Bupropion as modulators of pharmaceutical activity

Abstract

The present disclosure relates to administering in a human patient a combination of: 1) about 100 to 110 mg, about 104 to 106 mg, or about 105 mg or less of bupropion hydrochloride or a molar equivalent amount of bupropion in a free base form or another salt form; and 2) a free base form or another salt form of dextromethorphan hydrobromide or a molar equivalent amount of dextromethorphan or a molar equivalent amount of dextromethorphan or another salt form of about 40-50 mg, about 44-46 mg, or about 45 mg or less for use in the treatment of neurological and psychiatric conditions, such as agitation associated with Alzheimer's disease, and / or reducing recurrence of agitation in Alzheimer's disease.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 385,205, filed on November 28, 2022, U.S. Provisional Application No. 63 / 589,325, filed on October 11, 2023, and U.S. Provisional Application No. 63 / 589,525, filed on October 11, 2023; all of which are incorporated herein by reference in their entirety. Summary of the Invention

[0003] The present disclosure is directed to administering to a human 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 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 amount of dextromethorphan in free base form or another salt form (the subject combination).

[0004] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) and / or delaying the time to recurrence of agitation in AD compared to placebo in a human, comprising: i) administering to a human patient once daily or twice daily a combination of about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of dextromethorphan in free base form or another salt form, and about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or a molar equivalent amount of bupropion in free base form or another salt form, wherein the human patient is experiencing Alzheimer's disease and / or agitation associated with AD. In some embodiments, the human patient experiences a sustained clinical response as a result of receiving the combination of bupropion and dextromethorphan, wherein the sustained clinical response comprises a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score maintained for at least four consecutive weeks.

[0005] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) using a combination of dextromethorphan and bupropion and / or delaying the time to recurrence of agitation in Alzheimer's disease compared to placebo in a human, comprising: orally administering to a human once daily or twice daily a dosage form containing a combination of 105 mg of bupropion hydrochloride, or a molar equivalent amount of bupropion free base or another salt form, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of dextromethorphan free base or another salt form. In some embodiments, the human patient experiences a sustained clinical response as a result of receiving the combination of bupropion and dextromethorphan, wherein the sustained clinical response includes an improvement of 30% or greater from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score for at least four consecutive weeks.

[0006] Some embodiments include a method of treating a human patient suffering from agitation associated with Alzheimer's disease by administering a combination of dextromethorphan and bupropion, comprising orally administering to the human patient once daily or twice daily a dosage form comprising: 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan.

[0007] Some embodiments include a method of reducing relapses of agitation in Alzheimer's disease by administering a combination of dextromethorphan and bupropion, comprising orally administering to a human patient once daily or twice daily a dosage form comprising: 105 mg of bupropion hydrochloride or a molar equivalent amount of bupropion free base or another salt form and 45 mg of dextromethorphan hydrobromide or a molar equivalent amount of dextromethorphan free base or another salt form.

[0008] Some embodiments include a method of maintaining a clinical response in a human patient suffering from agitation associated with Alzheimer's disease, comprising orally administering a dosage form to the human patient twice daily, wherein the human patient experiences a sustained clinical response as a result of receiving a combination of bupropion and dextromethorphan, wherein the sustained clinical response comprises a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score for at least four consecutive weeks, wherein the dosage form comprises: 105 mg of bupropion hydrochloride, or a molar equivalent amount of bupropion free base or another salt form, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of dextromethorphan free base or another salt form. In some embodiments, the sustained clinical response further comprises maintaining a Patient Global Impression of Change (PGI-C) score of 3 or less for at least four consecutive weeks.

[0009] Some embodiments include a method of reducing recurrences of agitation in Alzheimer's disease comprising orally administering a dosage form to a human patient twice daily, wherein the human patient experiences a sustained clinical response as a result of receiving the combination of bupropion and dextromethorphan, wherein the sustained clinical response comprises a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score maintained for at least four consecutive weeks, wherein the dosage form comprises: 105 mg of bupropion hydrochloride or a molar equivalent amount of bupropion free base or another salt form and 45 mg of dextromethorphan hydrobromide or a molar equivalent amount of dextromethorphan free base or another salt form.

[0010] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) in a human patient, wherein oral administration of a subject combination to the human patient results in rapid improvement of Alzheimer's disease agitation.

[0011] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) in a human patient, wherein a lower percentage of the human patients experience recurrence of agitation when administered the subject combination compared to when administered a placebo.

[0012] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) in a human patient, wherein oral administration of a subject combination to the human patient delays time to recurrence of agitation symptoms compared to placebo.

[0013] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) in a human patient, wherein oral administration of a subject combination to the human patient delays time to recurrence of agitation symptoms by about 3.6 times lower risk of recurrence compared to placebo.

[0014] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) in a human patient, wherein oral administration of a subject combination to the human patient prevents recurrence of Alzheimer's disease agitation (ADA) compared to placebo. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1Depicted is the design of the ACCORD randomized discontinuation study for the subject combination of dextromethorphan and bupropion (45 mg DM / 105 mg BUP). aSustained response was defined as a ≥30% improvement from baseline in the CMAI total score and an improvement (score ≤3) in the PGI-C, both of which were maintained for ≥4 consecutive weeks. bAgitation recurrence was defined as a worsening of the CMAI total score by ≥10 points from randomization or a CMAI total score greater than the score at study entry; or hospitalization or institutionalization due to ADA. AD = Alzheimer's disease; ADA = Alzheimer's disease-associated agitation; BID = twice daily; BL = baseline; BUP = bupropion; CMAI = Cohen-Mansfield Agitation Inventory; DM = dextromethorphan; PGI-C = Patient Global Impression of Change.

[0016] Figure 2A Depicted are mean changes from baseline in CMAI over time during the open-label period for the subject combination of dextromethorphan and bupropion (45 mg DM / 105 mg BUP). ***P<0.001 for change from baseline by paired t-test at each time point.

[0017] Figure 2B Participants with CMAI responses over time during the open-label period for the subject combination of dextromethorphan and bupropion (45 mg DM / 105 mg BUP) are depicted. a CMAI response was defined as a ≥30% reduction from baseline. CMAI, Cohen-Mansfield Agitation Inventory.

[0018] Figure 3A Depicted are the probability of agitation relapse-free survival over time during the double-blind period for the subject combination of dextromethorphan and bupropion (45 mg DM / 105 mg BUP) compared to placebo.

[0019] Figure 3B The probability of relapse during the double-blind period for the subject combination of dextromethorphan and bupropion (45 mg DM / 105 mg BUP) compared with placebo is depicted. a Relapse of agitation was defined as a worsening (increase) of 10 points or greater in the CMAI total score from randomization or a CMAI total score greater than the score at study entry for two consecutive weeks. CMAI = Cohen-Mansfield Agitation Inventory; mITT = modified intention-to-treat. DETAILED DESCRIPTION

[0020] As described above, the present disclosure relates to administering 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 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 amount of dextromethorphan in its free base form or another salt form. For convenience, this combination is referred to herein as the "subject combination." In each instance herein of referring to the subject combination, the combination of 105 mg of bupropion hydrochloride, or a molar equivalent amount of bupropion in its free base form, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of dextromethorphan in its free base form, is expressly contemplated.

[0021] Dextromethorphan hydrobromide is a noncompetitive NMDA receptor antagonist and sigma-1 receptor agonist.

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

[0023]

[0024] Dextromethorphan hydrobromide powder is white or almost white crystals and is slightly soluble in water.

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

[0026] The chemical name of bupropion hydrochloride is (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The empirical formula of bupropion hydrochloride is C 13 H 18 ClNO·HCl, and its molecular weight is 276.2. Its structural formula is:

[0027]

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

[0029] The subject combination may be contained in an oral dosage form, including a tablet, such as an extended release tablet. In some embodiments, the subject combination is contained in a dosage form for oral administration and may be used as a round bilayer tablet.

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

[0031] In some embodiments, a tablet comprising the subject combination comprises L-cysteine ​​hydrochloride monohydrate. In some embodiments, a tablet comprising the subject combination comprises carbomer homopolymer. In some embodiments, a tablet comprising the subject combination comprises microcrystalline cellulose. In some embodiments, a tablet comprising the subject combination comprises colloidal silicon dioxide. In some embodiments, a tablet comprising the subject combination comprises crospovidone. In some embodiments, a tablet comprising the subject combination comprises stearic acid. In some embodiments, a tablet comprising the subject combination comprises magnesium stearate.

[0032] In some embodiments, a tablet comprising the subject combination comprises the following inactive ingredients: L-cysteine ​​hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silicon dioxide, crospovidone, stearic acid, and magnesium stearate.

[0033] In some embodiments, the dosage is one tablet (or one dosage form containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride) twice daily, for example, administered at least 8 hours apart. In some embodiments, no more than two doses, each containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride, are administered on the same day.

[0034] The subject combination can be administered orally with or without food.In some embodiments, the tablet is swallowed whole, rather than crushed, split, or chewed.

[0035] In the subject combination, bupropion inhibits the metabolism of dextromethorphan via CYP2D6. When co-administered with bupropion, dextromethorphan exhibits nonlinear pharmacokinetics at steady state, with AUC and C values ​​varying from 30 to 60 mg for different doses of dextromethorphan. max The changes in α and β were greater than dose proportional and less than dose proportional for different doses of bupropion (75 to 150 mg).

[0036] When administered in the subject combination, steady-state plasma concentrations of dextromethorphan and bupropion were achieved within 8 days. max and AUC 0-12 , the accumulation rates of dextromethorphan at steady state are about 20 and about 32, respectively. max and AUC 0-12, the accumulation rates of bupropion at steady state were 1.1 and 1.5, respectively.

[0037] After administration of the subject combination, the median T of dextromethorphan was max is about 3 hours, while the median T of bupropion is max The C of hydroxybupropion metabolite is about 2 hours. max It occurs approximately 3 hours after dosing and is approximately 14 times the peak level of bupropion. 0-12 It is about 19 times that of bupropion. C of erythrohydroxybupropion and threohydroxybupropion metabolites max The AUCs for erythrohydroxybupropion and threohydroxybupropion are approximately equal to and five times that of bupropion, respectively. 0-12 The values ​​were approximately 1.2 times and approximately 7 times those of bupropion, respectively.

[0038] The subject combination may be taken with or without food. When the subject combination is administered with food, dextromethorphan C max and AUC 0-12 remained unchanged and decreased by 14%, respectively, while bupropion C max and AUC 0-12 An increase of 3% and 6% respectively.

[0039] Dextromethorphan is approximately 60-70% bound to plasma proteins, and bupropion is 84%. The extent of protein binding of the hydroxybupropion metabolite is similar to that of bupropion, while the extent of protein binding of the threohydroxybupropion metabolite is approximately half that of bupropion.

[0040] Following 8 days of administration of the subject combination in extensive metabolizers, the mean elimination half-life of dextromethorphan was increased approximately 3-fold to approximately 22 hours compared to dextromethorphan administered without bupropion.

[0041] The mean elimination half-lives of dextromethorphan and bupropion are 22 hours and 15 hours, respectively. The apparent elimination half-lives of hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion metabolites are approximately 35, 44, and 33 hours, respectively.

[0042] Unlike the combination of quinidine and dextromethorphan, the subject combination did not prolong the QT interval to any clinically relevant extent at a dose of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide given twice daily. Therefore, electrocardiographic evaluation of the QT interval is not typically performed on human patients who are experiencing agitation associated with Alzheimer's disease and are at risk for QT prolongation and torsades de pointes.

[0043] In addition to agitation associated with Alzheimer's disease, the subject combinations can also be used to treat other conditions in the patient populations or situations described herein. For example, the subject combinations can be used to treat pain or neurological disorders. Examples of neurological disorders that can be treated with the subject combinations include, but are not limited to, affective disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron disease, neurodegenerative diseases, epilepsy, and headaches.

[0044] Affective disorders that may be treated by the subject combinations include, but are not limited to, depression, major depressive disorder, refractory depression, refractory bipolar depression, bipolar disorder including cyclothymia, seasonal affective disorder, mood disorders, chronic depressive disorder (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH) and attention deficit / hyperactivity disorder (AD / HD), bipolar disorder and mania, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychotic sexual dysfunction, pseudobulbar mood, and mood lability.

[0045] Depression can be manifested by depressive symptoms. These symptoms can include psychological changes (such as mood changes), feelings of extreme sadness, despair, mental dullness, difficulty concentrating, pessimistic worries, agitation, anxiety, irritability, guilt, anger, a sense of worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-deprecation. The physical symptoms of depression can include insomnia, anorexia, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, irritability, aches, pains, headaches, cramps, digestive problems, and / or abnormal circadian rhythms of hormones.

[0046] The mental disorder that can be treated by subject combination includes but is not limited to: anxiety disorder, including but not limited to phobia, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder and post-traumatic stress disorder (PTSD); mania, manic-depressive illness, hypomania, unipolar depression, depression, stress disorder, somatoform disorder, personality disorder, psychosis, schizophrenia, paranoia, schizoaffective disorder, schizotypy, aggressive behavior, aggressive behavior in Alzheimer's disease, agitation and the agitation in Alzheimer's disease. Alzheimer's disease can also be referred to as Alzheimer's type dementia. Other neurobehavioral symptoms of Alzheimer's disease that can be treated include disinhibition and emotional indifference.

[0047] As the disease progresses, Alzheimer's disease can develop agitation. Agitation may manifest itself as inappropriate speech, emotions, and / or physical behavior. Inappropriate behavior can include, but is not limited to, incoherent speech, inappropriate emotional reactions, demands for attention, threats, irritability, frustration, screaming, repetitive questioning, mood swings, swearing, abusive language, physical outbursts, emotional distress, restlessness, tearing, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body movements, hoarding, stalking, hitting, scratching, biting, belligerence, hyperactivity, and / or kicking.

[0048] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral and psychological symptoms (including agitation). AD is the most common form of dementia and affects approximately 6 million individuals in the United States, a figure that is expected to increase to approximately 14 million by 2050. It is reported that up to 70% of AD patients suffer from agitation and is characterized by emotional distress, aggressive behavior, disruptive irritability, and disinhibition. Managing agitation is a priority for AD. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, premature nursing home placement, and increased mortality. Currently, the FDA has not approved a therapy for the treatment of agitation in AD patients.

[0049] It is known that neurobehavioral symptoms can occur during dementia, and it can be treated by combination therapy. Compared to the patient's cognitive impairment, caregivers or family members may feel more unbearable due to the patient's behavior / psychological symptoms. The common form of syndrome includes Alzheimer's disease, vascular dementia, Lewy bodies (abnormal protein aggregates formed in nerve cells) dementia and a group of diseases causing frontotemporal dementia (degeneration of the frontal lobe of the brain). The symptoms of dementia patients are similar to those of mental disorders, but slightly different from each other. The neurobehavioral symptoms associated with dementia include depression, apathy, agitation, disinhibition, hallucinations, delusions, psychosis, impulse, aggressiveness, compulsion, hypersexuality and personality disorder. In other morbidities (such as traumatic brain injury), neurobehavioral symptoms may also be found, such as disinhibition.

[0050] Agitation in patients with Alzheimer's disease can be assessed using the Cohen-Mansfield Agitation Inventory, or CMAI. The CMAI assesses a variety of behaviors, including hitting (including self), kicking, grabbing, pushing, throwing, biting, scratching, spitting, injuring self or others, tearing or destroying property, making physical advances, pacing, wandering aimlessly, dressing inappropriately or undressing, trying to get to different places, intentionally falling down, eating or drinking inappropriate substances, handling things inappropriately, hiding things, hoarding things, repetitive habits, general irritability, screaming, making verbal advances, swearing or verbally aggressing, repeating sentences or questions, making strange noises (weird laughter or crying), complaining, whining, and constantly and unprovoked requests for attention or help.

[0051] Schizophrenia may be treated by a combination of positive and / or negative symptoms of schizophrenia or residual symptoms of schizophrenia.Other conditions that may be treated include intermittent explosive disorder.

[0052] The brain dysfunction that the subject combination can treat includes, but is not limited to, conditions involving intellectual disability, such as Alzheimer's disease, Alzheimer's disease, amnesia, amnesia / amnestic syndrome, epilepsy, impaired consciousness, coma, decreased attention span, speech disorder, voice spasm, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperactivity syndrome and schizophrenia. Brain dysfunction also includes conditions caused by cerebrovascular disease, including but not limited to stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head injury, etc., wherein symptoms include impaired consciousness, Alzheimer's disease, coma, decreased attention span and speech disorder.

[0053] Substance addictions that can be treated by the subject combinations include, but are not limited to, drug dependence, cocaine addiction, psychostimulants (e.g., crack, cocaine, speed, methamphetamine), nicotine, alcohol, opioids, anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking cigarettes, cigars and / or pipes, e-cigarettes or vaping, and chewing tobacco addiction.

[0054] Movement disorders that may be treated by the subject combinations include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's disease chorea, chorea rheumatica, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette syndrome and Wilson's disease.

[0055] Dementias that may be treated by the subject combinations include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff Syndrome, and Pick's disease.

[0056] Motor neuron diseases that may be treated by the subject combinations include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

[0057] Neurodegenerative diseases that may be treated by the subject combinations include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxias, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease, and disease, CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0058] Epileptic disorders that may be treated by the subject combinations include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile convulsions; partial seizures, including but not limited to simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsy continua partial; generalized seizures, including but not limited to generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0059] Headache types that may be treated by the subject combination include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0060] Other neurological conditions that may be treated by the subject combinations include Rett Syndrome, autism, tinnitus, impaired consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; voice disorders caused by uncontrolled laryngeal muscle spasms, including but not limited to abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscular tension dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence, including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0061] In some embodiments, the subject combinations may be used to treat pain, joint pain, pain associated with sickle cell disease, pseudobulbar mood, depression (including refractory depression), disorders related to memory and cognition, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rhett syndrome, seizures, cough (including chronic cough), and the like.

[0062] In some embodiments, the subject combinations can be administered orally to relieve musculoskeletal pain, including low back pain, as well as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatic diseases, periarticular disorders, axial spondyloarthritis (including ankylosing spondylitis), Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral compression fractures, osteoporosis, and the like.

[0063] In some embodiments, the subject combinations may be administered to relieve inflammatory pain, including musculoskeletal pain, arthritic pain, and complex regional pain syndrome.

[0064] Arthritis refers to inflammatory joint diseases that may be associated with pain. Examples of arthritis pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, periarticular disease, neuropathic arthropathy (including Charcot foot), axial spondyloarthritis (including ankylosing spondylitis), and SAPHO syndrome.

[0065] In some embodiments, the subject combinations are used to treat chronic musculoskeletal pain.

[0066] In some embodiments, the subject compositions can be administered to alleviate complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is a type of inflammatory pain. CRPS can also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the limbs, which may be accompanied by edema and autonomic, motor, and sensory changes.

[0067] In some embodiments, the subject compositions can be administered orally to relieve neuropathic pain.

[0068] Examples of neuropathic pain include pain caused by diabetic peripheral neuropathy or diabetic peripheral neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, central pain, pain caused by multiple sclerosis, etc. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and radiation- or chemotherapy-related neuropathy.

[0069] In some embodiments, the subject compositions can be administered to relieve fibromyalgia.

[0070] The terms "treating" or "treatment" include any activity that affects the structure or any function of the body of a human or other animal, including the diagnosis, cure, alleviation, treatment, or prevention of disease.

[0071] In some embodiments, the subject combination can reduce the CMAI (Cohen-Mansfield Agitation Inventory) total score from baseline by at least 5, about 5-10, about 10-15, about 15-20, about 20-25, about 25-30, or about 30-35, or any value bounded by or therebetween, after oral administration of the subject combination to a human patient for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks.

[0072] In some embodiments, the subject combination is administered twice daily for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 2 years, up to 1 year, up to 2 years, up to 3 years, up to 4 years, up to 5 years, up to 10 years, or longer after achieving a sustained clinical response as a result of receiving the combination of bupropion and dextromethorphan, wherein the sustained clinical response comprises a 30% or greater improvement from baseline in Cohen-Mansfield Agitation Inventory (CMAI) total score in human patients maintained for at least 4 consecutive weeks.

[0073] In some embodiments, the percentage of human patients with a CMAI response, or the likelihood of a CMAI response (defined as a ≥30% reduction from baseline) after oral administration of a subject combination to human patients for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks can be at least 20%, about 20-40%, about 40-60%, about 60-80%, about 80-90%, about 90-95%, about 80-100%, about 40%, about 50-55%, about 60%, about 70%, about 60-70%, about 70-80%, about 22%, about 54%, about 61%, about 79%, about 91%, about 93%, about 95%, or any value bounded by or between these ranges.

[0074] Recurrence of agitation is defined as a worsening (increase) in the CMAI total score of ≥10 points for 2 consecutive weeks greater than the total score at the beginning of the study. In some embodiments, the probability (%) of surviving without recurrence of agitation in human patients with the subject combination treatments may be higher than that in human patients taking placebo. In some embodiments, the probability (%) of surviving without recurrence of agitation with treatment with the subject combination can be at least 80%, at least 85%, at least 90%, about 90-95%, about 95-100%, about 90-92%, about 92-94%, about 94-96%, about 96-98%, or any value bounded by or in between these ranges, following oral administration of the subject combination to a human patient for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 15-20 weeks, about 20 weeks, about 20-25 weeks, about 25 weeks, about 26 weeks, or more. In some embodiments, the risk of relapse is reduced by about at least 2-fold, at least 3-fold, 3-4-fold, about 3-fold, about 4-fold, about 3.6-fold, or about 4-5-fold with the subject combination compared to placebo.

[0075] In some embodiments, the percentage of human patients experiencing recurrence of agitation can be substantially reduced with the subject combination treatments compared to placebo. In some embodiments, the percentage of human patients experiencing recurrence of agitation can be very low, such as less than 10%, about 5-10%, about 5%, about 5-6%, about 5-8%, about 7.5%, about 6-8%, or about 7-8%.

[0076] In some embodiments, the subject combination can substantially delay the time to recurrence of agitation symptoms compared to placebo. In some embodiments, the subject combination can delay the time to recurrence of agitation symptoms compared to placebo, with a risk of recurrence being about 2-fold, about 3-fold, about 4-fold, about 3-4-fold, about 4-5-fold, or about 3.6-fold lower than placebo.

[0077] In some embodiments, the subject combination can significantly prevent the recurrence of Alzheimer's disease agitation (ADA) compared to placebo.

[0078] In some embodiments, treatment with the subject combinations can result in rapid and substantial improvement in agitation in Alzheimer's disease.

[0079] The subject combination may be used to treat any of the diseases or conditions identified in 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, 9,427,619, 457,023、9,457,025、9,474,731、9,486,450、9,700,528、9,700,553、9,707,191、9,763,932、9,861,595、9,867,819、9,968,568、10,058,518、10,064,857、10,080,727、10,092,560、10,092,56 1, 10,105,327, 10,105,361, 10,251,879, 10,463,634, 10,512,643, 10,548,857, 10,596,167, 10,772,850, 10,780,064, 10,780,066, 10,786,469, 10,786,496, 10,799,497, 10,806,710, 10,8 64,209, 10,874,663, 10,874,664, 10,874,665, 10,881,624, 10,881,657, 10,894,046, 10,894,047, 10,898,453, all of which are incorporated herein by reference in their entirety for their disclosure of conditions treatable by a combination of bupropion and dextromethorphan, including the specific embodiments and combinations described therein.

[0080] Example 1

[0081] Efficacy and safety of DM / BUP (dextromethorphan-bupropion) in agitation associated with Alzheimer's disease: results from ACCORD, a phase 3, double-blind, placebo-controlled relapse prevention trial.

[0082] Dextromethorphan-bupropion, or DM / BUP, e.g., 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride, is a novel, oral, investigational N-methyl-D-aspartate (NMDA) receptor antagonist with multimodal activity that is being developed for the treatment of agitation in Alzheimer's disease (AD) and other central nervous system (CNS) disorders.

[0083] DM / BUP utilizes proprietary formulations and dosages of dextromethorphan and bupropion, along with Axsome's metabolic inhibition technology, to modulate the delivery of the components. The dextromethorphan component of DM / BUP is a non-competitive NMDA receptor antagonist (also known as a glutamate receptor modulator) and sigma-1 receptor agonist. The bupropion component of DM / BUP is designed to increase the bioavailability of dextromethorphan and is a norepinephrine and dopamine reuptake inhibitor.

[0084] DM / BUP tablets for oral administration were prepared. They are round, bilayer tablets. Each tablet contains 45 mg of dextromethorphan hydrobromide (equivalent to 32.98 mg of dextromethorphan free base) in an immediate-release formulation and 105 mg of bupropion hydrochloride (equivalent to 91.14 mg of bupropion free base) in a sustained-release formulation. Each tablet contains the following inactive ingredients: carbomer homopolymer, colloidal silicon dioxide, crospovidone, monocaprylic and capric glyceride, L-cysteine ​​hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide, and / or yellow iron oxide.

[0085] introduce

[0086] Alzheimer's disease (AD) is the most common cause of dementia, affecting 6.7 million Americans in 2023, a number projected to rise to 13.8 million by 2060 due to an aging population. AD-associated agitation (ADA) is reported in up to 70% of AD patients and is characterized by emotional distress, aggressive behavior, disruptive irritability, and disinhibition. ADA and other behavioral symptoms are associated with increased caregiver burden, decreased functional ability, accelerated cognitive decline, premature nursing home placement, and increased mortality. Non-pharmacological treatments for ADA are not always effective, and the only U.S. Food and Drug Administration (FDA)-approved treatment for agitation in dementia caused by AD is brexpiprazole, a neuroleptic that carries a black box warning for use in dementia-related psychosis due to an increased risk of death.

[0087] DM / BUP (dextromethorphan-bupropion extended-release tablets) is a novel oral N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist approved by the FDA for the treatment of major depressive disorder in adults. Neurotransmitter imbalances in AD patients lead to agitation, and these neurotransmitters can be modulated with DM / BUP.

[0088] Methods and research design

[0089] Key inclusion and exclusion criteria for participants with probable AD and clinically significant agitation enrolled in this study are shown in Table 1 .

[0090]

[0091] Note: AD, Alzheimer's disease; IPA, International Psychogeriatric Association; MMSE, Mini-Mental State Examination; NIA-AA, National Institute on Aging-Alzheimer's Association

[0092] The ACCORD (Assessing Clinical Outcomes in Alzheimer's Disease Agitation; NCT04797715) study is a phase 3, randomized, withdrawal, double-blind, placebo-controlled, multicenter trial evaluating the efficacy and safety of DM / BUP in the treatment of agitated Alzheimer's disease (ADA) in patients with ADA. Figure 1 Patients diagnosed with probable Alzheimer's disease and clinically significant agitation related to their disease were enrolled in a 9-week open-label period during which they were treated with DM / BUP and monitored for sustained clinical response. Sustained clinical response was defined as a ≥30% improvement from baseline in the Cohen-Mansfield Agitation Inventory (CMAI) total score and an improvement in the PGI-C (score ≤3), both of which were maintained for at least 4 consecutive weeks.

[0093] Patients who experienced a sustained clinical response during the open-label treatment period were then randomized in a 1:1 ratio to continue treatment with DM / BUP or switch to placebo in a double-blind manner for up to 26 weeks. Treatment continued until recurrence of agitation or the end of the 26-week double-blind period, whichever occurred first. Relapse was defined as a worsening of the CMAI total score by ≥10 points since randomization or a CMAI total score greater than the score at the beginning of the study; or hospitalization or other specialized institution due to agitation associated with Alzheimer's disease.

[0094] A total of 178 patients were enrolled in the open-label phase and treated with DM / BUP, and 108 patients were randomized to continue receiving DM / BUP (n=53) or switch to placebo (n=55). The mean Cohen-Mansfield Agitation Inventory (CMAI) total score at the start of the baseline study was 70.9. The mean CMAI total score at randomization was 43.7 (DM / BUP) and 44.9 (placebo). The lowest CMAI score is 29, corresponding to the complete absence of symptoms, with higher scores corresponding to more severe agitation.

[0095] The primary endpoint of the study was the time from randomization to relapse of Alzheimer's agitation (in the double-blind phase) calculated by Kaplan-Meier estimates and hazard ratios. The key secondary endpoint for assessing relapse prevention was the percentage of patients who relapsed. The primary time point for open-label efficacy assessment was Week 5, and the key secondary time point was Week 2. The P value for the open-label phase was calculated compared to baseline.

[0096] exist Figure 1 In the table, AD denotes Alzheimer's disease; ADA denotes Alzheimer's disease-associated agitation; BID denotes twice daily; BL denotes baseline; BUP denotes bupropion; CMAI denotes Cohen-Mansfield Agitation Inventory; DM denotes dextromethorphan; and PGI-C denotes Patient Global Impression of Change.

[0097] Patient population

[0098] Participants had moderately severe AD dementia as measured by the Mini-Mental State Examination (MMSE). Baseline demographics and clinical characteristics were similar between groups during the double-blind phase (Table 2). During the double-blind phase, 54.2% of participants completed the study, with sponsor termination being the most common reason for discontinuation (22.4%).

[0099]

[0100]

[0101] aNPI-AA total scores for n = 49 participants in the DM / BUP and placebo groups during the double-blind phase. CGI-S, Clinical Global Impression-Severity; CMAI, Cohen-Mansfield Agitation Inventory; ITT, intention-to-treat; MMSE, Mini-Mental State Examination; NPI-AA, Neuropsychiatric Inventory-Agitation and Aggression domain.

[0102] Efficacy in the open-label period before randomized discontinuation

[0103] A total of 178 patients were treated with open-label DM / BUP for up to 9 weeks and evaluated for efficacy. The primary time point for open-label efficacy evaluation was 5 weeks, and the key secondary time point was 2 weeks. P values ​​were calculated relative to baseline. The mean CMAI total score at baseline was 70.9.

[0104] The mean change from baseline in CMAI during the open-label period and participants with a CMAI response were shown in Figure 2A and 2B In. Figure 2A P<0.001 for change from baseline by paired t-test at each time point. CMAI denotes Cohen-Mansfield Agitation Inventory, and a CMAI response was defined as a decrease of ≥30% from baseline.

[0105] like Figure 2A and 2B As shown, during the open-label period, there was a statistically significant improvement in the Cohen-Mansfield Agitation Questionnaire total score at all time points as early as Week 1 ( Figure 2A ), the response rate increased over time ( Figure 2B ). More detailed open-label period results are summarized below.

[0106] DM / BUP treatment was associated with a mean reduction from baseline in CMAI total score of 6.7 points at week 1, 11.0 points at week 2, and 20.6 points at week 5 (all p<0.001) ( Figure 2A ).

[0107] After DM / BUP treatment, 21.8% of patients achieved a clinical response to CMAI (defined as a ≥30% reduction from baseline) at week 1, 40.4% at week 2, and 70.0% at week 5 ( Figure 2B ).

[0108] DM / BUP treatment was also associated with improvements on all CMAI subscales, including the physical aggression subscale at all time points (p<0.001).

[0109] Following DM / BUP treatment, 47.1% of patients achieved improvement in Alzheimer's disease agitation at week 1, 66.3% at week 2, and 86.3% at week 5 (assessed using clinician-rated mACS-CGIC).

[0110] Following DM / BUP treatment, 51.2% of patients achieved improvement in Alzheimer's agitation at week 1, 67.5% at week 2, and 89.3% at week 5 (assessed using caregiver-rated PGI-C).

[0111] Caregiver distress (assessed using the NPI Agitation and Aggression Caregiver Distress Scale) was significantly reduced following DM / BUP treatment (p<0.001 at both Weeks 4 and 8).

[0112] Caregiver burden (assessed using the ZBI) was significantly reduced after DM / BUP treatment (week 4, p = 0.006, week 8, p = 0.003).

[0113] Patients' quality of life (assessed using the caregiver-rated QoL-AD scale) significantly improved after DM / BUP treatment (week 4, p<0.001, week 8, p=0.013).

[0114] Depressive symptoms (assessed using the CSDD) were significantly reduced after DM / BUP treatment (weeks 4 and 8, p < 0.001).

[0115] Efficacy in the double-blind phase

[0116] A total of 108 patients were randomized, 53 continued DM / BUP treatment, and 55 switched to placebo. The mean CMAI total scores at randomization were 43.7 and 44.9 in the DM / BUP and placebo groups, respectively.

[0117] The probability of relapse-free survival and relapse occurrence in the double-blind period is shown in Figure 3A and Figure 3B .exist Figure 3A In 3B or 3B, recurrence of agitation was defined as a worsening (increase) of 10 or more points in the CMAI total score from randomization or a CMAI total score greater than the score at study entry for two consecutive weeks. CMAI denotes the Cohen-Mansfield Agitation Inventory; and mITT denotes modified intention-to-treat.

[0118] like Figure 3A and Figure 3B As shown, DM / BUP achieved the primary endpoint by substantially and statistically prolonging the time to recurrence of agitation symptoms compared with placebo (hazard ratio, 0.275, P = 0.014) ( Figure 3A ). In the setting of DM / BUP, the risk of recurrence was reduced by 3.6-fold compared with placebo.

[0119] DM / BUP also achieved a key secondary endpoint by significantly preventing the recurrence of Alzheimer's agitation compared to placebo (7.5% vs. 25.9% of participants, respectively, p=0.018) ( Figure 3B ).

[0120] The adverse event rate in the double-blind period was 28.3% in the DM / BUP group and 22.2% in the placebo group. The discontinuation rate due to adverse events in the double-blind period was low (0% for DM / BUP and 1.9% for placebo).

[0121] Security

[0122] Treatment-emergent adverse events are summarized in Table 3. There were no sedation-emergent adverse events with DM / BUP. No clinically significant cardiovascular changes were observed with DM / BUP. There was no evidence of cognitive decline in participants treated with DM / BUP based on the MMSE (mean change from baseline to week 8 in the open-label period, 0.4; P = 0.421). No deaths occurred in the DM / BUP group during any period.

[0123]

[0124] aDeath due to cardiac arrest; bTEAEs reported by preferred term. TEAE, treatment-emergent adverse event.

[0125] One serious adverse event (fecal tumor) was reported in the DM / BUP group, which the researchers determined was not related to the study drug, and two serious adverse events (cardiac arrest, femoral fracture) were reported in the placebo group. Four patients reported falls in the DM / BUP group, all of which were not related to serious adverse events and the researchers determined were not related to the study drug; and two patients reported falls in the placebo group, one of which was associated with a femoral fracture. One death was reported in the placebo group. There was no evidence of cognitive decline in patients treated with DM / BUP as shown by the Mini-Mental State Examination (MMSE), a widely used quantitative measure of general cognitive function. DM / BUP treatment was not associated with sedation.

[0126] in conclusion

[0127] During the double-blind period, DM / BUP significantly prolonged the time to recurrence of agitation symptoms compared with placebo.

[0128] In the initial open-label period, improvements in agitation symptoms were rapid and durable in the setting of DM / BUP.

[0129] Overall, DM / BUP was generally well tolerated, and no new safety signals were identified based on previous phase 2 trials.

[0130] In this study, no sedation-emergent adverse events, clinically significant cardiovascular changes, or evidence of cognitive decline were observed among participants treated with DM / BUP.

[0131] Therefore, DM / BUP is a promising drug candidate for the treatment of agitation in patients with Alzheimer's disease.

[0132] In addition, clinicians and caregivers reported rapid and substantial improvements in Alzheimer's disease agitation based on global measures. Clinicians reported that 66.3% of patients had improved agitation at week 2 and 86.3% at week 5 after DM / BUP treatment, as assessed using the modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change in Agitation (mADCS-CGIC). Caregivers reported that 67.5% of patients had improved agitation at week 2 and 89.3% at week 5 after DM / BUP treatment, as assessed using the Caregiver-rated Patient Global Impression of Change (PGI-C).

[0133] After treating patients with open-label DM / BUP, there was a statistically significant improvement in caregiver distress and burden, patient quality of life, and depressive symptoms compared to baseline. Caregiver distress was assessed using the NPI agitation and aggression caregiver distress score (p < 0.001 at week 4 and week 8). Caregiver burden was assessed using the Zarit Burden Interview (ZBI) (week 4, p = 0.006, week 8, p = 0.003). The quality of life of patients was assessed using the caregiver-rated Alzheimer's disease quality of life (QoL-AD) scale (week 4, p < 0.001, week 8, p = 0.013). Depressive symptoms were assessed using the Cornell Scale for Depression in Dementia (CSDD) (week 4 and week 8, p < 0.001).

[0134] Finally, DM / BUP statistically significantly delayed the time to relapse of Alzheimer's disease agitation compared to placebo (p=0.014, primary endpoint), statistically significantly reduced the relapse of Alzheimer's disease agitation compared to placebo (p=0.018, key secondary endpoint), and as measured by CMAI total score, using open-label DM / BUP starting at week 1 (all time points, compared to baseline, p<0.001). 66% of patients achieved improvement in Alzheimer's disease agitation at 2 weeks and 86% of patients at 5 weeks (assessed by the Modified Alzheimer's Disease Cooperative Investigator-CGIC scale). 68% of patients achieved improvement in Alzheimer's disease agitation at 2 weeks and 89% of patients achieved improvement in Alzheimer's disease agitation at 5 weeks (assessed by the PGI-C scale).

[0135] "Agitation is one of the most distressing and important aspects of Alzheimer's disease for patients and their caregivers because it is associated with earlier nursing home admission, accelerated cognitive decline, and increased mortality," said Jeffrey Cummings, MD, ScD, Director Emeritus of the Lou Ruvo Center for Brain Health at Cleveland Clinic and Chambers Professor of Brain Sciences at the University of Nevada, Las Vegas. "Results from the ACCORD trial demonstrate that DM / BUP has compelling clinical activity for agitation associated with Alzheimer's disease, based on a significant delay in symptom relapse and a reduction in relapses compared to placebo. Treatment with [DM / BUP] during the open-label period in this large patient cohort resulted in rapid and clinically meaningful improvements in agitation in Alzheimer's disease. These improvements were particularly noteworthy because they were reflected on the aggressive symptom subscale of the agitation measure. Agitation is present in the majority of patients with Alzheimer's disease, and there are currently no approved treatments for this condition. If approved, based on the observed positive efficacy and favorable safety and tolerability results, [DM / BUP] could potentially address this high unmet medical need for patients and their caregivers."

[0136] Unless otherwise indicated, all numbers used in the specification and claims expressing quantities of components, properties, such as amounts, percentages, etc., should in all cases be understood to indicate the exact value shown and to be modified by the term "about". Therefore, unless otherwise indicated, the numerical parameters listed in the specification and the appended claims are approximate values ​​that may vary depending on the desired properties to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be interpreted in light of the number of reported significant digits and by applying customary rounding techniques.

[0137] The use of the terms "comprising" or "including" herein also encompasses the use of "consisting essentially of" or "consisting essentially of" in its place; or "consisting of" or "consisting of."

[0138] Anywhere herein, the affirmative recitation of elements should be understood to contemplate both the inclusion and exclusion of the elements.

[0139] Unless otherwise indicated herein or clearly contradicted by the context, the terms "one", "a", "said" and similar references used in the context of describing an embodiment (especially in the context of the following claims) should be interpreted as covering both singular and plural references. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein can be performed in any suitable order. The use of any and all embodiments or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the embodiment and does not limit the scope of any claim. Any language in this specification should not be interpreted as indicating that any unclaimed element is necessary to practice the claim.

[0140] The grouping of alternative elements or embodiments disclosed herein should not be interpreted as limiting. Each group member may be mentioned and claimed individually, or mentioned and claimed in any combination with other members of the group or other elements found herein. For reasons of convenience and / or to speed up the application process, it is contemplated that one or more members of the group may be included in the group or deleted from the group. When any such inclusion or deletion occurs, this specification is deemed to include the modified group, and therefore satisfies the written description of all Markush groups used in the appended claims.

[0141] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations of these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect that skilled artisans will employ such variations as appropriate, and the inventors expect that the claimed embodiments may be practiced in ways other than those specifically described herein. Accordingly, 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 above elements in all possible variations is encompassed unless otherwise indicated herein or clearly contradicted by the context.

[0142] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications may be employed and are within the scope of the claims. Therefore, by way of example and not limitation, alternative embodiments may be used in accordance with the teachings herein. Therefore, the claims are not limited to the precise embodiments shown and described.

Claims

1. A method of maintaining a clinical response in a human patient suffering from agitation associated with Alzheimer's disease, comprising orally administering to the human patient a dosage form twice daily, wherein the human patient experiences a sustained clinical response as a result of receiving a combination of bupropion and dextromethorphan, wherein the sustained clinical response comprises a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score maintained for at least four consecutive weeks, wherein the dosage form comprises: 105 mg of bupropion hydrochloride or a molar equivalent amount of bupropion free base or another salt form and 45 mg of dextromethorphan hydrobromide or a molar equivalent amount of dextromethorphan free base or another salt form.

2. The method of claim 1, wherein the sustained clinical response further comprises maintaining a Patient Global Impression of Change (PGI-C) score of 3 or less for at least 4 consecutive weeks.

3. A method of reducing recurrences of agitation in Alzheimer's disease comprising orally administering a dosage form to a human patient twice daily, wherein the human patient experiences a sustained clinical response as a result of receiving a combination of bupropion and dextromethorphan, wherein the sustained clinical response comprises a 30% or greater improvement from baseline in the Cohen-Mansfield Agitation Inventory (CMAI) total score in human patients maintained for at least four consecutive weeks, wherein the dosage form comprises: 105 mg of bupropion hydrochloride or a molar equivalent amount of the free base or another salt form of bupropion and 45 mg of dextromethorphan hydrobromide or a molar equivalent amount of the free base or another salt form of dextromethorphan.

4. The method of claim 1, 2, or 3, wherein the dosage form comprising 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide is orally administered to the patient twice daily.

5. The method according to any one of the preceding claims, wherein the dosage form is administered twice daily for at least 4 weeks.

6. The method according to any one of the preceding claims, wherein the dosage form is administered twice daily for at least 3 months.

7. The method according to any one of the preceding claims, wherein the dosage form is administered twice daily for at least 6 months.

8. The method according to any one of the preceding claims, wherein the dosage form is a solid dosage form.

9. The method of claim 8, wherein the solid dosage form further comprises a carbomer homopolymer.

10. The method of claim 8 or 9, wherein the solid dosage form further comprises colloidal silicon dioxide.

11. The method of claim 8, 9 or 10, wherein the solid dosage form further comprises crospovidone.

12. The method of claim 8, 9, 10, or 11, wherein the solid dosage form further comprises caprylic / decanoic acid glyceryl monoester.

13. The method of claim 8, 9, 10, 11 or 12, wherein the solid dosage form further comprises L-cysteine ​​hydrochloride monohydrate.

14. The method of claim 8, 9, 10, 11, 12, or 13, wherein the solid dosage form further comprises magnesium stearate.

15. The method of claim 8, 9, 10, 11, 12, 13, or 14, wherein the solid dosage form further comprises microcrystalline cellulose.

16. The method of claim 8, 9, 10, 11, 12, 13, 14, or 15, wherein the solid dosage form further comprises polyvinyl alcohol.

17. The method of claim 8, 9, 10, 11, 12, 13, 14, 15, or 16, wherein the solid dosage form further comprises red iron oxide.

18. The method of claim 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the solid dosage form further comprises sodium lauryl sulfate.

19. The method of claim 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein the solid dosage form further comprises stearic acid.

20. The method of claim 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein the solid dosage form further comprises talc.

21. The method of claim 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein the solid dosage form further comprises titanium dioxide.

22. The method of claim 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein the solid dosage form further comprises yellow iron oxide.

23. The method of claim 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22, wherein the solid dosage form is a tablet.

24. The method of claim 23, wherein the tablet is a bilayer tablet.

25. The method of any one of the preceding claims, wherein dextromethorphan hydrobromide is in the form of an immediate release formulation.

26. The method of any preceding claim, wherein bupropion hydrochloride is in the form of a sustained release formulation.

27. The method of any one of the preceding claims, wherein oral administration of the dosage form to the human patient results in rapid improvement of Alzheimer's disease agitation.

28. The method of any one of the preceding claims, wherein the percentage of human patients who experience recurrence of agitation is lower when administered the dosage form compared to when administered a placebo.

29. The method of any one of the preceding claims, wherein oral administration of the dosage form to the human patient delays time to recurrence of agitation symptoms compared to placebo.

30. The method of any one of the preceding claims, wherein oral administration of the dosage form to the human patient delays time to recurrence of agitation symptoms by about 3.6 times lower risk of recurrence compared to placebo.

31. The method of any one of the preceding claims, wherein oral administration of the dosage form to the human patient reduces the risk of relapse of Alzheimer's disease agitation (ADA) compared to placebo.

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