Compounds for the treatment of neurological and psychiatric disorders and combinations thereof

Abstract

The present disclosure relates to a method of treating a nervous system disorder, comprising administering bupropion or a combination of bupropion and dextromethorphan to a person in need thereof, monitoring the person for Brugada patterns / syndrome, drug reactions with eosinophilia and systemic symptoms, or acute generalized exanthematous pustulosis, and reducing or discontinuing the use of the bupropion or the combination of the bupropion and the dextromethorphan if the person develops Brugada patterns / syndrome, a subcutaneous tissue disorder, drug reactions with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis.

Description

[0001] Inventor: Herriot Tabuteau

[0002] Cross-reference to related applications

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 557,860, filed February 26, 2024, which is incorporated herein by reference in its entirety. Summary of the Invention

[0004] This disclosure relates to the administration of bupropion. Some embodiments involve a combination of bupropion and dextromethorphan for the treatment of neurological disorders.

[0005] Some implementations include a method for treating a neurological disorder, the method comprising administering bupropion or a combination of bupropion and dextromethorphan to a person in need, monitoring the person for Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis, and reducing or discontinuing the use of bupropion or the combination of bupropion and dextromethorphan if the person develops Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms, or acute generalized exanthematous pustulosis. Attached Figure Description

[0006] Figure 1 The effects of renal impairment, hepatic impairment, and CYP2D6 poor metabolizer status on the pharmacokinetics of tablets containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride were investigated.

[0007] Figure 2 The changes in the total MADRS score relative to baseline were depicted on a weekly basis for patients who received tablets containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride twice daily. Detailed Implementation

[0008] As described above, this disclosure relates to a method for treating a neurological disorder, the method comprising administering bupropion to a person in need, monitoring the person for Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis, and reducing or discontinuing the use of bupropion if the person develops Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis.

[0009] In some implementations, bupropion is administered daily to a person requiring treatment for a neurological disorder at approximately 5-100 mg, 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, or 300-450 mg, and the person is monitored for Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms, or acute generalized exanthematous pustulosis. If the person develops Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis, the use of bupropion is reduced or discontinued.

[0010] Some implementations relate to a method for treating a neurological disorder, the method comprising administering a combination of bupropion and dextromethorphan to a person in need, monitoring the person for Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis, and reducing or discontinuing the use of the combination of bupropion and dextromethorphan if the person develops Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis.

[0011] In some implementations, a combination of bupropion (such as about 5-100 mg, about 100-150 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, or about 300-450 mg of bupropion daily) and dextromethorphan (such as about 30-50 mg, about 50-100 mg, or about 100-150 mg of dextromethorphan daily) is administered to a person requiring treatment for a neurological disorder. The person is monitored for Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis. If the person develops Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis, the use of bupropion or the combination of bupropion and dextromethorphan is reduced or discontinued.

[0012] In some implementations, the following combination is administered once or twice daily to a person requiring treatment of a neurological disorder: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or a molar equivalent of dextromethorphan in its free base form or another salt form; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan in its free base form or another salt form. For convenience, this combination is referred to herein as the “subject combination.” In each instance of the subject combination mentioned herein, a combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is specifically considered.

[0013] It has been found that treatment with bupropion can lead to adverse cardiovascular events such as complete atrioventricular block, premature contractions, hypotension, hypertension (severe in some cases), phlebitis, pulmonary embolism, or Brugada figure / syndrome. Patients receiving bupropion or a combination of bupropion and dextromethorphan (including the main combination) should be monitored for these adverse events.

[0014] Bupropion treatment has been found to cause skin and subcutaneous tissue disorders such as alopecia, angioedema, exfoliative dermatitis, hirsutism, Schwarz-Jones syndrome, acute generalized exanthematous pustulosis, and drug response with eosinophilia and systemic symptoms (DRESS). Patients receiving bupropion or a combination of bupropion and dextromethorphan (including the main combination) should be monitored for these disorders.

[0015] In some implementations, patients are monitored for the possibility of subcutaneous tissue disorders, and if such disorders occur, bupropion or a combination of bupropion and dextromethorphan (including the main combination) is discontinued.

[0016] In some implementations, patients are monitored for the possibility of DRESS, and if the patient develops the disorder, bupropion or a combination of bupropion and dextromethorphan (including the main combination) is discontinued.

[0017] In some implementations, patients are monitored for the possibility of Brugada graph / syndrome, and if the patient experiences this adverse event, bupropion or a combination of bupropion and dextromethorphan (including the main combination) is discontinued.

[0018] In some implementations, patients are monitored for the possibility of acute generalized exanthematous pustulosis, and if the patient develops the disorder, bupropion or a combination of bupropion and dextromethorphan (including the main combination) is discontinued.

[0019] In some implementations, bupropion treatment is discontinued if a person develops Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis.

[0020] In some implementations, bupropion treatment is reduced if a person develops Brugada pattern / syndrome, subcutaneous tissue disturbance, drug response with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis. For example, approximately 105 mg or less of bupropion or a pharmaceutically acceptable salt thereof may be administered daily.

[0021] Dextromethorphan hydrobromide is a non-competitive NMDA receptor antagonist and σ-1 receptor agonist.

[0022] The chemical name of dextromethorphan hydrobromide is morphinan, 3-methoxy-17-methyl-,(9α,13α,14α) hydrobromide monohydrate. The empirical formula of dextromethorphan hydrobromide is C0. 18 H 25 NO•HBr•H2O, with a molecular weight of 370.33. The structural formula is:

[0023]

[0024] Dextromethorphan hydrobromide powder is a white or almost white crystalline powder that is slightly soluble in water.

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

[0026] 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 C1. 13 H 18 ClNO•HCl, with a molecular weight of 276.2. The structural formula is:

[0027]

[0028] Bupropion hydrochloride powder is white and readily soluble in water.

[0029] The subject combination can be contained in oral dosage forms, including tablets, such as extended-release tablets. In some embodiments, the subject combination is contained in a dosage form for oral administration and is available as a round bilayer tablet.

[0030] In some embodiments, each tablet containing the subject combination contains 45 mg of dextromethorphan hydrobromide as an immediate-release formulation. In some embodiments, each tablet containing the subject combination contains 105 mg of bupropion hydrochloride as an extended-release formulation. In some embodiments, each tablet containing the subject combination contains 45 mg of dextromethorphan hydrobromide as an immediate-release formulation and 105 mg of bupropion hydrochloride as an extended-release formulation.

[0031] In some embodiments, the tablet containing the theme combination contains L-cysteine ​​hydrochloride monohydrate. In some embodiments, the tablet containing the theme combination contains carbomer homopolymer. In some embodiments, the tablet containing the theme combination contains microcrystalline cellulose. In some embodiments, the tablet containing the theme combination contains colloidal silica. In some embodiments, the tablet containing the theme combination contains crospovidone. In some embodiments, the tablet containing the theme combination contains stearic acid. In some embodiments, the tablet containing the theme combination contains magnesium stearate.

[0032] In some embodiments, tablets containing the theme combination contain the following inactive ingredients: L-cysteine ​​hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silica, cropovidone, stearic acid, and magnesium stearate.

[0033] In some embodiments, the starting dose of the combination is one tablet containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride, administered once daily in the morning. In some embodiments, after 3 days, the dose is increased to twice daily (e.g., given at least 8 hours apart), one tablet (or a dosage form containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride). In some embodiments, no more than two doses containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride are administered on the same day.

[0034] No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) liver impairment compared to the dose recommended for patients with normal liver function.

[0035] The pharmacokinetics of the combination of 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride have not been evaluated in patients with severe hepatic impairment (Child-Pugh C). The combination of 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride is not recommended or should be avoided in patients with severe hepatic impairment.

[0036] The combination tablets can be taken orally with or without food. In some embodiments, the tablets should be swallowed whole and should not be crushed, split, or chewed.

[0037] Patients with kidney damage may require special medication.

[0038] In some implementations, the renal impairment status of a subject can be determined by measuring an individual's estimated glomerular filtration rate (eGFR). eGFR is calculated using the modified diet for renal disease (MDRD) equation, in mL / min / 1.73 m 2 count:

[0039] (eGFR in mL / min) / 1.73m 2 = 175 × (serum creatinine in mg / dL) -1.154 × Age -0.203 × 0.742 (if female) × 1.212 (if Black).

[0040] Further details regarding the calculation of eGFR can be found, for example, Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van Lente F: Chronic Kidney Disease Epidemiology Collaboration. Expressing the Modification of Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate with Standardized Serum Creatinine Values. Ann Intern Med. 2009;150(9):604-12.

[0041] The following are the kidney damage statuses based on the guidelines of the Food and Drug Administration (FDA).

[0042] Normal: eGFR ≥ 90 mL / min / 1.73 m 2

[0043] • Mild: eGFR 60-89 mL / min / 1.73 m2 (i.e., ≥ 60 to < 90)

[0044] • Moderate: eGFR 30-59 mL / min / 1.73 m 2 (That is, ≥ 30 to < 60)

[0045] • Severe: eGFR 15-29 mL / min / 1.73 m 2(i.e., ≥ 15 to < 30) and not receiving hemodialysis

[0046] • End-stage renal disease (ESRD): eGFR < 15 mL / min / 1.73 m 2 And did not receive hemodialysis or received hemodialysis

[0047] See, Guidance for Industry Pharmacokinetics in Patients with Impaired Renal Function-Study Design, Data Analysis and Impact on Dosing and Labeling, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), February 2010. As used herein, “subjects with renal impairment” may have mild, moderate, or severe renal impairment, or may have ESRD.

[0048] In some implementations, the target renal impairment is moderate (estimated glomerular filtration rate (eGFR) or glomerular filtration rate (GFR) of 30 to 59 mL / min / 1.73 m 2 For patients requiring this treatment, the recommended dose of the combination is 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride, or a molar equivalent of another form of dextromethorphan and / or bupropion, such as a once-daily tablet (or a formulation containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride), such as a tablet once daily in the morning or other oral formulation, or a combination of 52.5 mg bupropion hydrochloride and approximately 22.5 mg dextromethorphan hydrobromide orally twice daily. In some implementations, patients are monitored for potential adverse reactions caused by dextromethorphan, such as drowsiness and dizziness.

[0049] In some embodiments, the subject matter combination is a dosage form, such as a tablet, which further comprises: colloidal silica, cropovidone, glyceryl monocaprylate, L-cysteine ​​hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide, or yellow iron oxide or combinations thereof.

[0050] Moderate renal impairment can be determined by measurements of biological samples from the patient, such as blood samples, to determine creatinine levels. Serum creatinine levels from blood samples can be used to estimate GFR.

[0051] Patients using the topical combination therapy in conjunction with a strong CYP2D6 inhibitor may require special dosing. Concomitant use of the topical combination therapy with a strong CYP2D6 inhibitor increases plasma concentrations of dextromethorphan. In some implementations, when co-administered with a strong CYP2D6 inhibitor, the recommended dose of the topical combination therapy is one tablet once daily (or a formulation containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride), such as one tablet once daily in the morning or other oral formulations. In some implementations, patients are monitored for potential adverse reactions that may be caused by dextromethorphan, such as drowsiness and dizziness.

[0052] Strong CYP2D6 inhibitors include, but are not limited to, compounds such as fluoxetine, propafenone, quinidine, and paroxetine.

[0053] Patients known to be poor metabolizers of CYP2D6 (PM) may require special dosing. In some implementations, the recommended dose for patients known to be poor metabolizers of CYP2D6 is one tablet once daily (or a formulation containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride), such as one tablet once daily in the morning or other oral formulations.

[0054] Special precautions may be required when switching a patient to a monoamine oxidase inhibitor (MAOI) antidepressant or from an MAOI to a theme combination. In some implementations, a minimum 14-day interval must be maintained between discontinuing the MAOI intended to treat depression and starting therapy with the theme combination. Conversely, in some implementations, a minimum 14-day interval must be maintained after stopping the theme combination and before starting the MAOI antidepressant.

[0055] Data have reported the presence of bupropion and its metabolites in human breast milk. There is no data on the effects of bupropion or its metabolites on breast milk production. Limited data associated with bupropion use in breastfeeding patients have not identified a clear association with adverse reactions in breastfed infants.

[0056] Neurotoxicity results were observed in juvenile rats treated with the combination of dextromethorphan / quinidine on day 7 postnatal day (PND), which corresponds to late pregnancy to the first few months of life and may extend to the first three years of human life. It is unclear whether dextromethorphan is present in human milk. There are no data on the effects of dextromethorphan on breastfed infants or on milk production. Due to potential neurotoxicity, in some implementation plans, patients should be informed that breastfeeding is not recommended during treatment with the combination of dextromethorphan and bupropion, and for 5 days after the final dose.

[0057] In some embodiments, children receiving the subject combination are at risk of epilepsy. In some embodiments, the children are approximately three years old or younger. In some embodiments, children receiving the subject combination are at risk of neurotoxicity.

[0058] For breastfeeding mothers, a combination of about 45 mg dextromethorphan hydrobromide and about 105 mg bupropion hydrochloride can be taken twice daily for about 1 week to about 6 weeks, about 6 weeks or at least 6 weeks, then treatment should be stopped for at least 5 days before breastfeeding can begin.

[0059] In some implementations, five days after the final dose of the combination, the breast milk produced by the human patient is substantially free of dextromethorphan.

[0060] In some implementations, breast milk produced by human patients is substantially free of bupropion five days after the final dose of the combination.

[0061] In some implementations, patients receiving the subject combination are not exposed to detectable amounts of dextromethorphan during breastfeeding.

[0062] In some implementations, patients receiving the subject combination are not exposed to detectable amounts of bupropion during breastfeeding.

[0063] In some implementations, the subject combination is administered to the patient twice daily until the patient experiences a reduction in her total MADRS score relative to baseline of at least approximately 7, at least approximately 11, at least approximately 13, or at least approximately 15.9. When the desired reduction in MADRS score is achieved, the patient may discontinue treatment, wait at least 5 days, and then begin breastfeeding her child.

[0064] In some implementations, the human child is a breastfed infant.

[0065] In some implementations, patients experience a greater reduction in their total MADRS score relative to baseline after administration of the subject combination than patients experienced when given a placebo. Patients taking the subject combination may experience a greater reduction in MADRS score than when given a placebo at, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or at other times.

[0066] In the combination of the two drugs, bupropion inhibits the metabolism of dextromethorphan via CYP2D6. When co-administered with bupropion, dextromethorphan exhibits nonlinear pharmacokinetics at steady state, with varying AUC and C2 at different doses of dextromethorphan (30 to 60 mg). max The changes were greater than the dose-proportional changes, and for different doses of bupropion (75 to 150 mg), the changes were less than the dose-proportional changes.

[0067] When administered as a combination of therapies, dextromethorphan and bupropion reached steady-state plasma concentrations within 8 days. (Based on C...) max and AUC 0-12 At steady state, the accumulation ratios of dextromethorphan are approximately 20% and 32%, respectively. Based on C max and AUC 0-12 The cumulative ratios of bupropion under steady state were 1.1 and 1.5, respectively.

[0068] After application of the topical combination, the median T value of dextromethorphan was... max The median T value for bupropion is approximately 3 hours. max It takes about 2 hours. The C of the hydroxybupropion metabolite... max It appears approximately 3 hours after administration and is about 14 times the peak level of bupropion. AUC of hydroxybupropion 0-12 It is approximately 19 times that of bupropion. The C-values ​​of erythrohydroxybupropion and threohydroxybupropion metabolites are... max Approximately 4 hours after administration, and each time the C value is approximately equal to that of bupropion. max And the C of bupropion max Approximately 5 times higher. The AUC values ​​of erythrohydroxybupropion and threohydroxybupropion... 0-12 The values ​​were approximately 1.2 times and 7 times that of bupropion, respectively.

[0069] The combination can be taken with or without food. When the combination is taken with food, dextromethorphan C... max and AUC 0-12 The values ​​remained unchanged and decreased by 14%, respectively, and bupropion C... max and AUC 0-12 They increased by 3% and 6% respectively.

[0070] Dextromethorphan has a plasma protein binding rate of approximately 60%-70%, while bupropion has a rate of 84%. The protein binding rate of the hydroxybupropion metabolite is similar to that of bupropion; however, the protein binding rate of the threo-hydroxybupropion metabolite is about half that of bupropion.

[0071] Eight days after administration of the subject combination in hypermetabolic individuals, the mean elimination half-life of dextromethorphan increased by approximately three times to approximately 22 hours compared to dextromethorphan not administered with bupropion.

[0072] The mean elimination half-lives of dextromethorphan and bupropion were 22 hours and 15 hours, respectively. The apparent elimination half-lives of the metabolites of hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion were approximately 35, 44, and 33 hours, respectively.

[0073] Esketamine is a non-competitive NMDA receptor antagonist indicated for use in combination with oral antidepressants to treat treatment-resistant depression in adults. Treatment of treatment-resistant depression carries the risk of dissociation. The esketamine label states that due to the risks of sedation and dissociation, patients must be monitored for at least 2 hours during each treatment session, followed by evaluation to determine when the patient is considered clinically stable and ready to leave the healthcare environment.

[0074] Dissociation includes: delusional perception; depersonalization / derealization disorder; derealization; double vision; dissociation; sensory dullness; cold sensation; hot sensation; sensation of changes in body temperature; hallucinations; auditory hallucinations; visual hallucinations; hyperacusis; illusions; eye discomfort; oral sensory dullness; paresthesia; oral paresthesia; pharyngeal paresthesia; photophobia; altered time perception; tinnitus; blurred vision; visual impairment.

[0075] The theme combination is a combination of dextromethorphan (a non-competitive N-methyl-D-aspartate (NDMA) receptor antagonist and σ-1 receptor agonist) and bupropion (an aminoketone and CYP450 2D6 inhibitor) indicated for the treatment of major depressive disorder (MDD) in adults. Unlike esketamine, the theme combination may not result in dissociation or dissociation events at the time of administration. In some embodiments, dissociation is not monitored in patients after administration of the theme combination.

[0076] The following information includes the types of dissociation effects and other effects that can be avoided by using a combination of dextromethorphan and bupropion.

[0077] In clinical trials, sedation occurred in 48% to 61% of patients treated with esketamine, according to the Modified Observer Alertness / Sedation Assessment Scale (MOAA / S), and loss of consciousness (MOAA / S score of 0) was experienced in 0.3% to 0.4% of patients treated with esketamine. The combination of dextromethorphan and bupropion achieved NMDA receptor antagonism without a significant risk of sedation.

[0078] Due to the possibility of delayed or prolonged sedation, patients receiving esketamine must be monitored by a healthcare provider for at least 2 hours during each treatment session, followed by evaluation to determine when the patient is considered clinically stable and ready to leave the healthcare setting. Such monitoring is not required for treatment with the combination of dextromethorphan and bupropion.

[0079] When esketamine is used in conjunction with CNS sedatives, close monitoring of sedation is necessary in patients treated with esketamine. Such monitoring is not required for treatment with the main combination of dextromethorphan and bupropion.

[0080] Esketamine is only available through a restricted program under the Risk Assessment and Mitigation Strategy (REMS). This restriction does not apply to the combination of dextromethorphan and bupropion.

[0081] The most common psychological effects of esketamine are dissociative changes and / or perceptual changes (including distortions and illusions of time and space), derealization, and depersonalization (based on physician-managed dissociative state scales, 61% to 84% of patients treated with esketamine experience dissociative or perceptual changes). Given its potential to induce dissociative effects, patients with psychosis must be carefully evaluated before administering esketamine. Such an evaluation is not required for treatment with the topical combination of dextromethorphan and bupropion. Esketamine should only be initiated if the benefits outweigh the risks. This restriction is not required for treatment with the topical combination of dextromethorphan and bupropion.

[0082] Due to the risk of dissociation, patients receiving esketamine must be monitored by a healthcare provider for at least 2 hours during each treatment session, followed by evaluation to determine when the patient is considered clinically stable and ready to leave the healthcare setting. Such monitoring, evaluation, or restriction is not required for treatment with the combination of dextromethorphan and bupropion.

[0083] Dissociation includes: delusional perception (including distortions of space and time and illusions); depersonalization / derealization disorder; derealization; double vision; dissociation; sensory dullness; feeling cold; feeling hot; sensing changes in body temperature; hallucinations; auditory hallucinations; visual hallucinations; mixed hallucinations; hyperacusis; illusions; eye discomfort; oral sensory dullness; paresthesia; oral paresthesia; pharyngeal paresthesia; photophobia; altered time perception; tinnitus; blurred vision; and visual impairment.

[0084] Esketamine is a Schedule III controlled substance (CIII) and is susceptible to abuse and resale. The combination of dextromethorphan and bupropion is not a controlled substance. The risk of abuse or misuse must be assessed in each patient before prescribing, and the development of these behaviors or conditions (including drug-seeking behavior) must be monitored in all patients receiving esketamine during treatment. Such monitoring or assessment is not required for treatment with the combination of dextromethorphan and bupropion.

[0085] Esketamine is only available through a restricted program under a risk assessment and mitigation strategy (REMS), and is therefore designated as an esketamine REMS due to the risks of sedation, dissociation, and serious adverse outcomes from abuse and misuse. Such restrictions are not required for the subject combination of dextromethorphan and bupropion.

[0086] The key requirements for esketamine REMS include the following:

[0087] • The healthcare environment must be certified in the program and ensure the presence of esketamine:

[0088] - Dispense and apply only in healthcare settings.

[0089] - Patients treated in outpatient settings (e.g., medical offices and clinics) must be enrolled in the program.

[0090] - Administered by the patient under the direct observation of a healthcare provider, and the patient is monitored by the healthcare provider for at least 2 hours after administration of esketamine.

[0091] These requirements do not apply to the combination of dextromethorphan and bupropion.

[0092] The safety of esketamine for treating depressive symptoms was evaluated in 262 adults with major depressive disorder (MDD) and acute suicidal ideation or behavior in two phase 3 studies (Study 3 and Study 4) and one phase 2 study.

[0093] Sedation was assessed using adverse event reporting and a modified observer alertness / sedation assessment (MOAA / S). In the MOAA / S, a score of 5 indicated a brisk response to being called by name in a normal tone; 0 indicated no response after trapezius squeeze pain; 4 indicated a sluggish response to being called by name in a normal tone; 3 indicated a response only after being called loudly and / or repeatedly; 2 indicated a response only after being gently pushed or shaken; and 1 indicated no response to being gently pushed or shaken. Any decrease in MOAA / S score relative to pre-dose levels was considered indicative of the presence of sedation, and such a decrease occurred more frequently in patients receiving esketamine than in those receiving placebo during the short-term treatment-resistant depression (TRD) study. A dose-related increase in the incidence of sedation (MOAA / S score < 5) was observed in the fixed-dose TRD study. Table 1 presents the incidence of sedation (MOAA / S score < 5) in fixed-dose studies of adult patients with TRD < 65 years of age and flexible-dose studies of patients with TRD ≥ 65 years of age.

[0094] Table 1: Incidence of sedation (MOAA / S score < 5) in double-blind, randomized, placebo-controlled studies (fixed-dose studies in adults < 65 years of age with treatment-resistant depression and flexible-dose studies in patients ≥ 65 years of age with treatment-resistant depression).

[0095]

[0096] *Patients evaluated using MOAA / S

[0097] In studies treating depressive symptoms in adults with MDD accompanied by acute suicidal ideation or behavior, the incidence of sedation (MOAA / S score < 5) was higher in patients treated with esketamine plus oral antidepressants compared to patients treated with placebo plus oral antidepressants (AD), similar to the findings in the treatment-resistant depression study in Table 1.

[0098] Dissociation / Perceived Change

[0099] Esketamine can cause dissociative symptoms (including derealization and depersonalization) and perceptual alterations (including distortions of time and space and illusions). In clinical trials, dissociation is transient and occurs on the day of administration. Dissociation is assessed by adverse event reporting and the clinician-managed Dissociative State Scale (CADSS). A total CADSS score greater than 4 indicates the presence of dissociative symptoms, and during short-term treatment-resistant depression studies, a greater number of patients receiving esketamine experienced this score increase to 4 or higher compared to placebo. A dose-related increase in the incidence of dissociative symptoms (CADSS total score > 4 and change > 0) was observed in fixed-dose treatment-resistant depression studies. Table 2 presents the incidence of dissociation (CADSS total score > 4 and change > 0) in fixed-dose studies in adult patients < 65 years of age with treatment-resistant depression and in flexible-dose studies in patients ≥ 65 years of age with treatment-resistant depression.

[0100] Table 2: Incidence of dissociation (CADSS total score > 4 and change > 0) in double-blind, randomized, placebo-controlled studies (fixed-dose studies in adults < 65 years of age with treatment-resistant depression and flexible-dose studies in patients ≥ 65 years of age with treatment-resistant depression).

[0101]

[0102] *Number of patients evaluated using CADSS

[0103] In studies treating depressive symptoms in adults with MDD accompanied by acute suicidal ideation or behavior, patients treated with esketamine plus oral AD also showed a higher percentage of patients with dissociation (CADSS total score > 4 and change > 0) compared to patients treated with placebo plus oral AD (16%).

[0104] Because the combination of dextromethorphan and bupropion can be administered without dissociation or dissociation events, its risk of abuse is reduced compared to esketamine. Abuse is defined as the intentional, non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Clinical studies using the combination of dextromethorphan and bupropion have not revealed drug-seeking behavior, although these observations are not systematic. Therefore, signs of misuse or abuse of the combination of dextromethorphan and bupropion (e.g., developing tolerance, increasing dose, drug-seeking behavior) can be closely monitored in patients with a history of drug abuse.

[0105] Unlike the combination of quinidine and dextromethorphan, the subject combination of bupropion hydrochloride 105 mg and dextromethorphan hydrobromide 45 mg twice daily does not prolong the QT interval to any clinically relevant degree. Therefore, ECG evaluation of the QT interval is typically not performed in patients experiencing major depressive disorder and with QT prolongation and torsades de pointes.

[0106] Thematic combinations can be used as an adjunct treatment for major depressive disorder or depression.

[0107] In addition to major depressive disorder, thematic combinations can also be used to treat other illnesses and conditions in the patient populations or situations described herein. For example, thematic combinations can be used to treat pain or neurological disorders. Examples of neurological disorders that can be treated with thematic combinations include, but are not limited to: mood disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, epilepsy, and headaches.

[0108] Mood disorders that can be treated with a combination of themes include, but are not limited to, depression, major depressive disorder, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorder (including cyclothymia), seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual anxiety disorder (PMDD), situational depression, atypical depression, mania, anxiety disorder, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH) and attention deficit / hyperactivity disorder (AD / HD), bipolar and manic disorders, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychogenic dysfunction, pseudobulbar mood and mood instability.

[0109] Depression can manifest as depressive symptoms. These symptoms can include psychological changes (such as mood swings), feelings of extreme sadness, hopelessness, lethargy, difficulty concentrating, pessimism, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-deprecation. Physical symptoms of depression can include insomnia, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, irritability, aches and pains, headaches, cramps, digestive problems, and / or circadian rhythm abnormalities.

[0110] Mental disorders that can be treated with a combination of themes include, but are not limited to, anxiety disorders, including but not limited to phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, 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, paranoid disorder, schizoaffective disorder, schizotypal traits, aggressive behavior, aggressive behavior in Alzheimer's disease, agitation, and agitation in Alzheimer's disease. Alzheimer's disease can also be called Alzheimer's dementia. Other treatable neurobehavioral symptoms of Alzheimer's disease include disinhibition and emotional blunting.

[0111] Agitation in Alzheimer's disease occurs as the disease progresses. Agitation can manifest itself as inappropriate verbal, emotional, and / or physical behaviors. Inappropriate behaviors can include, but are not limited to, incoherent rambling, inappropriate emotional reactions, attention demands, threats, irritability, frustration, screaming, repetitive questioning, mood swings, cursing, abusive language, physical outbursts, emotional distress, agitation, tearing, sleep disturbances, delusions, hallucinations, pacing, loitering, searching, rummaging, repetitive bodily movements, hoarding, stalking, hitting, scratching, biting, aggression, hyperactivity, and / or kicking.

[0112] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral and psychological symptoms, including agitation. AD is the most common form of dementia, affecting an estimated 6 million individuals in the United States, a number projected to increase to approximately 14 million by 2050. Up to 70% of people with AD have been reported to experience agitation, characterized by mood disturbances, aggressive behavior, disruptive irritability, and disinhibition. Managing agitation is a priority in AD management. Agitation in patients with AD is associated with increased caregiver burden, functional decline, accelerated cognitive decline, earlier nursing home admission, and increased mortality. Currently, there are no FDA-approved treatments for agitation in patients with AD.

[0113] Neurobehavioral symptoms are known to occur during dementia and can be treated with the aforementioned combination of therapies. Caregivers or families may find the patient's behavioral / psychological symptoms more unbearable than the cognitive impairment. Common forms of the syndrome include Alzheimer's disease, vascular dementia, Lewy body (abnormal protein aggregates forming within nerve cells) dementia, and a group of diseases leading to frontotemporal dementia (frontal lobe degeneration). The symptoms of dementia are similar to those of mental disorders, but some symptoms differ slightly from one another. Neurobehavioral symptoms associated with dementia include depression, emotional blunting, agitation, disinhibition, hallucinations, delusions, psychosis, impulsivity, aggression, compulsive behaviors, excessive sexual desire, and personality disorders. Neurobehavioral symptoms (such as disinhibition) can also be found in other conditions, such as traumatic brain injury.

[0114] Agitation in patients with Alzheimer's disease can be assessed using the Cohen-Mansfield Agitation Inventory (CMAI). The CMAI assesses a variety of behaviors, including hitting (including self-hitting), kicking, grabbing, shoving, throwing, biting, scratching, spitting, harming oneself or others, tearing objects or damaging property, making physical provocations, pacing, aimless wandering, inappropriate clothing or undressing, attempting to go to different places, deliberately falling, eating / drinking inappropriate substances, handling things inappropriately, hiding things, hoarding things, engaging in repetitive quirks, general agitation, screaming, making verbal provocations, cursing or verbal aggression, repeating sentences or questions, making strange noises (laughter or crying), complaining, negativity, and constantly and unjustifiably requesting attention or help.

[0115] Schizophrenia can be treated with the aforementioned combination of methods, including positive and / or negative symptoms of schizophrenia, or residual symptoms of schizophrenia. Other conditions that can be treated include intermittent fulminant disorder.

[0116] Brain dysfunctions that can be treated with a combination of therapies include, but are not limited to, disorders involving intellectual impairment (such as Alzheimer's disease, dementia, amnesia / amnesia syndrome), epilepsy, altered consciousness, coma, decreased attention, speech disorders, vocal dysphagia, Parkinson's disease, Lennox-Gasto syndrome, autism, hyperkinesia syndrome, and schizophrenia. Brain dysfunctions also include those caused by cerebrovascular diseases, including but not limited to stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, and head injury, among which symptoms include altered consciousness, Alzheimer's disease, coma, decreased attention, and speech disorders.

[0117] Substance abuse that can be treated with a combination of themes includes, but is not limited to, drug dependence, cocaine addiction, stimulants (e.g., crack, cocaine, speed pills, methamphetamine), nicotine, alcohol, opioids, anti-anxiety and hypnotic drugs, cannabis (cannabis, marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking cigarettes, cigars and / or pipes, e-cigarettes or vaping, and chewing tobacco addiction.

[0118] Movement disorders that can be treated with a combination of themes include, but are not limited to, akathisia, dyskinesia, synkinesis, choreoathetosis, ataxia, throwing disorder, hemispheric throwing disorder, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's disease-related chorea, rheumatic chorea, syphilis, movement disorders, 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.

[0119] Dementias that can be treated with a combination of therapies include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, Kreutzfeldt-Jacob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakov syndrome, and Pick's disease.

[0120] Motor neuron diseases that can be treated with a combination of therapies include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-poliomyelitis syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sach's disease, Sandhof's disease, and hereditary spastic paraplegia.

[0121] Neurodegenerative diseases that can be treated with thematic 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, and Menkes disease. Diseases including: adrenoleukodystrophy, autosomal dominant cerebral arteriosclerosis with subcortical infarction and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatum-substantia nigra degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0122] Epilepsy disorders that can be treated with a combination of therapies include, but are not limited to, epileptic seizures, non-epileptic seizures, epilepsy, febrile seizures; partial seizures, including but not limited to simple partial seizures, Jacksonian seizures, complex partial seizures, and continuous partial epilepsy; generalized seizures, including but not limited to generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0123] Headache types that can be treated with thematic combinations include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0124] Other neurological disorders that can be treated with thematic combinations include Rett syndrome, autism, tinnitus, altered consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; voice disorders caused by uncontrolled laryngeal spasms, including but not limited to abducens spasmodic dysarthria, adductor spasmodic dysarthria, tonic dysarthria, 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.

[0125] In some implementations, the combination of themes can be used to treat pain, arthralgia, sickle cell disease-related pain, pseudobulbar mood, depression (including treatment-resistant depression), memory and cognitive impairment, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rhett's syndrome, epilepsy, cough (including chronic cough), etc.

[0126] In some implementations, the combination of therapies can be administered orally to relieve musculoskeletal pain, including lower 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, etc.

[0127] In some implementations, a combination of themes may be applied to relieve inflammatory pain, including musculoskeletal pain, arthritis pain, and complex regional pain syndromes.

[0128] Arthritis refers to inflammatory joint diseases that can 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 rheumatic diseases, periarticular disorders, neuropathic arthropathy (including Charcot's foot), axial spondyloarthritis (including ankylosing spondylitis), and SAPHO syndrome.

[0129] In some implementations, the combination of themes is used to treat chronic musculoskeletal pain.

[0130] In some embodiments, the subject composition can be applied to relieve complex regional pain syndromes, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is a type of inflammatory pain. CRPS may also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome characterized by severe limb pain, which may be accompanied by edema and autonomic, motor, and sensory changes.

[0131] In some implementations, the subject composition can be administered orally to relieve neuropathic pain.

[0132] Examples of neuropathic pain include pain caused by diabetic peripheral neuropathy or diabetic peripheral neuropathy pain, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, central nervous system pain, and pain caused by multiple sclerosis. 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.

[0133] In some implementations, the subject composition can be applied to relieve fibromyalgia.

[0134] In some embodiments, the subject composition may be co-administered with one or more strong inhibitors of CYP2D6. It has been found that concomitant use of the subject composition with one or more strong CYP2D6 inhibitors increases plasma concentrations of dextromethorphan. Therefore, monitoring for adverse reactions or those possibly attributable to dextromethorphan, such as drowsiness and dizziness, is recommended.

[0135] When the subject composition is co-administered with one or more strong CYP2D6 inhibitors, dose adjustments may be necessary. Adjusting the dose of bupropion and / or dextromethorphan in the subject composition to a lower dose or reducing the frequency of administration of the subject composition can reduce adverse effects or reactions in patients, such as, but not limited to, somnolence, dizziness, or a combination thereof. For example, when co-administered with one or more strong CYP2D6 inhibitors, the recommended dose of the subject composition is one tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride once daily (e.g., once every morning).

[0136] Administering the theme combination once daily to patients receiving a concomitant strong CYP2D6 inhibitor may reduce adverse effects, such as, but not limited to, drowsiness, dizziness, or a combination thereof, compared to administering the theme combination twice daily for the same number of days. In some embodiments, reducing the dose or frequency of administration of the theme combination may reduce drowsiness. In some embodiments, reducing the dose or frequency of administration may reduce dizziness. Because dizziness may be associated with falls, adjusting the dose to a lower amount or lower frequency of administration of the theme combination may reduce the risk of falls in patients taking the theme combination. For example, administering the theme combination once daily may reduce the risk of falls in patients compared to administering it twice daily for the same number of days. This may be important, for example, for elderly patients or patients with dementia (such as Alzheimer's disease).

[0137] In some implementations, the subject composition can be administered to patients with moderate renal impairment. As explained herein, it has been found that administration of the subject composition to CYP2D6 poor metabolizers increases dextromethorphan plasma concentrations compared to patients who are not CYP2D6 poor metabolizers. Therefore, monitoring for adverse reactions or those possibly attributable to dextromethorphan, such as drowsiness and dizziness, is recommended.

[0138] Dosage adjustment may be necessary when a patient has moderate renal impairment. Adjusting the dose of bupropion and / or dextromethorphan in the theme combination to a lower dose or reducing the frequency of administration of the theme combination may reduce adverse effects or reactions in the patient, or lower the risk of such adverse effects or reactions, including but not limited to drowsiness, dizziness, or a combination thereof. For example, when administered to a patient with moderate renal impairment, the recommended dose of the theme combination is one tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride once daily (e.g., once every morning).

[0139] Administering the theme combination once daily to patients with moderate renal impairment may reduce adverse effects or the risk of adverse effects, such as, but not limited to, drowsiness, dizziness, or a combination thereof, compared to administering the theme combination twice daily for the same number of days. In some embodiments, reducing the dose or frequency of administration of the theme combination may reduce drowsiness. In some embodiments, reducing the dose or frequency of administration may reduce dizziness. Since dizziness may be associated with falls, adjusting the dose to a lower amount or lower frequency of administration of the theme combination may reduce the risk of falls in patients taking the theme combination. For example, administering the theme combination once daily may reduce the risk of falls in patients compared to administering it twice daily for the same number of days. This may be important, for example, for elderly patients or patients with dementia (such as Alzheimer's disease).

[0140] The term "treating" includes any activity that diagnoses, cures, alleviates, treats, or prevents disease in a person or other animal, or otherwise affects the structure or any function of the body in a person or other animal.

[0141] The combination of these ingredients can be used to treat any disease or condition identified in any of the following U.S. patents as treatable by the 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、10,092,561、10,105,327、10,105,361、10,251,879、10,4 63,634, 10,512,643, 10,548,857, 10,596,167, 10,772,850, 10,780,064, 10,780,066, 10,786,469, 10,786,496, 10,799,497, 10,806,710, 10,864,209, 10,874,663, 10 All of these patents, 874,664, 10,874,665, 10,881,624, 10,881,657, 10,894,046, 10,894,047, and 10,898,453, concerning their disclosures of diseases that can be treated by combination of bupropion and dextromethorphan, are incorporated herein by reference in their entirety, including the specific embodiments and combinations described therein.

[0142] Example 1

[0143] In a combined study, seven subjects with moderate renal impairment (GFR 30–60 mL / min) were compared with six matched controls with normal renal function (matched for sex, age, and weight ranges of the impaired subjects). The exposure to both dextromethorphan and bupropion was approximately 2-fold increased and clearance was 50% decreased.

[0144] Example 2

[0145] Approximately 7% to 10% of Caucasians and 3% to 8% of African Americans lack the ability to metabolize CYP2D6 substrates and are classified as poor metabolizers. Compared to strong metabolizers, the pharmacokinetics of the subject combination in three poor metabolizers resulted in dextromethorphan C... max and AUC0-12 The increases were approximately 3-fold and 3.4-fold, respectively. In efficacy trials, exploration of steady-state pharmacokinetic data in 12 poor metabolizers receiving the subject combination therapy showed that plasma concentrations of dextromethorphan were generally higher than those in non-poor metabolizers.

[0146] Example 3

[0147] The co-administration of the SSRI paroxetine with a theme combination containing dextromethorphan and bupropion was studied in 29 healthy volunteers. Paroxetine increased overall exposure to dextromethorphan by 2.5-fold and had no effect on bupropion. When co-administered with the theme combination, overall exposure to paroxetine increased by 1.2-fold. Based on these results, when the theme combination is prescribed in conjunction with drugs that inhibit CYP2D6, it should be administered once daily. Caution should be exercised when co-administering the theme combination with drugs that are strongly metabolized via CYP2D6.

[0148] Example 4

[0149] Tablets for oral administration were prepared. They are spherical, 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 an extended-release formulation. Each tablet contains the following inactive ingredients: carbomer homopolymer, colloidal silica, crospovidone, glyceryl monocaprylate, L-cysteine ​​hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide, and / or yellow iron oxide.

[0150] Example 5

[0151] The properties of the tablets of Example 4 were investigated. The tablets contained a combination of dextromethorphan hydrobromide (a non-competitive NMDA receptor antagonist and σ-1 receptor agonist) and bupropion hydrochloride (an aminoketone and CYP450 2D6 inhibitor).

[0152] The effects of renal impairment, hepatic impairment, and CYP2D6 poor metabolizer status on the exposure of the tablet in Example 4 are summarized in Figure 1 middle.

[0153] Figure 1The results described herein are based on plasma concentrations in human patients after 8 days of twice-daily administration of tablets containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride. Data are presented as GMR and 90% CI. Matched healthy subjects from renal and hepatic impairment studies, as well as strong or ultra-strong CYP2D6 metabolizers, were used as references. AUC represents the area under the plasma concentration-time curve from 0 to 12 hours; BUP represents bupropion; CI is the confidence interval; C max Maximum plasma concentration; DM represents dextromethorphan; GMR represents geometric mean ratio; PK represents pharmacokinetics.

[0154] exist Figure 1 In this study, the outcomes of patients with moderate renal impairment were designated as "Group 1", the outcomes of patients with moderate hepatic impairment were designated as "Group 2", and the outcomes of patients who were poor metabolizers of CYP2D6 were designated as "Group 3". The results are summarized in Table 3 below.

[0155] Table 3

[0156]

[0157] For example, in patients with moderate hepatic impairment (Group 2), the AUC of dextromethorphan and bupropion was... 0-12 and C max There was no significant difference compared to healthy patients.

[0158] Dextromethorphan AUC in patients with moderate liver damage and healthy patients 0-12 The average ratio is 1.17, with a 90% confidence interval of 0.85–1.61.

[0159] Dextromethorphan C in patients with moderate liver damage and healthy patients max The average ratio is 1.21, with a 90% confidence interval of 0.90–1.62.

[0160] Bupropion AUC in patients with moderate hepatic impairment and healthy patients 0-12 The average ratio is 1.36, with a 90% confidence interval of 0.86–2.15.

[0161] Bupropion C in patients with moderate liver damage and healthy patients max The average ratio is 1.44, with a 90% confidence interval of 0.90–2.30.

[0162] Based on these results, dose adjustment is not recommended in patients with known mild or moderate liver impairment.

[0163] In patients with moderate renal impairment, a dextromethorphan AUC was observed. 0-12 Increased by 2.21 times, dextromethorphan Cmax The AUC of bupropion increased by 2.10 times. 0-12 Increased by 1.80 times, and bupropion C max Increased by 1.87 times.

[0164] Based on these results, dose adjustment is recommended in patients with known moderate renal impairment, as their concentrations of dextromethorphan and bupropion are higher than those in patients with healthy kidney function. For patients with known moderate renal impairment, the recommended total daily dose is approximately 45 mg of dextromethorphan hydrobromide and approximately 105 mg of bupropion hydrochloride (e.g., a tablet containing approximately 45 mg of dextromethorphan hydrobromide and approximately 105 mg of bupropion hydrochloride, to be administered once daily, such as in the morning) or an equivalent dose of another form of dextromethorphan and / or bupropion.

[0165] Example 6

[0166] The effect of concomitant administration of 20 mg paroxetine on dextromethorphan exposure was determined in patients taking the tablets of Example 4, containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride, twice daily. The dextromethorphan AUC was significantly lower in patients taking the tablets twice daily without paroxetine. 0-12 Increased by 2.69 times, and dextromethorphan C max Increased by 2.38 times.

[0167] Example 7

[0168] The efficacy of the tablets of Example 4 in treating major depressive disorder in adults was demonstrated in a placebo-controlled clinical trial (Study 1). In this study, adult patients (18 to 65 years of age) meeting the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) MDD criteria were randomized to receive either the tablets of Example 4 (“DM / BU”, 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride) twice daily (N = 156) or placebo twice daily (N = 162) for 6 weeks. The median age of patients in Study 1 was 41 years, and 67% were female, 55% were Caucasian, 35% were Black, and 5% were Asian. Here, “N” represents the number of adult patients.

[0169] The primary outcome measure was the change in the total score of the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 6. The MADRS is a clinician-assessed scale used to evaluate the severity of depressive symptoms. Patients were rated on 10 items to assess feelings of sadness, anxiety, decreased sleep or loss of appetite, difficulty concentrating, lethargy, lack of interest, pessimism, and suicidal ideation. MADRS scores range from 0 to 60, with higher scores indicating more severe depression. As measured by the decrease in the total MADRS score at week 6, DM / BU was statistically significantly superior to placebo in improving depressive symptoms (see Table 4).

[0170] Table 4: Main power results of changes in total MADRS score relative to baseline at week 6 in adult patients with MDD

[0171]

[0172] SD = Standard Deviation; SE = Standard Error; LS Mean = Least Squares Mean; CI = Confidence Interval.

[0173] a Drug-Placebo

[0174] Figure 2 The changes in total MADRS scores relative to baseline on a weekly basis are presented. Changes in total MADRS scores from baseline to week 1 and from baseline to week 2 are pre-specified secondary efficacy endpoints. The differences in changes in total MADRS scores relative to baseline between DM / BU and placebo at weeks 1 and 2 were statistically significant.

[0175] Examination of demographic subgroups by age, sex, and race did not reveal differences in response.

[0176] Unless otherwise indicated, all figures representing quantities, characteristics (such as amounts, percentages), etc., of the expressed components used in the specification and claims should in all cases be understood as indicating precise values ​​as shown and modified by the term "about". Therefore, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximate values ​​that may vary depending on the desired characteristic being sought. At least and without attempt to limit the application of the doctrine of equivalence to the claims, each numerical parameter should be interpreted at least based on the number of significant figures reported and by applying common rounding techniques.

[0177] The use of the term "comprising" or "comprises" in this article is also considered to be replaced by "consisting essentially of" or "consisting of" or "consists of".

[0178] Any affirmative statement about an element in this document should be understood to consider both inclusion and exclusion of the element.

[0179] Unless otherwise indicated herein or clearly contradicted by the context, the terms “a” and “an”, “described,” and similar pronouns used in the context of describing embodiments (especially in the context of the appended claims) should be interpreted as encompassing both the singular and plural. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all examples or exemplary language (e.g., “such”) provided herein is intended only to better illustrate the embodiments and does not constitute a limitation on the scope of any claim. No language in this specification should be construed as indicating that any unclaimed element is necessary for the practice of the claims.

[0180] The grouping of alternative elements or embodiments disclosed herein should not be construed as limiting. Each member of a group may be mentioned and claimed individually or in any combination with other members of the group or other elements found herein. For convenience and / or to expedite the application process, it is contemplated that one or more members of a group may be included in or removed from the group. When any such inclusion or removal occurs, this specification shall be deemed to include the modified group, thereby satisfying the written description of all Markush groups if used in the appended claims.

[0181] This document describes certain embodiments, including the best mode known to the inventors for implementing the claimed embodiments. Of course, variations of these embodiments will be apparent to those skilled in the art after reading the foregoing description. The inventors anticipate that those skilled in the art can employ such variations as needed, and 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. Furthermore, any combination of the foregoing elements in all possible variations is contemplated unless otherwise indicated herein or clearly contradicted by the context.

[0182] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be adopted are within the scope of the claims. Therefore, alternative embodiments may be used in accordance with the teachings of this document, by way of example rather than limitation. Thus, the claims are not precisely limited to the embodiments shown and described.

Claims

1. A method for treating a neurological disorder, the method comprising administering bupropion or a combination of bupropion and dextromethorphan to a person in need, monitoring the person for Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis, and reducing or discontinuing the use of bupropion or the combination of bupropion and dextromethorphan if the person develops Brugada pattern / syndrome, subcutaneous tissue disorder, drug response with eosinophilia and systemic symptoms (DRESS), or acute generalized exanthematous pustulosis.

2. The method of claim 1, wherein the person suffers from subcutaneous tissue disorder.

3. The method of claim 1, wherein the person experiences DRESS.

4. The method of claim 1, wherein the person has Brugada pattern / syndrome.

5. The method of claim 1, wherein the person suffers from acute generalized exanthematous pustulosis.

6. The method according to claim 1, 2, 3, 4 or 5, wherein the bupropion is bupropion hydrochloride, or a molar equivalent of free base form or another salt form of bupropion.

7. The method according to claim 1, 2, 3, 4, 5 or 6, wherein the dextromethorphan is dextromethorphan hydrobromide, or a molar equivalent of a free base form or another salt form of dextromethorphan.

8. The method according to claim 1, 2, 3, 4, 5, 6 or 7, wherein the bupropion is a sustained-release formulation.

9. The method according to claim 1, 2, 3, 4, 5, 6, 7 or 8, wherein the dextromethorphan is an immediate-release formulation.

10. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the bupropion or the combination of the bupropion and the dextromethorphan is a dosage form.

11. The method according to claim 10, wherein the dosage form further comprises: colloidal silica, cropovidone, glyceryl monocaprylate, L-cysteine ​​hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide, or yellow iron oxide or a combination thereof.

12. The method according to claim 11, wherein the dosage form is an oral dosage form.

13. The method of claim 12, wherein the oral dosage form is a tablet.

14. The method of claim 13, wherein the tablet is a bilayer tablet.

15. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein the combination of the bupropion and the dextromethorphan is administered to the person.

16. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the person is given a combination of the following once or twice daily: 1) about 100-110 mg, about 104-106 mg or about 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in its free base form or another salt form; and 2) about 40-50 mg, about 44-46 mg or about 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in its free base form or another salt form.

17. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein approximately 105 mg or less of the bupropion is administered daily after the person develops Brugada pattern / syndrome, subcutaneous tissue disorder, DRESS or acute generalized exanthematous pustulosis.

18. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein after the person develops Brugada pattern / syndrome, subcutaneous tissue disorder, DRESS or acute generalized exanthematous pustulosis, a combination comprising about 105 mg or less of bupropion hydrochloride and about 45 mg or less of dextromethorphan hydrobromide is administered daily.

19. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, wherein the administration of the bupropion is discontinued after the person develops Brugada pattern / syndrome, subcutaneous tissue disorder, DRESS or acute generalized exanthematous pustulosis.

20. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, wherein the administration of the combination of the bupropion and the dextromethorphan is discontinued after the person develops Brugada pattern / syndrome, subcutaneous tissue disorder, DRESS or acute generalized exanthematous pustulosis.

Images