Treatment of depression

Abstract

The present disclosure relates to the administration of a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or a molar equivalent amount of bupropion in the form of the free base or in the form of another salt; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg dextromethorphan hydrobromide, or a molar equivalent amount of dextromethorphan in the form of the free base or in the form of another salt, for the treatment of depression in a patient with a certain level of dextromethorphan.

Description

[0001] This application is a divisional application of Chinese patent application No. 202280051609.4 (filed on July 21, 2022, entitled "Treatment of Depression").

[0002] Cross-references to related applications

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 224,323, filed July 21, 2021, the entire contents of which are incorporated herein by reference. Summary of the Invention

[0004] This disclosure relates to the combined administration of the following substances 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 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.

[0005] Some embodiments include a method of treating major depressive disorder comprising administering a combination comprising 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt or free base form of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base form of bupropion, to a human patient in need twice daily for at least six weeks; wherein, 12 hours after administration of the combination dose on day 42, the human patient’s plasma level of dextromethorphan is at least approximately 19 ng / mL.

[0006] Some embodiments include a method of treating major depressive disorder, comprising administering a dosage form comprising 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt or free base form of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base form of bupropion, to a human patient in need twice daily for at least six weeks; wherein, 24 hours after discontinuation of the dosage form, the human patient has a plasma level of dextromethorphan of at least approximately 15 ng / mL.

[0007] Some embodiments include methods for treating major depressive disorder, comprising administering a dosage form comprising 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt or free base form of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base form of bupropion, to a human patient in need twice daily for at least six weeks; wherein, at any time after the eighth day of administration of the combination, the human patient has a plasma level of at least approximately 15 ng / mL of dextromethorphan.

[0008] Some embodiments include a pharmaceutical combination for treating major depressive disorder comprising 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt or free base form of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base form of bupropion, wherein the pharmaceutical combination is administered twice daily to a human patient in need for at least six weeks, and wherein, 12 hours after administration of the dose of the combination on day 42, the human patient has a plasma level of at least approximately 19 ng / mL of dextromethorphan.

[0009] Some embodiments include a dosage form for treating major depressive disorder comprising 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt or free base form of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base form of bupropion, wherein the dosage form is administered to a human patient twice daily for at least six weeks, and wherein, 24 hours after discontinuation of the dosage form, the human patient has a plasma level of dextromethorphan of at least approximately 15 ng / mL.

[0010] Some embodiments include the use of a combination of dextromethorphan and bupropion in the preparation of a medicament for the treatment of major depressive disorder, wherein the combination comprises 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt or free base form of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base form of bupropion, and the combination is administered to a human patient in need twice daily for at least six weeks, wherein, 12 hours after administration of the dose of the combination on day 42, the plasma level of dextromethorphan in the human patient is at least about 19 ng / mL.

[0011] Some embodiments include the use of a combination of dextromethorphan and bupropion in the preparation of a medicament for the treatment of major depressive disorder, wherein the combination comprises 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt or free base form of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base form of bupropion, administered twice daily for at least six weeks; wherein, 24 hours after discontinuation of the medication, the patient’s plasma level of dextromethorphan is at least approximately 15 ng / mL. Attached Figure Description

[0012] Figure 1 This is a graph showing the change of the subject's total MADRS score relative to baseline over time, as described in Example 1.

[0013] Figure 2 This is a graph showing the change of the subject's QIDS-SR-16 total score relative to baseline over time, as described in Example 1.

[0014] Figure 3 This is a graph showing the percentage of subjects who achieved remission (QIDS-SR-16 score ≤ 5) as described in Example 1 over time.

[0015] Figure 4 This is a graph showing the change of the MGH-CPFQ cognitive items of the subjects described in Example 1 over time relative to baseline.

[0016] Figure 5 This is a graph showing the change of the subject's total MADRS score relative to baseline over time, as described in Example 2.

[0017] Figure 6 This is a graph showing the change over time of the subject's mean domain score on the Sheehan Disability Scale (SDS) relative to baseline, as described in Example 2.

[0018] Figure 7A This is a graph showing the percentage of subjects with a clinical response based on MADRS improvement (where MADRS improvement ≥ 50%) compared to subjects using bupropion alone as described in Example 2.

[0019] Figure 7B This is a graph showing the percentage of subjects with improved clinical remission based on MADRS (MADRS ≤ 10) compared to subjects using bupropion alone as described in Example 2.

[0020] Figure 8 This is a graph showing the changes in the HAM-A and MADRS mental stress items of the subjects described in Example 2 over time relative to baseline.

[0021] Figure 9 This is a graph showing the changes in the subjects' CPFQ cognitive and MADRS attention scores relative to baseline over time, as described in Example 2. Detailed Implementation

[0022] As stated above, this disclosure relates to the combined administration of the following substances: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or in the form of a molar equivalent of a free base (e.g., 91 mg of bupropion free base) or another salt of bupropion; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide, or in the form of a molar equivalent of a free base (e.g., 33 mg of dextromethorphan free base) or another salt of dextromethorphan. For convenience, this combination is referred to herein as the “test combination”. In each case of the test combination mentioned herein, the combination of 105 mg of bupropion hydrochloride (or 91 mg of bupropion free base) and 45 mg of dextromethorphan hydrobromide (or 33 mg of dextromethorphan free base) is particularly considered.

[0023] Dextromethorphan hydrobromide is a non-competitive NMDA receptor antagonist and A sigma-1 receptor agonist.

[0024] It has been found that plasma drug concentration measurement is a direct method for assessing treatment adherence when using the combination of dextromethorphan and bupropion. Treatment adherence can improve outcomes when using the combination of dextromethorphan and bupropion because the achievement of therapeutic concentrations depends not only on the dose and frequency of the study drug but also on the time-dependent inhibition of CYP2D6.

[0025] Treatment adherence to the combination of 45 mg dextromethorphan hydrobromide (or another molar equivalent in the form of a salt or free base) and 105 mg bupropion hydrochloride (or another molar equivalent in the form of a salt or free base) can be determined based on a dextromethorphan plasma concentration of at least 15 ng / mL at any time after approximately 8 days of treatment (including 24 hours after administration of the last dose of the combination). This also corresponds to a dextromethorphan plasma concentration of at least approximately 19 ng / mL once the drug level has reached a steady state, such as at approximately 8 days, approximately 14 days, approximately 28 days, approximately 42 days, etc., 12 hours after dose administration.

[0026] In some embodiments, a blood sample may be collected from the patient at any time after eight days of taking the drug combination. If the sample shows that the patient's dextromethorphan plasma concentration is below 15 ng / mL, the patient is encouraged to take the drug combination more compliantly and / or discontinue treatment to facilitate patient compliance.

[0027] The chemical name of dextromethorphan hydrobromide is morphinan, 3-methoxy-17-methyl-, (9α,13α,14α), hydrobromic acid monohydrate. The empirical formula of dextromethorphan hydrobromide is C1. 18 H 25 NO•HBr•H2O, with a molecular weight of 370.33. Its structural formula is:

[0028]

[0029] Dextromethorphan hydrobromide powder is white or almost white, crystalline, and slightly soluble in water.

[0030] Bupropion hydrochloride is an aminoketone and CYP450 2D6 inhibitor.

[0031] 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. Its structural formula is:

[0032]

[0033] Bupropion hydrochloride powder is white and readily soluble in water.

[0034] The test combination may be contained in an oral dosage form, including tablets, such as sustained-release tablets. In some embodiments, the test combination is contained in an oral dosage form and may be available as a round bilayer tablet.

[0035] In some embodiments, each tablet containing the test combination contains 45 mg of dextromethorphan hydrobromide in an immediate-release formulation. In some embodiments, each tablet containing the test combination contains 105 mg of bupropion hydrochloride in a sustained-release formulation. In some embodiments, each tablet containing the test combination comprises 45 mg of dextromethorphan hydrobromide in an immediate-release formulation and 105 mg of bupropion hydrochloride in a sustained-release formulation.

[0036] In some embodiments, the tablet containing the test combination contains L-cysteine ​​hydrochloride monohydrate. In some embodiments, the tablet containing the test combination contains carbomer homopolymer. In some embodiments, the tablet containing the test combination contains microcrystalline cellulose. In some embodiments, the tablet containing the test combination contains colloidal silica. In some embodiments, the tablet containing the test combination contains crospovidone. In some embodiments, the tablet containing the test combination contains stearic acid. In some embodiments, the tablet containing the test combination contains magnesium stearate.

[0037] In some embodiments, the tablet containing the test combination contains the following inactive ingredients: L-cysteine ​​hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silica, crospovidone, stearic acid, and magnesium stearate.

[0038] In some embodiments, the starting dose of the test 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 one tablet (or one dose containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride) twice daily, for example, at least 8-hour intervals. In some embodiments, no more than two doses containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride are administered on the same day.

[0039] The test combination can be administered orally with or without food. In some embodiments, the tablets are swallowed whole, rather than crushed, broken, or chewed.

[0040] When administered as the test combination, steady-state plasma concentrations of dextromethorphan and bupropion were reached within 8 days. Based on C max and AUC 0-12 Under steady-state conditions, the accumulation rates of dextromethorphan are approximately 20% and 32%, respectively. Based on C... max and AUC 0-12 Under steady-state conditions, the cumulative ratios of bupropion were 1.1 and 1.5, respectively.

[0041] Median T after administration of the tested combination of dextromethorphan max The median T of bupropion is approximately 3 hours. max Approximately 2 hours. The C of hydroxybupropion metabolites... max It occurred approximately 3 hours after administration and was about 14 times the peak level of bupropion. AUC 0-12 Hydroxybupropion is approximately 19 times more potent than bupropion. The C-values ​​of erythrohydroxybupropion and threohydroxybupropion metabolites are... max Approximately 4 hours after administration, C values ​​appeared, approximately equal to and approximately 5 times that of bupropion, respectively. max AUC of red hydroxybupropion and threonine hydroxybupropion 0-12 The values ​​were approximately 1.2 times and 7 times that of bupropion, respectively.

[0042] The test combination can be taken with or without food. When the test combination is administered with food, dextromethorphan C max and AUC 0-12 Bupropion C remained unchanged and decreased by 14%, respectively.max and AUC 0-12 They increased by 3% and 6% respectively.

[0043] The plasma protein binding rate of dextromethorphan is approximately 60-70%, while that of bupropion is 84%. The protein binding rate of the hydroxybupropion metabolite is similar to that of bupropion; however, the protein binding rate of the threonine hydroxybupropion metabolite is about half that of bupropion.

[0044] Eight days after administration of the test combination to a wide range of metabolizers, the mean elimination half-life of dextromethorphan increased by approximately 3-fold to approximately 22 hours compared to the combination administered dextromethorphan without bupropion.

[0045] 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, red hydroxybupropion, and threonine hydroxybupropion were approximately 35, 44, and 33 hours, respectively.

[0046] In addition to major depressive disorder, the test combination can also be used to treat other disease symptoms in the patient groups or environments described in this article. For example, the test combination can be used to treat pain or neurological disorders. Examples of neurological disorders that can be treated with the test combination include, but are not limited to: mood disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, episodic symptoms, and headaches.

[0047] The mood disorders that can be treated by the test combination include, but are not limited to, depression, major depressive disorder, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorder (including cyclic psychosis), seasonal affective disorder, mood disorders, chronic depression (psychotic depression), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH), and attention deficit / hyperactivity disorder (AD / HD), bipolar disorder and mania, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, sexual dysfunction, pseudobulbar effects, and mood instability.

[0048] Depression can manifest as depressive symptoms. These symptoms may include psychological changes such as mood swings, intense 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 may include insomnia, loss of appetite, decreased appetite, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches, pains, headaches, cramps, digestive problems, and / or circadian rhythm abnormalities.

[0049] Mental disorders that can be treated by the combination of tests 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, paranoia, schizoaffective disorder, schizophrenia type, aggression, aggression in Alzheimer's disease, and agitation in Alzheimer's disease.

[0050] As Alzheimer's disease progresses, patients may experience agitation. Agitation can manifest as inappropriate speech, emotions, and / or physical behavior. Inappropriate behavior may include, but is 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, restlessness, tearing, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive limb movements, hoarding, stalking, hitting, scratching, biting, aggression, hyperactivity, and / or kicking.

[0051] Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and behavioral and psychological symptoms, including agitation. AD is the most common form of dementia, affecting approximately 6 million people in the United States, a number projected to rise to approximately 14 million by 2050. Up to 70% of AD patients are reported to experience agitation, characterized by mood disturbances, aggressive behavior, disruptive irritability, and inability to control. Managing agitation is a top priority for AD patients. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, earlier nursing home placement, and increased mortality. Currently, there are no FDA-approved treatments for agitation in AD patients.

[0052] Brain dysfunction that can be treated with the tested combination of methods includes, but is not limited to, disorders involving intellectual impairment, such as Alzheimer's disease, memory loss, amnesia / amnesia syndrome, epilepsy, altered consciousness, coma, decreased attention, speech disorders, vocal dysarthria, Parkinson's disease, Lennox-Gastaut syndrome, autism, ADHD, and schizophrenia. Brain dysfunction also includes disorders 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.

[0053] The tested combination of treatable substance addictions includes, but is not limited to, drug dependence, cocaine addiction, stimulants (such as crack, cocaine, meth, and methamphetamine), nicotine, alcohol, opioids, anti-anxiety and hypnotic drugs, cannabis (cannabis), 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 hookahs, and chewing tobacco addiction.

[0054] Movement disorders that can be treated by the tested combination include, but are not limited to: akathisia, dyskinesia, related movement, choreoathetosis, ataxia, twitching, hemiparesis, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's chorea, rheumatic chorea, Sidnuma's chorea, movement disorders, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, Tourette's syndrome, and Wilson's disease.

[0055] Dementias that can be treated with the combination of tests include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakov syndrome, and Pick's disease.

[0056] Motor neuron diseases that can be treated with the tested combination include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sach's disease, Sandoff disease, and hereditary spastic paraplegia.

[0057] Neurodegenerative diseases that can be treated with the tested combination 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 Lewy Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, and cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL). Subcortical infarcts and leukoencephalopathy, muscle atrophy, Charcot-Marie Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontine atrophy or degeneration, striatal degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0058] The tested combination can treat paroxysmal disorders including but not limited to epileptic seizures, non-epileptic seizures, epilepsy, and febrile seizures; partial seizures including but not limited to simple partial seizures, Jacksonian seizures, complex partial seizures, and continuous incomplete 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.

[0059] Headache types that can be treated with the tested combination include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0060] Other neurological disorders that can be treated with the test combination include Rett syndrome, autism, tinnitus, altered consciousness, sexual dysfunction, intractable cough, somnolence, cataplexy; voice disorders caused by uncontrolled laryngeal muscle spasms, including but not limited to abductor spasm dysphonia, adductor spasm dysphonia, muscle tension dysphonia, and vocal fremitus; 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.

[0061] In some embodiments, the tested combination can be used to treat injuries, joint pain, sickle cell disease-related pain, pseudobulbar effects, depression (including treatment-resistant depression), memory and cognitive impairments, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Reed syndrome, epilepsy, cough (including chronic cough), etc.

[0062] In some embodiments, the test combination may be administered orally to relieve musculoskeletal pain, including low back pain and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, periarticular disorders, axial spondyloarthritis, including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient hip osteoarthritis, vertebral compression fractures, osteoporosis, etc.

[0063] In some embodiments, the test combination may be administered to relieve inflammatory pain, including musculoskeletal pain, arthritis pain, and complex regional pain syndrome.

[0064] Arthritis refers to inflammatory joint diseases that are associated with pain. Examples of arthritis pain include pain associated with the following conditions: osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatoid diseases, periarticular diseases, neuropathic arthropathy (including Charcot's foot), axial spondyloarthritis (including ankylosing spondylitis), and SAPHO syndrome.

[0065] In some embodiments, the tested combination is used to treat chronic musculoskeletal pain.

[0066] In some embodiments, the test combination may be administered to relieve complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is an inflammatory pain condition. CRPS may also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome characterized by severe limb pain accompanied by edema, autonomic, motor, and sensory changes.

[0067] In some embodiments, the test combination may be administered orally to relieve neuropathic pain.

[0068] Examples of neuropathic pain include diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, and central nervous system pain. 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 neuropathy associated with radiation or chemotherapy.

[0069] In some embodiments, the test combination may be administered to alleviate fibromyalgia.

[0070] The term “treatment” includes the diagnosis, cure, relief, treatment or prevention of disease in humans or other animals, or any activity that otherwise affects the structure or function of the human or other animal body.

[0071] The tested combination can be used to treat any disease or condition that is treatable by the combination of bupropion and dextromethorphan as confirmed in any of the following U.S. patents: 8,569,328, 9,168,234, 9,189,905, 9,205,083, 9,238,032, 9,278,095, 9,314,462, 9,370,513, 9,375,429, 9,408,815, 9,421,17 6, 9,457,023, 9,457,025, 9,474,731, 9,486,450, 9,700,528, 9,700,553, 9,707,191, 9,763,932, 9,861,595, 9,867,819, 9,968,568, 10,058,518, 10,064,857, 10,080,727, 10,092,560, 10,092,561, 10,105,327, 10,105,361, 10,251,879, 10,463,634, 10,512,643, 10,548,857, 10,596,167, 10,772,850, 10,780,064, 10,780,066, 10,786,469, 10,786,496, 10,799,497, 10,806,710, 10,864,209, 10,874,663, 10,874,664, 10,874,665, All of the disclosures in these documents concerning diseases that can be treated with a combination of bupropion and dextromethorphan, including the specific embodiments and combinations described therein, are incorporated herein by reference.

[0072] Example 1

[0073] A phase 3, randomized, double-blind, active-controlled trial was conducted to evaluate the efficacy and safety of DM / BU in treating treatment-resistant depression (TRD). Patients with major depressive disorder (MDD) who had previously failed one or two antidepressant treatments received 150 mg bupropion twice daily (total daily dose 300 mg) on ​​an open-label basis during a 6-week introductory period (n=799, n represents the number of patients). Patients who did not respond to bupropion during this introductory period were randomized 1:1 to receive the same total daily dose of bupropion (n=156) or DM / BU twice daily (45 mg dextromethorphan / 105 mg bupropion) (total daily dose of 90 mg dextromethorphan / 210 mg bupropion) (n=156) for 6 weeks. Inclusion criteria for the open-label period included men or women aged 18–65 years with one or two previous adverse responses to antidepressant treatment, established using the Antidepressant Treatment Response Questionnaire (ATRQ), and a total score ≥18 on the Hamilton Depression Rating Scale (HAMD-17). Inclusion criteria for the double-blind period included two or three previous adverse responses to antidepressant treatment, including failure during the open-label period. Exclusion criteria included a history of electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, or any experimental central nervous system treatment during the current episode or within the past 6 months; schizophrenia; bipolar disorder; obsessive-compulsive disorder; and psychiatric symptoms secondary to any other general medical condition.

[0074] The statistical characteristics and baseline characteristics are shown in Table 1 below. The study completion rates were similar in the two treatment groups: 89% for dextromethorphan / bupropion and 94% for bupropion.

[0075] Table 1. Population statistics and baseline characteristics

[0076]

[0077] Unless otherwise stated, all data are averages (SD).

[0078] Abbreviations: BMI = Body Mass Index; CGI-S = Clinical Global Impression - Severity.

[0079] MADRS = Montgomery-Åsberg Depression Rating Scale.

[0080] The Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms-Self-Rated (QIDS-SR-16) were used to measure changes in depressive symptoms over time. The primary endpoint was the change in MADRS relative to baseline after 6 weeks of treatment. Key secondary endpoints were the changes in MADRS relative to baseline after 1 week and 2 weeks of treatment, the mean change over the entire 6-week double-blind treatment period, and the Sheehan Disability Scale (SDS). Other pre-specified secondary efficacy variables included the cognitive subscale of the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) and the Hamilton Anxiety Scale (HAM-A).

[0081] like Figure 1 As shown, DM / BU rapidly and significantly improved symptoms in patients with TRD, as measured by mean MADRS over the entire 6-week treatment period (a key secondary endpoint), with a mean reduction of 8.6 for DM / BU (n=154) and 6.7 for bupropion (n=155) (p=0.031). The rapid onset of action of DM / BU treatment was demonstrated in the statistically significant reduction in mean MADRS. In week 1 (the earliest time point measured), the mean MADRS of DM / BU and bupropion decreased by 5.2 and 3.6, respectively (p=0.02), and in week 2, the mean MADRS of DM / BU and bupropion decreased by 8.0 and 6.1, respectively (p=0.035), both of which were key secondary endpoints. At week 6 (the primary endpoint), DM / BU showed a greater numerical improvement in MADRS, with an average reduction of 11.6 for DM / BU and an average reduction of 9.4 for bupropion (p=0.117), but this did not reach statistical significance at week 6.

[0082] like Figure 2As shown, based on the mean of the Rapid Self-Rating Depression Scale (QIDS-SR-16) over the entire 6-week treatment period, DM / BU rapidly and significantly improved depressive symptoms in patients with TRD, with a mean reduction of 3.3 for DM / BU and a mean reduction of 2.3 for bupropion (p=0.013).

[0083] like Figure 3 As shown, at week 1 (p=0.001) and at each time point thereafter, the remission rate of depression (defined as QIDS-SR-16≤5) was statistically significantly higher in DM / BU compared to bupropion. By week 6 (p=0.012), 18.2% of DM / BU patients achieved a remission rate of depression compared to 8.2% of bupropion patients.

[0084] like Figure 4 As shown, assessed using the cognitive subscale of the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) (p=0.011), DM / BU significantly improved cognitive function in patients with TRD compared to bupropion. Cognitive impairment is well-documented at different stages of depression and plays a crucial role in functional recovery from depression. Compared to bupropion, cognitive function improved rapidly with DM / BU, reaching statistical significance as early as week 2 (p=0.01) and at every subsequent time point. The CPFQ cognitive subscale assessed alertness / mental acuity, as well as the ability to focus / maintain attention, remember / recall information, and find words. The advantage of DM / BU over bupropion was also statistically significant throughout the CPFQ (which assesses both cognitive and physical function) (p=0.014).

[0085] Assessment using the Hamilton Anxiety Rating Scale (HAM-A) revealed that DM / BU rapidly and significantly reduced anxiety symptoms in patients with TRD compared to bupropion (p=0.009). Among all other efficacy variables assessed, DM / BU showed numerical improvement compared to the active control, bupropion.

[0086] DM / BU was well tolerated in the trial. The most frequently reported adverse events in the DM / BU treatment group were dizziness and nausea. Discontinuation rates due to adverse events were low in both treatment groups (2.6% for DM / BU and 1.9% for bupropion). Three serious adverse events occurred in the DM / BU treatment group, including migraine, overdose, and suicidal ideation, occurring more than one week after treatment discontinuation. DM / BU treatment was not associated with psychotic effects, weight gain, or sexual dysfunction. Adverse events are shown in Table 2 below.

[0087] Table 2 Treatment - Sudden Adverse Events

[0088]

[0089] Abbreviation: AE = Adverse Event. Data is expressed as the number of participants (percentage of participants).

[0090] a. Reported treatment-emergent adverse events (TEAEs) in ≥3 subjects during the open-label period or ≥5% of subjects during the double-blind period.

[0091] b. During the double-blind period, an acute adverse event during treatment is defined as any adverse event that occurs on or after the date of randomization, before or on the date of the 9th visit, or before or on the date of early termination of Phase 2.

[0092] Example 2

[0093] A study was conducted based on the clinical trial described in Example 1 to evaluate the efficacy of the dextromethorphan and bupropion combination in patients with poor treatment adherence, based on the analysis of plasma drug concentrations. This study found that plasma drug concentration measurement is a direct method for assessing treatment adherence. Treatment adherence can improve the efficacy of the dextromethorphan and bupropion combination therapy because the achievement of therapeutic concentrations can be predicted not only based on the dose and frequency of the studied drugs but also based on the time-dependent inhibition of CYP2D6.

[0094] In patients of Example 1, plasma samples were collected and analyzed after up to 6 weeks of treatment in the clinical trial (end of treatment visit). Treatment adherence was assessed based on the following plasma drug concentration thresholds:

[0095] DM / BU group: Dextromethorphan concentration ≥15 ng / mL

[0096] Bupropion SR group: bupropion concentration ≥10 ng / mL

[0097] Under 100% compliance conditions, the selected drug concentration threshold was close to the lowest observed concentration 24 hours after the last dose of the study drug. The threshold of 15 ng / mL 24 hours after the last dose corresponds to a plasma concentration of approximately 19 ng / mL approximately 12 hours after the last dose after reaching a steady state (e.g., day 42).

[0098] The primary endpoint was the change in MADRS relative to baseline after 6 weeks of treatment. Key secondary endpoints were the changes in MADRS relative to baseline after 1 and 2 weeks of treatment, the overall change in the total MADRS score, and the change in the Sheehan Disability Scale (SDS) relative to baseline at week 6. Other efficacy assessments included the Self-Rating Depressive Symptoms Rapid Scale (QIDS-SR-16), the Hamilton Anxiety Rating Scale, and the Cognition and Physical Functioning Questionnaire (CPFQ).

[0099] The statistical characteristics and baseline characteristics of patients with treatment compliance are shown in Table 3 below.

[0100] Table 3. Population Statistical Characteristics and Baseline Characterization

[0101]

[0102] Unless otherwise stated, all data are averages (SD).

[0103] Abbreviations: BMI = Body Mass Index; CGI-S = Clinical Global Impression-Severity; MADRS = Montgomery-Asperger's Depression Rating Scale

[0104] The two treatment groups had similar population statistics and baseline characteristics. Treatment adherence was analyzed based on the following plasma concentrations:

[0105] Subjects treated with DM / BU: Dextromethorphan concentration ≥15 ng / mL (N=122)

[0106] Subjects treated with bupropion: bupropion concentration ≥10 ng / mL (N=131)

[0107] Based on plasma concentrations, 82% of subjects maintained adherence to the study drug. DM / BU rapidly and significantly improved depressive symptoms in patients with treatment adherence to antidepressants. Compared to bupropion, DM / BU showed a statistically significant improvement in MADRS total score from baseline at all time points, including week 1, the earliest time point of assessment. Figure 5 Compared with bupropion, DM / BU treatment was associated with a statistically significant improvement in SDS function (). Figure 6 Compared with bupropion, DM / BU achieved statistically significantly higher clinical response and remission rates. Figure 7A and Figure 7B Compared to bupropion, BU / DM also showed anxiety ( Figure 8 ) and cognition ( Figure 9 Significant improvements in ( ) aspects.

[0108] DM / BU was generally safe and well-tolerated in the trials (Table 4).

[0109] Table 4. Treatment-Sudden Adverse Events

[0110]

[0111] The discontinuation rate due to adverse events was low in both groups; DM / BU was 2.5% and bupropion was 0.8%.

[0112] This disclosure relates to the following implementation plan:

[0113] 1. A method for treating major depressive disorder, comprising: administering a combination of dextromethorphan hydrobromide in the form of a salt or free base, comprising 45 mg of dextromethorphan hydrobromide or a molar equivalent of another salt or free base of bupropion hydrochloride, twice daily for at least six weeks; wherein, 12 hours after administration of the dose of said combination on day 42, the plasma level of dextromethorphan in said human patient is at least about 19 ng / mL.

[0114] 2. A method of treating major depressive disorder, comprising: administering a dosage form comprising 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt form or a free base form of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt form or a free base form of bupropion, twice daily for at least six weeks; wherein, 24 hours after discontinuation of the dosage form, the plasma level of dextromethorphan in the human patient is at least about 15 ng / mL.

[0115] 3. A pharmaceutical combination for treating major depressive disorder, comprising: 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt form or a free base form of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt form or a free base form of bupropion, wherein the pharmaceutical combination is administered twice daily to a human patient in need for at least six weeks, and wherein, 12 hours after administration of the dose of the combination on day 42, the plasma level of dextromethorphan in the human patient is at least about 19 ng / mL.

[0116] 4. A dosage form for treating major depressive disorder comprising: 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt or free base of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base of bupropion, wherein the dosage form is administered to a human patient twice daily for at least six weeks; and wherein, 24 hours after discontinuation of the dosage form, the plasma level of dextromethorphan in the human patient is at least about 15 ng / mL.

[0117] 5. Use of the combination of dextromethorphan and bupropion in the preparation of a medicament for the treatment of major depressive disorder, wherein the combination comprises 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt or free base of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base of bupropion, the combination being administered to a human patient in need twice daily for at least six weeks, and wherein, 12 hours after administration of the dose of the combination on day 42, the human patient has a plasma level of dextromethorphan of at least about 19 ng / mL.

[0118] 6. Use of the combination of dextromethorphan and bupropion in the preparation of a medicament for the treatment of major depressive disorder, wherein the combination comprises 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt form or a free base form of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt form or a free base form of bupropion, the combination being administered twice daily for at least six weeks, and wherein, 24 hours after discontinuation of administration, the patient's plasma level of dextromethorphan is at least about 15 ng / mL.

[0119] 7. The method, dosage form, drug combination, or use according to any one of the preceding items, wherein the major depressive disorder is an anti-therapeutic depressive disorder.

[0120] 8. The use according to any one of the preceding items, wherein the human patient takes the tablet orally once daily for three days, and then takes the tablet orally twice daily thereafter, wherein the tablet contains about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide.

[0121] 9. The method, dosage form, pharmaceutical combination, or use according to any one of the preceding items, wherein the dextromethorphan hydrobromide is an immediate-release formulation.

[0122] 10. The method, dosage form, pharmaceutical combination, or use according to any one of the preceding items, wherein the bupropion hydrochloride is a sustained-release formulation.

[0123] 11. The method, dosage form, pharmaceutical combination, or use according to any one of items 8 to 10, wherein the tablet is a bilayer tablet.

[0124] 12. The method, dosage form, drug combination, or use according to any one of the preceding items, wherein the dextromethorphan T max It takes about 3 hours.

[0125] 13. The method, dosage form, drug combination, or use according to any one of the preceding items, wherein, at steady-state plasma levels of dextromethorphan, based on C... max The cumulative rate of dextromethorphan is approximately 20%.

[0126] 14. The method, dosage form, drug combination, or use according to any one of the preceding items, wherein, at steady-state plasma levels of dextromethorphan, based on AUC 0-12 The cumulative ratio of dextromethorphan is approximately 32%.

Claims

1. A method for treating major depressive disorder, comprising: A combination of dextromethorphan hydrobromide (45 mg or a molar equivalent of another salt or free base) and bupropion hydrochloride (105 mg or a molar equivalent of another salt or free base) was administered to a human patient in need twice daily for at least six weeks; wherein, 12 hours after administration of the combined dose on day 42, the plasma level of dextromethorphan in the human patient was at least about 19 ng / mL.

2. A method for treating major depressive disorder, comprising: A human patient in need shall be administered a formulation comprising 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt or free base, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base, twice daily for at least six weeks; wherein, 24 hours after discontinuation of the formulation, the plasma level of dextromethorphan in the human patient shall be at least approximately 15 ng / mL.

3. A pharmaceutical combination for treating major depressive disorder, comprising: 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt form or a free base form of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt form or a free base form of bupropion, wherein, The combination of drugs was administered to human patients in need twice daily for at least six weeks, wherein, 12 hours after administration of the dose of the combination on day 42, the plasma level of dextromethorphan in the human patients was at least approximately 19 ng / mL.

4. A dosage form for treating major depressive disorder, comprising: 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt form or a free base form of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt form or a free base form of bupropion, wherein, The dosage form was administered to human patients twice daily for at least six weeks; and wherein, 24 hours after discontinuation of the dosage form, the plasma level of dextromethorphan in the human patients was at least about 15 ng / mL.

5. The use of the combination of dextromethorphan and bupropion in the preparation of a drug for the treatment of major depressive disorder, wherein, The combination comprises 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt or free base of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base of bupropion, administered to human patients in need twice daily for at least six weeks, wherein, 12 hours after administration of the dose of the combination on day 42, the human patient has a plasma level of dextromethorphan of at least approximately 19 ng / mL.

6. The use of the combination of dextromethorphan and bupropion in the preparation of a drug for the treatment of major depressive disorder, wherein, The combination comprises 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt or free base of dextromethorphan, and 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base of bupropion, administered twice daily for at least six weeks, wherein, 24 hours after discontinuation of administration, the patient’s plasma level of dextromethorphan is at least approximately 15 ng / mL.

7. The method, dosage form, pharmaceutical combination, or use according to any one of the preceding claims, wherein, The severe depression mentioned is treatment-resistant depression.

8. The use according to any one of the preceding claims, wherein, The human patient takes the tablets orally once daily for three days, followed by twice-daily oral administration of the tablets, wherein the tablets contain approximately 105 mg of bupropion hydrochloride and approximately 45 mg of dextromethorphan hydrobromide.

9. The method, dosage form, pharmaceutical combination, or use according to any one of the preceding claims, wherein, The dextromethorphan hydrobromide is an immediate-release formulation.

10. The method, dosage form, pharmaceutical combination, or use according to any one of the preceding claims, wherein, The bupropion hydrochloride is a sustained-release formulation.

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