31. The method according to any preceding claim, wherein the dosage form further comprises talc.

32. The method of any preceding claim, wherein the dosage form further comprises titanium dioxide.

33. The method of any preceding claim, wherein the dosage form further comprises yellow iron oxide.

34. The method of any preceding claim, wherein the dosage form is a solid dosage form.

35. The method of any preceding claim, wherein administering the solid dosage form twice daily to the human patient for 8 days results in an AUC of bupropion in the human patient of 0-12 The AUC of bupropion resulting from twice daily administration of the solid dosage form to human patients who are extensive or ultra-extensive metabolizers of CYP2D6 is 0-12 Compared to about the same.

36. The method of any preceding claim, wherein administering the solid dosage form twice daily to the human patient for 8 days results in a C of bupropion in the human patient of max The C of bupropion resulting from twice daily administration of the solid dosage form to human patients who are extensive or ultra-extensive metabolizers of CYP2D6 was max Compared to about the same.

37. The method of any preceding claim, wherein the neurological condition is major depressive disorder.

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

39. A method according to any preceding claim, wherein the patient is at risk of falling.

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

41. The method of any preceding claim, wherein the neurological condition is neuropathic pain.

42. The method of any preceding claim, wherein the neurological condition is generalized anxiety disorder.

43. The method of any preceding claim, wherein the patient has a CYP2D6G1846(AA) genotype.

44. The method of any preceding claim, wherein the patient has the CYP2D6G1846(AG) genotype.

45. The method of any preceding claim, wherein the patient has the CYP2D6C100T (TT) genotype.

46. ​​The method of any preceding claim, wherein the patient has the CYP2D6C100T (CT) genotype.

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