Bupropion dosage form that reduces the effects of diet and alcohol intake

Abstract

The present disclosure relates to dosage forms comprising bupropion hydrochloride, other salt forms of bupropion, or the free base form of bupropion, and a polymer, the dosage forms further comprising dextromethorphan hydrobromide, other salt forms of dextromethorphan, or the free base form of bupropion. In some embodiments, the dosage form does not exhibit significant dose dumping of bupropion in vitro in the presence of ethanol. In some embodiments, the dosage form is not affected by food with respect to bupropion when administered with a high-fat meal in a human subject. Some embodiments include methods of treating symptoms of the nervous system (e.g., depression such as major depressive disorder including treatment-resistant depression, agitation associated with Alzheimer's disease (or agitation associated with Alzheimer's type dementia), agitation associated with dementia, anxiety (or generalized anxiety disorder), neuropathic pain, or peripheral diabetic neuropathic pain), the method comprising administering a dosage form described herein to a human in need thereof.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 357,521, filed on June 30, 2022; U.S. Provisional Patent Application No. 63 / 370,590, filed on August 5, 2022; and U.S. Provisional Patent Application No. 63 / 370,771, filed on August 8, 2022, and this application is also a continuation of 18 / 157,393, filed on January 20, 2023, the entire disclosure of which is incorporated herein by reference.

[0002] (Technical Field) The present disclosure relates to dosage forms containing bupropion, optionally in the presence of dextromethorphan, and the use of these dosage forms for various therapeutic purposes.

Summary of the Invention

Means for Solving the Problems

[0003] The present disclosure relates to dosage forms containing bupropion hydrochloride, other salt forms of bupropion, or the free base form of bupropion, and a polymer, and dextromethorphan hydrobromide, other salt forms of dextromethorphan, or the free base form of dextromethorphan. In some embodiments, the dosage form does not exhibit significant dose dumping of bupropion in vitro in the presence of ethanol. In some embodiments, the dosage form is not affected by food with respect to bupropion when taken with a high - fat meal in a human subject. In some embodiments, the dosage form is not affected by food with respect to dextromethorphan when taken with a high - fat meal in a human subject.

[0004] Some embodiments include a dosage form comprising 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form or free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form or free base form of dextromethorphan, and a polymer, the dosage form showing no significant dose dumping of bupropion in vitro in the presence of ethanol.

[0005] Some embodiments include methods of treating a condition of the nervous system (such as depression (e.g., major depressive disorder including treatment-resistant depression), agitation associated with Alzheimer's disease (or agitation associated with Alzheimer's type dementia), agitation associated with dementia, anxiety (or generalized anxiety disorder), neuropathic pain, or peripheral diabetic neuropathic pain), the method comprising administering to a human patient in need thereof the dosage form once or twice daily, the dosage form comprising 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form or free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form or free base form of dextromethorphan, and a polymer, the dosage form showing no significant dose dumping of bupropion in vitro in the presence of ethanol.

[0006] Some embodiments include methods of treating a symptom of the nervous system (such as depression (e.g., major depressive disorder), agitation associated with Alzheimer's disease (or agitation associated with Alzheimer's type dementia), agitation associated with dementia, anxiety (or generalized anxiety disorder), neuropathic pain, or peripheral diabetic neuropathic pain), the method comprising administering to a human patient in need thereof who has consumed alcohol on the day of administration of the dosage form once or twice daily, the dosage form comprising 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form or free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form or free base form of dextromethorphan, and a polymer.

[0007] Some embodiments include a method of treating neurological symptoms (such as depression, e.g., major depressive disorder, agitation associated with Alzheimer's disease (or agitation associated with Alzheimer's type dementia), agitation associated with dementia, anxiety (or generalized anxiety disorder), neuropathic pain, or peripheral diabetic neuropathic pain, etc.) in a human patient who consumes alcohol. The method includes administering a dosage form to a human patient in need thereof once or twice a day, and including reducing but not ceasing alcohol consumption by the human patient. The dosage form includes 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer.

[0008] Some embodiments include a method of treating neurological symptoms (such as depression, e.g., major depressive disorder, agitation associated with Alzheimer's disease (or agitation associated with Alzheimer's type dementia), agitation associated with dementia, anxiety (or generalized anxiety disorder), neuropathic pain, or peripheral diabetic neuropathic pain, etc.) in a human patient who consumes alcohol. The method includes administering a dosage form to a human patient in need thereof once or twice a day, and including reducing but not ceasing alcohol consumption by the human patient. The dosage form includes 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer.

[0009] Some embodiments include a method of treating neurological symptoms (such as depression, e.g., major depressive disorder, agitation associated with Alzheimer's disease (or agitation associated with Alzheimer's type dementia), agitation associated with dementia, anxiety (or generalized anxiety disorder), neuropathic pain, or peripheral diabetic neuropathic pain, etc.) in a human patient who is consuming alcohol. This method includes administering a dosage form once or twice a day to a human patient in need thereof, and minimizing but not ceasing alcohol consumption by the human patient. The dosage form includes 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer.

[0010] Some embodiments include a method of treating major depressive disorder in an adult human patient who is consuming alcohol. This method includes administering a dosage form once or twice a day to a human patient in need thereof. The dosage form includes 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer. When the human patient is male, the human patient consumes no more than 2 drinks of alcohol per day. When the human patient is female, the human patient consumes no more than 1 drink of alcohol per day.

[0011] Some embodiments include a method of treating major depressive disorder, which includes administering the dosage form described herein to a human in need thereof. In some embodiments, the dosage form is taken with an alcoholic beverage. In some embodiments, the dosage form is taken with a high-fat meal.

Mode for Carrying Out the Invention

[0012] Dose dumping is a phenomenon in which a relatively large amount of drug in a controlled-release formulation is rapidly released, potentially introducing toxic amounts of drug into the systemic circulation.

[0013] The pharmaceutical compositions or dosage forms described herein may contain or be prepared from bupropion in any suitable form, such as a salt form, e.g., bupropion hydrochloride form, free base form, hydrate form, solvate form, polymorphic form, other solid forms, etc. In some embodiments, the pharmaceutical composition does not contain any other active pharmaceutical agent.

[0014] The pharmaceutical dosage form can contain any suitable amount of bupropion, such as about 90 - 100 mg, about 100 - 110 mg, about 110 - 120 mg, about 103 - 107 mg, or about 105 mg, in the form of bupropion hydrochloride, in a molar equivalent amount of other salt forms of bupropion, or in the free base form of bupropion.

[0015] The chemical name of bupropion hydrochloride is (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The empirical formula of bupropion hydrochloride is C 13 H 18 ClNO·HCl, and the molecular weight is 276.2 (bupropion base 239.74). The structural formula is as follows.

Chem.

[0016] Bupropion hydrochloride powder is white and very soluble in water.

[0017] The pharmaceutical compositions or dosage forms described herein may contain or be prepared from dextromethorphan in any suitable form, such as a salt form, e.g., dextromethorphan hydrochloride form, free base form, hydrate form, solvate form, polymorphic form, other solid forms, etc. In some embodiments, the pharmaceutical composition does not contain any other active pharmaceutical agent.

[0018] The pharmaceutical dosage form can contain, for example, any suitable amount of dextromethorphan, such as about 30 - 60 mg, about 30 - 50 mg, about 30 - 34 mg, about 34 - 38 mg, about 38 - 42 mg, about 42 - 46 mg, about 46 - 50 mg, about 40 - 45 mg, about 45 - 50 mg, about 44 - 46 mg, or about 45 mg, for example, bupropion hydrochloride, other salt forms of dextromethorphan in molar equivalent amounts, or the free base form of dextromethorphan.

[0019] The chemical name of dextromethorphan hydrobromide is Morphinan, 3-methoxy-17-methyl-, (9α,13α,14α), hydrobromide monohydrate. The empirical formula of dextromethorphan hydrobromide is C 18 H 25 NO·HBr·H2O, and the molecular weight is 370.33 (dextromethorphan base 271.4). The structural formula is as follows. [Chemical formula]

[0020] Dextromethorphan hydrobromide powder is white or almost white, crystalline, and hardly soluble in water.

[0021] In some embodiments, the dosage form can contain bupropion and dextromethorphan and can be free of other active pharmaceutical ingredients. In some embodiments, bupropion and dextromethorphan are in two different layers or phases of the dosage form. For example, each layer contains only bupropion or dextromethorphan and no other substances.

[0022] The pharmaceutical composition or dosage form can contain, for example, about 30 - 100 mg, or about 50 - 100 mg of cysteine (such as L-cysteine), for example, L-cysteine hydrochloride, other salt forms of L-cysteine, or the neutral or zwitterionic form of L-cysteine. These amounts of cysteine can help stabilize bupropion in the presence of other excipients.

[0023] The pharmaceutical composition or dosage form may further comprise a crosslinked or non-crosslinked acrylate polymer or copolymer (including poly(acrylic acid) or poly(alkacrylic acid), such as poly(methacrylic acid), such as Carbomer homopolymer type A like Carbopol 971P), a cellulose derivative, such as a sustained release or controlled release polymer like methylcellulose. In some embodiments, the controlled release polymer (such as Carbomer copolymer type A) is about 1 to 40%, about 1 to 5%, about 5 to 10%, about 10 to 15%, about 15 to 20%, about 20 to 30%, about 30 to 40%, about 11 to 13%, or about 12% of the weight of the pharmaceutical composition. In some embodiments, the controlled release polymer is about 0.1 to 20%, about 0.1 to 2%, about 2 to 4%, about 4 to 6%, about 6 to 8%, about 8 to 10%, about 10 to 15%, about 15 to 20%, or about 7% of the weight of the dosage form.

[0024] The pharmaceutical composition or dosage form may further comprise a filler such as microcrystalline cellulose. In some embodiments, the filler may be about 20 to 60%, about 20 to 30%, about 30 to 40%, about 40 to 50%, or about 50 to 60% of the weight of the pharmaceutical composition or dosage form.

[0025] The pharmaceutical composition or dosage form may further comprise a lubricant such as magnesium stearate. In some embodiments, the lubricant is about 0.1 to 10%, about 0.1 to 2%, about 2 to 4%, about 4 to 6%, about 6 to 8%, or about 8 to 10% of the weight of the pharmaceutical composition or dosage form.

[0026] The dosage form can be formulated according to a suitable route of administration such as oral administration.

[0027] Dosage forms such as solid dosage forms such as capsules, tablets, or pills for oral administration may contain one or more of binders such as gum tragacanth, acacia, corn starch, gelatin, additives such as dicalcium phosphate, disintegrants such as corn starch, potato starch, alginic acid, sweeteners such as sucrose, lactose, saccharin, or flavoring forms such as peppermint, wintergreen oil, or cherry flavor. When the dosage form is a capsule, in addition to the materials of the above type, a liquid carrier may be included. Various other materials may be present as coatings, for example, tablets, pills, capsules may be coated with shellac, sugar, or both. The materials in the dosage form or pharmaceutical composition may desirably be pharmaceutically pure and non-toxic in the amounts used.

[0028] In some embodiments, the dosage form comprises cysteine, carbopol 971P, microcrystalline cellulose, silicon dioxide, and magnesium. In some embodiments, the dosage form comprises a first layer comprising bupropion and cysteine, and a second layer comprising dextromethorphan, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0029] Examples of single-layer dosage forms are shown below.

[0030] (Layer 1) [Table 1]

[0031] Two-layer dosage forms may include a first layer (Layer 1) of the above composition and a second layer (Layer 2) described in detail below.

[0032] (Layer 2) [Table 2]

[0033] In some embodiments, the dosage form is for oral administration and can be a round bilayer tablet. Each tablet can contain 45 mg of dextromethorphan hydrobromide (equivalent to 32.98 mg of dextromethorphan base) as an immediate-release formulation and 105 mg of bupropion hydrochloride (equivalent to 91.14 mg of bupropion base) as a sustained-release formulation. Each tablet can further contain any or all of the following inactive ingredients. Carbomer homopolymer, colloidal silicon dioxide, crospovidone, glyceryl monocaprylocaprate, 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. The pharmaceutical compositions or dosage forms described herein can be useful for the treatment of neurological or psychiatric symptoms such as depression, including major depressive disorder or treatment-resistant major depressive disorder, agitation such as agitation associated with Alzheimer's disease, and intoxication such as nicotine intoxication. For example, the pharmaceutical composition of the dosage form can be administered once or twice a day to a human suffering from neurological or psychiatric symptoms. The treatment can be continued as needed as long as the treatment is effective and safe, for example, for at least 1 week, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year, from 1 week to 2 months, 1 to 3 months, 3 to 6 months, 6 to 12 months, 1 to 2 years, or longer.

[0034] The US Food and Drug Administration (FDA) is concerned about the dose dumping of bupropion hydrochloride when taken with ethanol, and currently, the FDA requires the dissolution test of dosage forms containing bupropion to be conducted using various concentrations of ethanol in the dissolution medium as follows.

[0035] Test conditions: 900 mL, 0.1 N HCl, USP Apparatus 2 (paddle) 50 rpm, with or without ethanol. Test 1: Test 12 units according to the proposed method (with 0.1 N HCl) and collect data every 15 minutes for a total of 2 hours. Test 2: Replace 5% (v / v) of the test medium with Alcohol USP (ethanol) and analyze 12 units, collecting data every 15 minutes over a total of 2 hours. Test 3: Replace 20% (v / v) of the test medium with Alcohol USP (ethanol) and analyze 12 units, collecting data every 15 minutes over a total of 2 hours. Test 4: Replace 40% (v / v) of the test medium with Alcohol USP (ethanol) and analyze 12 units, collecting data every 15 minutes over a total of 2 hours.

[0036] According to the FDA, it is necessary to properly test both the test product and the reference product and provide data on individual units, averages, ranges, and %CV for both concentrations. (FDA Draft Guidance on Bupropion Hydrochloride, p. 2.)

[0037] (Example from the literature) According to FDA documents, the bupropion product ForfivoXL was tested for ethanol dose dumping. (Center for Drug Evaluation and Research, Application No. 022497Orig1s000), CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) (the "Forfivo Resubmission"), p. 17.) In the Forfivo resubmission documents, it is disclosed that Forfivo contains bupropion hydrochloride, hydroxypropyl cellulose, hydrochloric acid, polyethylene oxide, stearic acid, colloidal silicon dioxide, magnesium stearate, methacrylic acid copolymer, talc, polyethylene glycol (PEG) 8000, titanium dioxide (TiO2), and sodium carboxymethyl cellulose (NaCMC). (Forfivo Resubmission, p. 10). The Forfivo resubmission further reports that the above experiment was also conducted on BUP450XL tablets. According to the resubmission of Forfivo, "After 2 hours, no bupropion HCl dissolved from the BUP450XL tablets was confirmed at an alcohol concentration of 0%. When 20% alcohol was present, it was confirmed that 7% of bupropion HCl dissolved from the BUP450XL tablets within 2 hours. When 40% alcohol was present, it was confirmed that 22% (in the range of 16 - 25%) of bupropion HCl dissolved from the BUP450XL tablets within 2 hours. This drug shows dose dumping when used in combination with alcohol in vitro." (p. 17)

[0038] According to the label of CONTRAVE, when a dosage form containing 8 mg of naltrexone HCl, 90 mg of bupropion HCl, microcrystalline cellulose, hydroxypropyl cellulose, anhydrous lactose, L-cysteine hydrochloride, crospovidone, magnesium stearate, hypromellose, disodium edetate, lactose monohydrate, colloidal silicon dioxide, Opadry II Blue, and FD&C Blue #2 aluminum lake was administered with a high-fat meal, the AUC and C max of naltrexone increased by 2.1-fold and 3.7-fold, respectively, and the AUC and C maxThey increased 1.4 - fold and 1.8 - fold respectively. At steady state, due to the effect of diet, the AUC and C of naltrexone max increased 1.7 - fold and 1.9 - fold respectively, and the AUC and C of bupropion max increased 1.1 - fold and 1.3 - fold respectively. Therefore, the label states that since the systemic exposure of bupropion and naltrexone increases significantly, CONTRAVE should not be taken with a high - fat meal.

[0039] The subject combination can be used for the adjunctive treatment of major depressive disorder or depression.

[0040] In addition to major depressive disorder, the subject combination can be used to treat other diseases of symptoms in the patient populations or situations described herein. For example, the subject combination can be used to treat pain and neuropathy. Examples of neurological diseases treated with the subject combination include, but are not limited to, mood disorders, mental disorders, brain function disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, headaches, etc.

[0041] Mood disorders that can be treated by the subject combination include, but are not limited to, depression, major depression, treatment - resistant depression, treatment - resistant bipolar depression, bipolar disorder including cyclothymic disorder, seasonal affective disorder, mood disorder, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorder, attention - deficit disorder (ADD), attention - deficit / hyperactivity disorder (ADHD), attention - deficit hyperactivity disorder (AD / HD), bipolar disorder and manic symptoms, obsessive - compulsive disorder, bulimia nervosa, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug intoxication or abuse, nicotine intoxication, psychotic dysfunction, emotional regulation disorder, emotional lability.

[0042] Depression can be manifested by depressive symptoms. These symptoms may include, for example, mood changes, intense feelings of sadness, despair, decreased mental activity, reduced concentration, pessimistic worry, excitement, anxiety, hyperactivity, guilt, anger, worthlessness, reckless behavior, suicidal thoughts or attempts, and / or humiliation. The physical symptoms of depression may include insomnia, anorexia, loss of appetite, weight loss, weight gain, decreased activity and libido, fatigue, restlessness, tingling, pain, headache, convulsions, digestive problems, and / or abnormal hormonal circadian rhythms.

[0043] The mental disorders treated by the combination of the subject matter may include, but are not limited to, anxiety disorders (including but not limited to anxiety disorders), phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, apathy, 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, delusional disorder, schizoaffective disorder, schizotypal aggression, aggression in Alzheimer's disease, agitation in Alzheimer's disease, and excitement. Alzheimer's disease may also be referred to as Alzheimer's type dementia. Other neurobehavioral symptoms of Alzheimer's disease that may be treated may include disinhibition and apathy.

[0044] The agitation in Alzheimer's disease occurs as the disease progresses. The agitation may be manifested as inappropriate words, emotions, and / or physical behaviors. Inappropriate actions may include incoherent babbling, inappropriate emotional responses, demands for attention, threats, hyperactivity, dissatisfaction, screaming, repeating questions, mood swings, scolding, swear words, physical outbursts, emotional distress, restlessness, disruption, sleep disorders, delusions, hallucinations, pacing, wandering, searching, searching everywhere, repeating body movements, huddling, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and / or kicking, but are not limited to these.

[0045] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral and psychological symptoms including agitation. AD is the most common form of dementia, affecting an estimated 6 million patients in the United States, and the number is expected to increase to approximately 14 million by 2050. Agitation is reported in up to 70% of AD patients and is characterized by emotional distress, aggressive behavior, disruptive hyperactivity, and disinhibition. In AD, the management of agitation is a priority. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, early placement in nursing facilities, and increased mortality. Currently, there is no FDA-approved treatment for agitation in AD patients.

[0046] Neurobehavioral symptoms are known to occur during dementia and may be treatable with this combination. Caregivers or family may be overwhelmed by the patient's behavioral and psychological symptoms rather than the cognitive impairment. The common forms of this syndrome are a series of disorders that contribute to Alzheimer's disease, vascular dementia, Lewy body dementia (aggregates of abnormal proteins that occur within nerve cells), and frontotemporal dementia (degeneration of the frontal lobe of the brain). The symptoms of dementia patients are similar to those of mental disorders, but some are slightly different from each other. Neurobehavioral symptoms associated with dementia include depression, apathy, excitability, disinhibition, hallucinations, delusions, psychosis, impulsivity, aggression, impulsive-compulsive behavior, hypersexuality, and personality disorders. Neurobehavioral symptoms such as disinhibition may also be seen in other conditions such as brain injury.

[0047] Agitation in Alzheimer's disease patients can be evaluated using the Cohen-Mansfield Agitation Inventory or the CMAI. The CMAI evaluates various behaviors such as hitting (including self), kicking, grabbing at people, pushing, throwing objects, biting, scratching, spitting, hurting oneself or others, tearing objects, or causing property damage, physical sexual advances, pacing, aimless wandering, inappropriate dressing or undressing, attempting to go to another place, intentional falls, eating or drinking inappropriate substances, inappropriately handling things, hiding things, hoarding things, repeatedly performing mannerisms, overall restlessness, shouting, verbal sexual solicitation, verbal abuse or attacks, repeated statements or questions, strange sounds (strange laughter or crying), complaining, refusal disorder, constantly seeking inappropriate attention or help, etc.

[0048] Schizophrenia can be treated in combinations that include positive and / or negative symptoms of schizophrenia, or residual symptoms of schizophrenia. Other symptoms that can be treated include intermittent explosive disorder.

[0049] Brain dysfunctions that can be treated by combinations of the subject matter include, but are not limited to, disorders associated with intellectual impairments such as senile dementia, Alzheimer's type dementia, memory loss, amnesia / amnesic syndrome, epilepsy, disturbance of consciousness, coma, decreased attention, speech disorder, tremor of the voice, Parkinson's disease, Lennox-Gastaut syndrome, autism, attention deficit hyperactivity disorder, schizophrenia, etc. Brain dysfunctions also include disorders caused by cerebrovascular disorders such as stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head trauma, etc., and their symptoms include disturbance of consciousness, senile dementia, coma, decreased attention, and speech disorder.

[0050] Substance use disorders treatable by the combination of the subject matter include drug dependence, cocaine intoxication, stimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anti-anxiety and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine intoxication includes all known forms of nicotine intoxication, such as tobacco, cigars and / or pipes, smoking of e-cigarettes and vaping, and intoxication with chewing tobacco.

[0051] Movement disorders treatable by the combination of the subject matter include, but are not limited to, akathisia, akinesia, associated movement, athetoid, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's chorea, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, Tourette syndrome, and Wilson's disease.

[0052] Dementias treatable by the combination of the subject matter 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-Korsakoff syndrome, Pick's disease, etc.

[0053] Motor neuron diseases treatable by the combination of the subject matter 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.

[0054] Neurodegenerative diseases that can be treated by the combination of the subject matter include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedreich'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, autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontine cerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, spastic paraplegia, etc.

[0055] Seizure disorders that can be treated by the combination of the subject matter include, but are not limited to, epileptic seizures, non-epileptic seizures, epilepsy, febrile convulsions, partial seizures including simple partial seizures - Jacksonian seizures - complex partial seizures - continuous partial epilepsy, generalized tonic-clonic seizures - absence seizures - atonic seizures - myoclonic seizures - juvenile myoclonic seizures - infantile spasms, and status epilepticus.

[0056] Types of headaches that can be treated by the combination of the subject matter include, but are not limited to, migraine, tension, and cluster headache.

[0057] Other neurological disorders that can be treated by the combination of the subject matter include, but are not limited to, Rett syndrome, autism, tinnitus, disturbances of consciousness disorders, sexual dysfunction, intractable cough, narcolepsy, cataplexy, vocal disorders due to uncontrollable laryngeal muscle spasms including abductor spastic dysphonia · adductor spastic dysphonia · muscle tension dysphonia · vocal tremor, diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity, incontinence including stress urinary incontinence · urge urinary incontinence · fecal incontinence, and erectile dysfunction.

[0058] In some embodiments, the combination of the subject matter can be used for the treatment of pain, arthralgia, pain associated with sickle cell disease, mood regulation disorders, depression (including treatment-resistant depression), disorders related to memory and cognition, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), etc.

[0059] In some embodiments, the combination of the subject matter can be orally administered to reduce pain associated with musculoskeletal pain including low back pain, and pain associated with osteoarthritis · juvenile idiopathic arthritis · osteoarthritis deformans · erosive osteoarthritis · seronegative (non-rheumatic) arthropathy · non-articular rheumatism · periarticular disorders · axial spondyloarthritis including ankylosing spondylitis · Paget's disease · fibrous dysplasia · SAPHO syndrome · transient coxarthrosis · vertebral compression fractures · osteoporosis, etc.

[0060] In some embodiments, the combination of the subject matter can be administered to reduce inflammatory pain such as musculoskeletal pain, arthritis pain, complex regional pain syndrome, etc.

[0061] Arthritis refers to an inflammatory joint disease that may be accompanied by pain. Examples of arthritis pain include pain associated with osteoarthritis deformans, erosive osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, periarticular disorders, neuropathic arthropathy such as Charcot foot, axial spondyloarthritis such as ankylosing spondylitis, and pain associated with SAPHO syndrome.

[0062] In some embodiments, the combination of the subject is used to treat chronic musculoskeletal pain.

[0063] In some embodiments, the composition of the subject may be administered to reduce 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 may also include elements of neuropathy. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the extremities that may be accompanied by edema and autonomic, motor, and sensory changes.

[0064] In some embodiments, the composition of the subject may be orally administered to reduce neuropathic pain.

[0065] Examples of neuropathic pain include pain due to diabetic peripheral neuropathy or diabetic peripheral neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, pain due to multiple sclerosis, etc. Other causes of neuropathic pain include cancer pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, radiation or chemotherapy-related neuropathy, etc.

[0066] In some embodiments, the composition of the subject may be administered to reduce fibromyalgia.

[0067] The term "treating" or "treatment" includes diagnosing, curing, alleviating, treating, or preventing a disease in a human or other animal, or other activities that affect the structure or function of the body of a human or other animal.

[0068] The combination of the subject matter can be used for the treatment of any disease or condition that has been identified as treatable by the combination of bupropion and dextromethorphan in any of the following U.S. patents.U.S. Patent No. 8,569,328, U.S. Patent No. 9,168,234, U.S. Patent No. 9,189,905, U.S. Patent No. 9,205,083, U.S. Patent No. 9,238,032, U.S. Patent No. 9,278,095, U.S. Patent No. 9,314,462, U.S. Patent No. 9,370,513, U.S. Patent No. 9,375,429, U.S. Patent No. 9,408,815, U.S. Patent No. 9,421,176, U.S. Patent No. 9,457,023, U.S. Patent No. 9,457,025, U.S. Patent No. 9,474,731, U.S. Patent No. 9,486,450, U.S. Patent No. 9,700,528, U.S. Patent No. 9,700,553, U.S. Patent No. 9,707,191, U.S. Patent No. 9,763,932, U.S. Patent No. 9,861,595, U.S. Patent No. 9,867,819, U.S. Patent No. 9,968,568, U.S. Patent No. 10,058,518, U.S. Patent No. 10,064,857, U.S. Patent No. 10,080,727, U.S. Patent No. 10,092,560, U.S. Patent No. 10,092,561, U.S. Patent No. 10,105,327, U.S. Patent No. 10,105,361, U.S. Patent No. 10,251,879, U.S. Patent No. 10,463,634, U.S. Patent No. 10,512,643, U.S. Patent No. 10,548,857, U.S. Patent No. 10,596,167, U.S. Patent No. 10,772,850, U.S. Patent No. 10,780,064, U.S. Patent No. 10,780,066, U.S. Patent No. 10,786,469, U.S. Patent No. 10,786,496, U.S. Patent No. 10,799,497, U.S. Patent No. 10,806,710, U.S. Patent No. 10,864,209, U.S. Patent No. 10,874,663, U.S. Patent No. 10,874,664, U.S. Patent No. 10,874,665, U.S. Patent No. 10,881,624, U.S. Patent No. 10,881,657, U.S. Patent No. 10,894,046, U.S. Patent No. 10,894,047, U.S. Patent No. 10,898,453. All of these are hereby incorporated by reference herein in their entirety for the disclosure of diseases treatable by the combination of bupropion and dextromethorphan, including the specific embodiments and combinations described therein.

[0069] As shown in the following examples, in the combination of the subject matter, dose dumping of bupropion does not occur in vitro in the presence of ethanol. As a result, patients can use alcohol as long as they minimize or limit their use. For example, adult women can consume less than one drink per day (one drink per day, less than four drinks per week, less than three drinks per week, less than one drink per week, less than one drink per month, less than one drink per year, etc.), and adult men can consume less than two drinks per day (two drinks per day, one drink per day, less than four drinks per week, less than three drinks per week, less than one drink per week, less than one drink per month, less than one drink per year, etc.).

[0070] (Example 1) For the two-layer dosage form having layer 1 and layer 2 as described above, the dose dumping by ethanol was tested as described above. Dose dumping of bupropion in the presence of ethanol in vitro was not confirmed.

[0071] (Example 2) For the two-layer dosage form having the first layer and the second layer as described above, the dosage form was administered to human subjects together with a high-fat meal, and the effect of the meal was tested by comparing with the values obtained when administered to fasting human subjects. No significant difference was confirmed between the two groups in either the AUC or C max of bupropion or dextromethorphan. max

[0072] U.S. Provisional Application No. 63 / 370,771, filed on August 8, 2022, is hereby incorporated by reference in its entirety.

[0073] ​Unless otherwise specified, all numerical values representing quantities, amounts, percentages, and other characteristics of the components used in the specification and claims are to be understood as indicating both the exact values shown and the values modified by the term "about" in all cases. Therefore, unless otherwise specified, the numerical parameters set forth in the specification and the appended claims are approximate values and may vary depending on the desired characteristics to be obtained. At least, rather than an attempt to limit the scope of the claims to the application of the doctrine of equivalents, each numerical parameter should be construed in light of the reported significant digits and by applying ordinary rounding techniques.

[0074] The use of the terms "comprising" or "comprises" in this specification is also intended to contemplate the use of "consisting essentially of," "consists essentially of," "onsisting of," or "consists of" instead.

[0075] Any affirmative statement of an element anywhere in this specification should be understood as intending to encompass both the inclusion and the exclusion of that element.

[0076] The terms "a," "an," "the," and similar referents used in the context of describing embodiments (particularly in the context of the following claims) are to be construed to include both the singular and the plural, unless otherwise stated herein or clearly contradicted by the context. All methods described herein can be performed in any suitable order, unless otherwise stated herein or clearly contradicted by the context. The use of any examples, or exemplary language (such as "such as") provided herein is intended merely to more clearly illustrate the embodiments and is not intended to impose any limitation on any claims. The language of the specification should not be construed as indicating any non-claimed element essential to the practice of the claims.

[0077] The grouping of alternative elements or embodiments disclosed herein should not be construed as limiting. Each group member can be referred to and claimed individually, or in combination with other members of the group or other elements described herein. For reasons of convenience or to expedite prosecution, it is contemplated that one or more members of the group may be included in or deleted from the group. In the event of such inclusion or deletion, the specification is considered to include the modified group, thereby satisfying the description of all Markush groups used in the appended claims.

[0078] This specification describes certain embodiments that include the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations of these described embodiments will be apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to adopt such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced in a manner different from that specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims to the extent permitted by applicable law. Further, any combination of any possible variations of the above-described elements is contemplated unless otherwise stated herein or clearly contradicted by context.

[0079] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Accordingly, alternative embodiments may be utilized in accordance with the teachings of this specification, but are not limited thereto. Accordingly, the claims are not strictly limited to the embodiments as illustrated and described.

[0080] (Appendix) (Appendix 1) 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer, and a dosage form comprising the same.

[0081] (Appendix 2) The dosage form according to Appendix 1, wherein the polymer comprises poly(acrylic acid), poly(alkacrylic acid), or a combination or copolymer thereof.

[0082] (Appendix 3) The dosage form according to Appendix 1 or 2, wherein the dextromethorphan is an immediate-release formulation and the bupropion is a sustained-release formulation.

[0083] (Appendix 4) A method for treating symptoms of the nervous system, comprising administering the dosage form to a human patient in need of treatment twice a day, wherein the dosage form comprises 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer, and wherein the dosage form does not exhibit significant dose dumping of bupropion in vitro in the presence of ethanol.

[0084] (Appendix 5) A method for treating symptoms of the nervous system, comprising administering the dosage form to a human patient in need of treatment twice a day on a day when the patient has ingested alcohol, wherein the dosage form comprises 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer.

[0085] (Appendix 6) A method for treating neurological symptoms in a human patient who is consuming alcohol, comprising administering a dosage form to a human patient in need of treatment twice a day, and restricting but not ceasing alcohol consumption by said human patient, wherein said dosage form comprises 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer.

[0086] (Appendix 7) A method for treating neurological symptoms in a human patient who is consuming alcohol, comprising administering a dosage form to a human patient in need of treatment twice a day, and reducing but not ceasing alcohol consumption by said human patient, wherein said dosage form comprises 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer.

[0087] (Appendix 8) A method for treating neurological symptoms in a human patient who is consuming alcohol, comprising administering a dosage form to a human patient in need of treatment twice a day, and minimizing but not ceasing alcohol consumption by said human patient, wherein said dosage form comprises 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer.

[0088] (Appendix 9) A method for treating neurological symptoms in adult human patients who consume alcohol, comprising administering a dosage form twice a day to a human patient who consumes alcohol and requires treatment, wherein the dosage form comprises 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer. When the human patient is male, the human patient consumes no more than 2 drinks of alcohol per day. When the human patient is female, the human patient consumes no more than 1 drink of alcohol per day.

[0089] (Appendix 10) The method according to any one of Appendices 4 to 9, wherein the polymer comprises poly(acrylic acid), poly(alkacrylic acid), or a combination or copolymer thereof.

[0090] (Appendix 11) The method according to any one of Appendices 4 to 10, wherein the dextromethorphan is an immediate-release formulation and the bupropion is a sustained-release formulation.

[0091] (Appendix 12) The human patient is an adult male and the human patient consumes no more than 2 drinks of alcohol per day. The method according to any one of Appendices 4 to 11.

[0092] (Appendix 13) The human patient is an adult male and the human patient consumes no more than 1 drink of alcohol per day. The method according to any one of Appendices 4 to 11.

[0093] (Appendix 14) A method of treating symptoms of the nervous system, comprising administering a dosage form to a human in need of treatment, said dosage form being ingested by said human together with a high-fat diet, said dosage form comprising 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer.

[0094] (Appendix 15) The method according to any one of Appendices 4 to 14, wherein the symptoms of the nervous system are major depressive disorders.

[0095] (Appendix 16) The method according to any one of Appendices 4 to 14, wherein the symptoms of the nervous system are excitement associated with Alzheimer's disease.

[0096] (Appendix 17) The method according to any one of Appendices 4 to 14, wherein the symptoms of the nervous system are neuropathic pain.

[0097] (Appendix 18) The method according to any one of Appendices 4 to 14, wherein the symptoms of the nervous system are anxiety.

[0098] (Appendix 19) The dosage form according to any one of Appendices 1 to 3, wherein the dosage form does not show significant dose dumping of bupropion in vitro in the presence of ethanol.

[0099] (Appendix 20) The dosage form according to any one of Appendices 1 to 3, 19, wherein the dosage form is not affected by food for bupropion when ingested by a human subject together with a high-fat diet.

[0100] (Appendix 21) The dosage form is the dosage form according to any one of Appendices 1 to 3, 19, and 20, which is not affected by food with respect to dextromethorphan when taken by a human subject together with a high-fat diet.

Claims

1. 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer, and a dosage form comprising the same.

2. The dosage form according to claim 1, wherein the polymer comprises poly(acrylic acid), poly(alkacrylic acid), or a combination or copolymer thereof.

3. The dosage form according to claim 1 or 2, wherein the dextromethorphan is an immediate release formulation and the bupropion is a sustained release formulation.

4. A method of treating a neurological condition, comprising administering the dosage form twice a day to a human patient in need of treatment, the dosage form comprising 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer, and wherein the dosage form does not exhibit significant dose dumping of bupropion in vitro in the presence of ethanol.

5. A method of treating a neurological condition, comprising administering the dosage form twice a day to a human patient in need of treatment who has consumed alcohol on the day of administration of the dosage form, the dosage form comprising 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer.

6. A method for treating neurological symptoms in a human patient who consumes alcohol, comprising administering a dosage form to a human patient in need of treatment twice a day, and restricting but not abstaining from alcohol consumption by said human patient, wherein said dosage form comprises 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer.

7. A method for treating neurological symptoms in a human patient who consumes alcohol, comprising administering a dosage form to a human patient in need of treatment twice a day, and reducing but not abstaining from alcohol consumption by said human patient, wherein said dosage form comprises 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer.

8. A method for treating neurological symptoms in a human patient who consumes alcohol, comprising administering a dosage form to a human patient in need of treatment twice a day, and minimizing but not abstaining from alcohol consumption by said human patient, wherein said dosage form comprises 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer.

9. A method for treating neurological symptoms in adult human patients who consume alcohol, comprising administering a dosage form twice a day to a human patient in need of treatment, said dosage form comprising 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer, wherein when the human patient is male, the human patient consumes no more than 2 drinks of alcohol per day, and when the human patient is female, the human patient consumes no more than 1 drink of alcohol per day. **Claim 10** The method according to any one of claims 4 to 9, wherein the polymer comprises poly(acrylic acid), poly(alkacrylic acid), or a combination or copolymer thereof. **Claim 11** The method according to any one of claims 4 to 10, wherein the dextromethorphan is an immediate release formulation and the bupropion is a sustained release formulation. **Claim 12** The method according to any one of claims 4 to 11, wherein the human patient is an adult male and the human patient consumes no more than 2 drinks of alcohol per day. **Claim 13** The method according to any one of claims 4 to 11, wherein the human patient is an adult male and the human patient consumes no more than 1 drink of alcohol per day. **Claim 14** A method for treating neurological symptoms, comprising administering a dosage form to a human in need of treatment, said dosage form being taken by the human with a high-fat meal, said dosage form comprising 105 mg of bupropion hydrochloride, or a molar equivalent amount of another salt form of bupropion or the free base form of bupropion, 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of another salt form of dextromethorphan or the free base form of dextromethorphan, and a polymer. **Claim 15** The method according to any one of claims 4 to 14, wherein the neurological symptom is a major depressive disorder. **Claim 16** The method according to any one of claims 4 to 14, wherein the neurological symptom is excitement associated with Alzheimer's disease. **Claim 17** The method according to any one of claims 4 to 14, wherein the symptom of the nervous system is neuropathic pain.

18. The method according to any one of claims 4 to 14, wherein the symptom of the nervous system is anxiety.

19. The dosage form according to any one of claims 1 to 3, wherein the dosage form does not show significant dose dumping of bupropion in vitro in the presence of ethanol.

20. The dosage form according to any one of claims 1 to 3, 19, wherein the dosage form is not affected by food with respect to bupropion when administered to a human subject with a high-fat meal.

21. The dosage form according to any one of claims 1 to 3, 19, 20, wherein the dosage form is not affected by food with respect to dextromethorphan when administered to a human subject with a high-fat meal.

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