Compounds and combinations thereof for treatment of neurological and psychiatric disorders

Abstract

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

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 582287, filed September 13, 2023, which is incorporated herein by reference in its entirety. Summary of the Invention

[0003] This disclosure relates to the administration of the following combinations in certain patient populations: 1) about 100-110 mg, about 104-106 mg or about 105 mg of bupropion hydrochloride or a molar equivalent of dextromethorphan in the form of a free base 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 the form of a free base or another salt form.

[0004] Some implementation methods include a method for treating major depressive disorder in patients with moderate renal impairment, the method comprising administering the following daily doses to a patient with moderate renal impairment and experiencing major depressive disorder: (i) about 105 mg bupropion hydrochloride and (ii) about 45 mg dextromethorphan hydrobromide.

[0005] Some implementation schemes include a method of treating a patient with a neurological disorder by administering a combination of dextromethorphan and bupropion, the method comprising:

[0006] The patient is given an oral administration once daily of a dosage form comprising: 105 mg or less of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide.

[0007] The patients were selected because they: 1) suffered from the aforementioned neurological condition and 2) suffered from moderate renal impairment, wherein the patients were identified as having moderate renal impairment by measurements of biological samples from the patients; and

[0008] The risk of drowsiness or dizziness in patients with moderate renal impairment who were given the dosage form containing the combination once daily was lower than the risk of drowsiness or dizziness in patients who were given the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide twice daily for the same number of days.

[0009] Some implementation schemes include a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing a neurological condition, the method comprising the following steps:

[0010] The following methods were used to determine whether the patient had moderate kidney damage:

[0011] Biological samples obtained from or already obtained from the patient; and

[0012] The biological sample has been or is being tested to determine whether the patient has moderate renal impairment; and

[0013] If the patient has moderate renal impairment, a dosage form containing 105 mg or less of bupropion hydrochloride or a molar equivalent of free base or another salt form of bupropion and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent of free base or another salt form of dextromethorphan is administered orally once daily to the patient, 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.

[0014] If the patient does not have kidney damage, administer orally twice daily a formulation containing 105 mg of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan.

[0015] The risk of drowsiness or dizziness in patients with moderate renal impairment who were given the dosage form containing the combination once daily was lower than the risk of drowsiness or dizziness in patients who were given the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide twice daily for the same number of days.

[0016] Some implementation schemes include a method for treating a patient experiencing a neurological disorder, the method comprising the following steps:

[0017] a) Determine whether the patient is at risk of adverse events related to overexposure to dextromethorphan by:

[0018] Obtaining or having obtained biological samples from the patient; and performing or having performed assays on the biological samples to determine whether the patient has moderate renal impairment, wherein the result of having moderate renal impairment indicates that the patient is at risk of adverse events related to overexposure to dextromethorphan; and

[0019] b) If the patient is at risk of adverse events related to overexposure to dextromethorphan, administer orally once daily a formulation containing 105 mg or less of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan, wherein the molar ratio of bupropion to dextromethorphan is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and

[0020] c) If the patient is not at risk of adverse events associated with overexposure to dextromethorphan, administer orally twice daily a formulation containing 105 mg of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan.

[0021] Some implementation schemes include a method of treating neurological disorders with a combination of dextromethorphan and bupropion, the method comprising:

[0022] A dosage form comprising, once daily, an oral administration to a patient of a combination of 105 mg or less of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and

[0023] The patients were selected because they: 1) suffered from the aforementioned neurological condition and 2) suffered from moderate renal impairment, wherein the patients were identified as having moderate renal impairment by measurements of biological samples from the patients; and

[0024] The patient described therein has a reduced risk of adverse events compared to the patient who would have the same risk of adverse events if the dosage form were administered to the patient twice daily.

[0025] Some implementation schemes include a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing a neurological condition, the method comprising the following steps:

[0026] The following methods were used to determine whether the patient had moderate kidney damage:

[0027] Biological samples obtained from or already obtained from the patient; and

[0028] The biological sample has been or is being tested to determine whether the patient has moderate renal impairment; and

[0029] If the patient has moderate renal impairment, a formulation containing 105 mg or less of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan shall be administered orally once daily, wherein the molar ratio of bupropion to dextromethorphan in the formulation 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

[0030] If the patient does not have kidney damage, administer orally twice daily a formulation containing 105 mg of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan.

[0031] Some implementation schemes include a method of treating a patient with a neurological disorder by administering a combination of dextromethorphan and bupropion, the method comprising:

[0032] The patient is given an oral administration once daily of a dosage form comprising: 105 mg or less of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is approximately the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide.

[0033] The patients were selected because they: 1) suffered from the aforementioned neurological condition and 2) suffered from moderate renal impairment, wherein the patients were identified as having moderate renal impairment by measurements of biological samples from the patients; and

[0034] The risk of drowsiness and dizziness in patients with moderate renal impairment who were given the dosage form containing the combination once daily was lower than the risk of drowsiness and dizziness in patients who were given the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide twice daily for the same number of days.

[0035] Some implementation schemes include a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing a neurological condition, the method comprising the following steps:

[0036] The following methods were used to determine whether the patient had moderate kidney damage:

[0037] Biological samples obtained from or already obtained from the patient; and

[0038] The biological sample has been or is being tested to determine whether the patient has moderate renal impairment; and

[0039] If the patient has moderate renal impairment, a dosage form containing 105 mg or less of bupropion hydrochloride or a molar equivalent of free base or another salt form of bupropion and 45 mg or less of dextromethorphan hydrobromide or a molar equivalent of free base or another salt form of dextromethorphan is administered orally once daily to the patient, 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.

[0040] If the patient does not have kidney damage, administer orally twice daily a formulation containing 105 mg of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan.

[0041] The risk of drowsiness and dizziness in patients with moderate renal impairment who were given the dosage form containing the combination once daily was lower than the risk of drowsiness and dizziness in patients who were given the combination of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide twice daily for the same number of days.

[0042] Some implementation methods include a method for treating major depressive disorder in a person requiring concomitant therapy with a strong CYP2D6 inhibitor, the method comprising administering once daily a combination of approximately 105 mg bupropion hydrochloride and approximately 45 mg dextromethorphan hydrobromide to the person experiencing major depressive disorder and receiving concomitant therapy with a strong CYP2D6 inhibitor. In some implementation methods, the strong CYP2D6 inhibitor is paroxetine.

[0043] Some implementation methods include a method for treating major depressive disorder in a person who requires concomitant treatment with propafenone or thioridazine, the method comprising administering once daily to the person about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide, wherein the person is experiencing major depressive disorder and is receiving concomitant treatment with propafenone or thioridazine, wherein the combination is in a solid dosage form, wherein the solid dosage form is administered orally in the morning, wherein the dextromethorphan is an immediate-release formulation, and wherein the bupropion is an extended-release formulation. Attached Figure Description

[0044] 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. Detailed Implementation

[0045] As mentioned above, this disclosure relates to the administration of the following combinations: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride or a molar equivalent of dextromethorphan in its 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 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.

[0046] Dextromethorphan hydrobromide is a non-competitive NMDA receptor antagonist and σ-1 receptor agonist.

[0047] 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:

[0048]

[0049] Dextromethorphan hydrobromide powder is a white or almost white crystalline powder that is slightly soluble in water.

[0050] Bupropion hydrochloride is an aminoketone and CYP450 2D6 inhibitor.

[0051] 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:

[0052]

[0053] Bupropion hydrochloride powder is white and readily soluble in water.

[0054] The subject matter combination can be contained in oral dosage forms, including tablets, such as extended-release tablets. In some embodiments, the subject matter combination is contained in a dosage form for oral administration and is available as a round bilayer tablet.

[0055] 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.

[0056] 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.

[0057] In some embodiments, tablets containing the theme combination contain the following inactive ingredients: L-cysteine ​​hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silica, crosspovidone, stearic acid, and magnesium stearate.

[0058] 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.

[0059] 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.

[0060] Patients with renal impairment may require specific medication. In some implementations, the dosage is 30 to 59 mL / min / 1.73 m for moderate renal impairment (estimated glomerular filtration rate (eGFR) or glomerular filtration rate (GFR) of 1.73 mL / min). 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.

[0061] Moderate kidney damage can be determined by measurements on biological samples from the patient, such as blood samples, to determine creatine levels. Creatine levels from blood samples can be used to estimate GFR.

[0062] Patients using a combination of medications and strong CYP2D6 inhibitors (such as fluoxetine, propafenone, quinidine, paroxetine, thioridazine, terbinafine, or duloxetine) may require special medication. The concomitant use of a combination of medications and strong CYP2D6 inhibitors increases the plasma concentration of dextromethorphan. For this reason, compounds that are CYP2D6 inhibitors can also be called dextromethorphan metabolism inhibitors or compounds used to inhibit the metabolism of dextromethorphan, such as norvenlafaxine, venlafaxine, escitalopram, (2S,3S)-hydroxybupropion, bupropion, (R,R)-hydroxybupropion, fluvoxamine, sertraline, (S)-duloxetine, threohydroxybupropion, erythrohydroxybupropion, etc. Some therapeutically active compounds, including antidepressants such as bupropion, inhibit the metabolism of dextromethorphan and increase its plasma concentration. Other antidepressants that inhibit CYP2D6 or dextromethorphan metabolism include clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, tramipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyindamine, and benatizine. Escitalopram, fluvoxamine, venlafaxine, norvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, mirtazapine, tersofencin, moclobemide, rasagiline, niacinamide, isoniazid, isopronil, toloxacin, butiline, duthiramine, dibenzapine, iproindole, lofepramine, octopiol, norfluoxetine, dapoxetine, ketamine, etc. Quinidine is another example of a strong CYP2D6 inhibitor. Quinidine can be co-administered with dextromethorphan to provide enhanced plasma levels of dextromethorphan. Terbinafine has been reported to potently inhibit cytochrome P-450 2D6-mediated dextromethorphan O-demethylation.

[0063] In some implementations, when co-administered with a strong CYP2D6 inhibitor, the recommended dose of the combination is one tablet once daily (or a formulation containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride), such as one tablet 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.

[0064] Patients known to be poor metabolizers of CYP2D6 (PM) may require special administration. 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.

[0065] 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.

[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; heat 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] 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.

[0077] Thematic combinations can be used as an adjunct treatment for major depressive disorder or depression.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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 burst disorder.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] Headache types that can be treated with thematic combinations include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] In some implementations, a combination of themes may be applied to relieve inflammatory pain, including musculoskeletal pain, arthritis pain, and complex regional pain syndromes.

[0099] 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.

[0100] In some implementations, the combination of themes is used to treat chronic musculoskeletal pain.

[0101] 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.

[0102] In some implementations, the subject composition can be administered orally to relieve neuropathic pain.

[0103] 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.

[0104] In some implementations, the subject composition can be applied to relieve fibromyalgia.

[0105] 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.

[0106] 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).

[0107] Administering the theme combination once daily to patients receiving strong CYP2D6 therapy 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.

[0108] 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 adverse reactions possibly attributable to dextromethorphan, such as drowsiness and dizziness, is recommended.

[0109] 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).

[0110] 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).

[0111] 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.

[0112] 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.

[0113] The following U.S. provisional applications are also incorporated herein by reference in their entirety: Serial No. 63 / 359,143, filed July 7, 2022; Serial No. 63 / 370,592, filed August 5, 2022; Serial No. 63 / 396,182, filed August 8, 2022; Serial No. 63 / 373,040, filed August 19, 2022; and Serial No. 63 / 401,541, filed August 26, 2022.

[0114] Example 1

[0115] 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.

[0116] Example 2

[0117] 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 AUC 0-12 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.

[0118] Example 3

[0119] The co-administration of the SSRI paroxetine and the twice-daily theme combination 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 a CYP2D6 inhibitor, it should be administered once daily. Caution should be exercised when co-administering the theme combination with drugs that are strongly metabolized via CYP2D6.

[0120] Example 4

[0121] The properties of tablets containing 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) were investigated.

[0122] The tablets are for oral administration and are round, bilayer tablets. Each tablet contains 45 mg of dextromethorphan hydrobromide (equivalent to 32.98 mg of dextromethorphan free base) as an immediate-release formulation and 105 mg of bupropion hydrochloride (equivalent to 91.14 mg of bupropion free base) as 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.

[0123] The effects of renal impairment, hepatic impairment, and CYP2D6 poor metabolizer status on exposure to tablets containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride are summarized in Table 1 and 2. Figure 1 middle.

[0124] Table 1

[0125]

[0126] Figure 1 The 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. The references used were matched healthy subjects from studies of renal and hepatic impairment, as well as strong or ultra-strong CYP2D6 metabolizers. 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.

[0127] In patients with moderate renal impairment, a dextromethorphan AUC was observed. 0-12 Increased by 2.21 times, dextromethorphan C max 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.

[0128] 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.

[0129] Example 5

[0130] The properties of tablets containing 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) were investigated.

[0131] The tablets are for oral administration and are round, bilayer tablets. Each tablet contains 45 mg of dextromethorphan hydrobromide (equivalent to 32.98 mg of dextromethorphan free base) as an immediate-release formulation and 105 mg of bupropion hydrochloride (equivalent to 91.14 mg of bupropion free base) as 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.

[0132] The effect of concomitant administration of 20 mg paroxetine on dextromethorphan exposure was determined in patients taking tablets containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride twice daily. The dextromethorphan AUC was compared with that of patients taking tablets twice daily without paroxetine. 0-12 Increased by 2.69 times, and dextromethorphan C max Increased by 2.38 times.

[0133] 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.

[0134] 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".

[0135] Any affirmative statement about an element in this document should be understood to consider both inclusion and exclusion of the element.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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 major depressive disorder in a person requiring concomitant treatment with propafenone or thioridazine, the method comprising administering once daily to the person about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide, wherein the person is experiencing major depressive disorder and is receiving concomitant treatment with propafenone or thioridazine, wherein the combination is in a solid dosage form, wherein the solid dosage form is administered orally in the morning, wherein the dextromethorphan is an immediate-release formulation, and wherein the bupropion is an extended-release formulation.

2. The method according to claim 1, wherein the solid dosage form further comprises a carbomer homopolymer.

3. The method according to claim 1 or 2, wherein the solid dosage form further comprises colloidal silica.

4. The method according to claim 1, 2 or 3, wherein the solid dosage form further comprises cropovidone.

5. The method according to claim 1, 2, 3 or 4, wherein the solid dosage form further comprises glyceryl monocaprylate.

6. The method according to claim 1, 2, 3, 4 or 5, wherein the solid dosage form further comprises magnesium stearate.

7. The method according to claim 1, 2, 3, 4, 5 or 6, wherein the solid dosage form further comprises microcrystalline cellulose.

8. The method according to claim 1, 2, 3, 4, 5, 6 or 7, wherein the solid dosage form further comprises polyvinyl alcohol.

9. The method according to claim 1, 2, 3, 4, 5, 6, 7 or 8, wherein the solid dosage form further comprises red iron oxide.

10. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the solid dosage form further comprises sodium lauryl sulfate.

11. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein the solid dosage form further comprises stearic acid.

12. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, wherein the solid dosage form further comprises talc.

13. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein the solid dosage form further comprises titanium dioxide.

14. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, wherein the solid dosage form further comprises yellow iron oxide.

15. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein administering the solid dosage form to the patient twice daily for 8 days will result in an AUC of bupropion in the patient. 0-12 The AUC of bupropion obtained after administering the solid dosage form twice daily to human patients for 8 days without concomitant treatment with propafenone or thioridazine. 0-12 They are roughly the same.

16. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein administering the solid dosage form to the patient twice daily for 8 days will result in the patient developing bupropion C. max Bupropion C obtained after administering the solid dosage form twice daily for 8 days to human patients without concomitant treatment with propafenone or thioridazine. max They are roughly the same.

17. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein the patient requiring concomitant treatment with propafenone is receiving concomitant treatment with a combination of propafenone and about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide.

18. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein the patient requiring concomitant treatment with thioridazine is receiving concomitant treatment with a combination of thioridazine and about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide.

Images