Bupropion dosage forms with reduced food and alcohol dosage effects

Abstract

The present disclosure relates to dosage forms comprising bupropion hydrochloride, bupropion in the form of another salt or bupropion in the form of a free base; dextromethorphan hydrobromide, dextromethorphan in the form of another salt or dextromethorphan in the form of a free base; and a polymer. In some embodiments, the dosage form does not have significant dose dumping of bupropion in vitro in the presence of ethanol. In some embodiments, the dosage form does not have a food effect on bupropion or dextromethorphan when taken in a human subject with a high fat diet. Some embodiments include a method of treating a nervous system condition, such as depression (e.g., major depression, including refractory depression), agitation associated with Alzheimer's disease (or agitation associated with dementia of Alzheimer's type), agitation associated with dementia, anxiety (or generalized anxiety), neuropathic pain, or peridiabetic neuropathic pain, it comprises administering to a person in need thereof a dosage form described herein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] 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; this application is also a continuation of 18 / 157,393 filed on January 20, 2023; all applications are incorporated herein by reference in their entirety. Technical Field

[0003] 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

[0004] The present disclosure relates to dosage forms comprising bupropion hydrochloride, bupropion in another salt form, or bupropion in free base form; dextromethorphan hydrobromide, dextromethorphan in another salt form, or bupropion in free base form; and a polymer. In some embodiments, the dosage form does not have significant dose dumping of bupropion in vitro in the presence of ethanol. In some embodiments, the dosage form has no food effect on bupropion when taken with a high-fat meal in a human subject. In some embodiments, the dosage form has no food effect on dextromethorphan when taken with a high-fat meal in a human subject.

[0005] Some embodiments include a dosage form comprising: 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer, wherein the dosage form does not exhibit significant bupropion dose dumping in vitro in the presence of ethanol.

[0006] Some embodiments include a method of treating a neurological disorder (such as depression (e.g., major depressive disorder, including refractory 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 diabetic peripheral neuropathic pain), comprising administering a dosage form to a human patient in need thereof once daily or twice daily, wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer, and wherein the dosage form does not exhibit significant bupropion dose dumping in vitro in the presence of ethanol.

[0007] Some embodiments include a method of treating a neurological disorder (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 diabetic peripheral neuropathic pain), comprising administering a dosage form to a human patient in need thereof once daily or twice daily, wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer, and wherein the patient consumes alcohol on the day the dosage form is administered.

[0008] Some embodiments include a method of treating a neurological disorder (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 diabetic peripheral neuropathic pain) in a human patient who drinks alcohol, comprising administering a dosage form to a human patient in need thereof once daily or twice daily, and limiting but not stopping the human patient's alcohol consumption, wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer.

[0009] Some embodiments include a method of treating a neurological disorder (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 diabetic peripheral neuropathic pain) in a human patient who drinks alcohol, comprising administering a dosage form once daily or twice daily to a human patient in need thereof, and reducing but not stopping the human patient's alcohol consumption, wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer.

[0010] Some embodiments include a method of treating a neurological disorder (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 diabetic peripheral neuropathic pain) in a human patient who drinks alcohol, comprising administering a dosage form to a human patient in need thereof once daily or twice daily, and minimizing but not stopping the human patient's alcohol consumption, wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer.

[0011] Some embodiments include a method of treating major depressive disorder in an adult patient who drinks alcohol, comprising administering a dosage form to a human patient in need thereof once daily or twice daily, wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer; wherein if the human patient is a male, the human patient consumes two or fewer servings of alcohol per day; and if the human patient is a female, the human patient consumes one or fewer servings of alcohol per day.

[0012] Some embodiments include a method of treating major depressive disorder comprising administering a dosage form described herein to a person 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. DETAILED DESCRIPTION

[0013] Dose dumping is a phenomenon in which a relatively large amount of drug in a controlled-release formulation is released rapidly and potentially toxic amounts of the drug are introduced into the systemic circulation.

[0014] 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), a free base form, a hydrate, a solvate, a polymorph, other solid forms, etc. In some embodiments, the pharmaceutical composition does not contain any other active pharmaceutical agent.

[0015] 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 of bupropion, such as bupropion hydrochloride, a molar equivalent of bupropion in another salt form, or bupropion in free base form.

[0016] 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 (239.74 bupropion base). The structural formula is:

[0017]

[0018] Bupropion hydrochloride powder is white and readily soluble in water.

[0019] The pharmaceutical compositions or dosage forms described herein can contain or be prepared from dextromethorphan in any suitable form, such as a salt form (e.g., dextromethorphan hydrochloride), a free base form, a hydrate, a solvate, a polymorph, other solid forms, etc. In some embodiments, the pharmaceutical composition does not contain any other active pharmaceutical agent.

[0020] The pharmaceutical dosage form can contain 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 of dextromethorphan, such as dextromethorphan hydrochloride, a molar equivalent of another form of dextromethorphan, or dextromethorphan in free base form.

[0021] 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 (271.4 dextromethorphan base). The structural formula is:

[0022]

[0023] Dextromethorphan hydrobromide powder is white or almost white crystals and is slightly soluble in water.

[0024] In some embodiments, the dosage form can contain bupropion and dextromethorphan and no 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 does not include the other.

[0025] The pharmaceutical composition or dosage form may include cysteine ​​(e.g., L-cysteine), such as about 30-100 mg or about 50-100 mg cysteine, such as L-cysteine ​​hydrochloride, L-cysteine ​​in another salt form, or L-cysteine ​​in neutral or zwitterionic form. These amounts of cysteine ​​may help stabilize bupropion in the presence of other excipients.

[0026] The pharmaceutical composition or dosage form may further comprise a sustained release or controlled release polymer, such as a cross-linked or uncross-linked acrylate polymer or copolymer (including poly (acrylic acid) or poly (alkyl acrylic acid), such as poly (methacrylic acid), for example, carbomer homopolymer type A, such as Carbopol 971P), a cellulose derivative, such as methylcellulose, and the like. In some embodiments, the controlled release polymer (e.g., carbomer copolymer type A) accounts for about 1-40%, about 1-5%, about 5-10%, about 10-15%, about 15-20%, about 20-30%, about 30-40%, about 11-13%, or about 12% by weight of the pharmaceutical composition. In some embodiments, the controlled release polymer is about 0.1-20%, about 0.1-2%, about 2-4%, about 4-6%, about 6-8%, about 8-10%, about 10-15%, about 15-20%, or about 7% by weight of the dosage form.

[0027] The pharmaceutical composition or dosage form may also include a filler, such as microcrystalline cellulose. In some embodiments, the filler may be about 20-60%, about 20-30%, about 30-40%, about 40-50%, or about 50-60% by weight of the pharmaceutical composition or dosage form.

[0028] The pharmaceutical composition or dosage form may also include a lubricant, such as magnesium stearate. In some embodiments, the lubricant is about 0.1-10%, about 0.1-2%, about 2-4%, about 4-6%, about 6-8%, or about 8-10% by weight of the pharmaceutical composition or dosage form.

[0029] Dosage forms can be formulated for any suitable route of administration, such as oral administration.

[0030] Dosage forms for oral administration, such as solid dosage forms (e.g., capsules, tablets, or pills), may also contain one or more of the following: a binder such as gum tragacanth, gum arabic, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, alginic acid, etc.; a sweetener such as sucrose, lactose, or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage form is a capsule, it may contain a liquid carrier in addition to the above types of materials. Various other materials may be present as coatings, for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. It may be desirable that the materials in the dosage form or pharmaceutical composition be pharmaceutically pure and nontoxic in the amounts employed.

[0031] 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.

[0032] An example of a single-layer dosage form is shown below:

[0033] Tier 1

[0034] Element Amount (mg) Bupropion 90-120 Cysteine 30-100 Carbopol 971P 20-60 Microcrystalline cellulose 200-300 Colloidal Silica 1-10 Magnesium Stearate 1-10

[0035] The two-layer dosage form may comprise a first layer (Layer 1) having the composition shown above and a second layer (Layer 2) described in detail below.

[0036] Tier 2

[0037] Element Amount (mg) Dextromethorphan 30-60 Microcrystalline cellulose 100-150 Croscarmellose Sodium 1-20 Magnesium Stearate 1-10

[0038] In some embodiments, the dosage form can be used for oral administration and can be a round bilayer tablet. Each tablet can contain 45 mg dextromethorphan hydrobromide (equivalent to 32.98 mg dextromethorphan base) in an immediate release formulation and 105 mg bupropion hydrochloride (equivalent to 91.14 mg bupropion base) in an extended release formulation. Each tablet can also contain any or all of the following inactive ingredients: carbomer homopolymer, colloidal silicon dioxide, cross-linked polyvinylpyrrolidone, 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 composition or dosage form described herein can be used to treat neurological or psychiatric disorders, such as depression (including major depressive disorder or refractory major depressive disorder), agitation (such as agitation associated with Alzheimer's disease), addiction (such as nicotine addiction), etc. For example, the dosage form of the pharmaceutical composition can be administered once or twice a day to a person suffering from a neurological or psychiatric disorder. Where the treatment is effective and safe, the treatment can be continued as needed, e.g., for at least 1 week, at least 4 weeks, at least one month, at least 2 months, at least 3 months, at least 6 months, at least 1 year, 1 week to 2 months, 1-3 months, 3-6 months, 6-12 months, 1-2 years, or possibly longer.

[0039] Because of concerns by the U.S. Food and Drug Administration (FDA) about dose dumping of bupropion hydrochloride when taken with ethanol, the FDA currently requires that dosage forms containing bupropion be tested for dissolution using the following concentrations of ethanol in the dissolution medium:

[0040] Test conditions: 900 mL, 0.1 N HCl, USP Apparatus 2 (paddles), at 50 rpm, with or without ethanol;

[0041] Test 1: 12 units were tested according to the proposed method (using 0.1N HCl), collecting data every 15 minutes for a total of 2 hours;

[0042] Test 2: By replacing 5% (v / v) of the test medium with alcohol USP (ethanol), 12 units were analyzed and data were collected every 15 minutes for a total of 2 hours;

[0043] Test 3: By replacing 20% ​​(v / v) of the test medium with alcohol USP (ethanol), 12 units were analyzed and data were collected every 15 minutes for a total of 2 hours; and

[0044] Test 4: By replacing 40% (v / v) of the test medium with alcohol USP (ethanol), 12 units were analyzed and data were collected every 15 minutes for a total of 2 hours.

[0045] According to the FDA, both the test and reference products must be tested accordingly and data on individual units, means, ranges, and %CV for both strengths must be provided. (FDA Draft Guidance on Bupropion Hydrochloride, p. 2.)

[0046] Literature Examples

[0047] According to FDA documents, the bupropion product Forfivo XL was tested for ethanol dose dumping. (Center for Drug Evaluation and Research, Application No. 022497 Originals 000, CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW (S) ("Forfivo Resubmission"), page 17.) Forfivo Resubmission 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, page 10). Forfivo Resubmission also reported that the above experiment was conducted on BUP 450XL tablets. According to the ForfivoResubmission, "No bupropion HCl was observed to dissolve from the BUP 450XL tablets in the presence of 0% alcohol over a 2-hour period. In the presence of 20% alcohol, 7% bupropion HCl was observed to dissolve from the BUP 450XL tablets over a 2-hour period. In the presence of 40% alcohol, 22% (range 16-25%) bupropion HCl was seen to dissolve from the BUP 450XL tablets over a 2-hour period. The drug product exhibited dose dumping in vitro in the presence of alcohol." (page 17)

[0048] According to the CONTRAVE labeling, when a dosage form containing 8 mg naltrexone HCl, 90 mg bupropion HCl, microcrystalline cellulose, hydroxypropyl cellulose, anhydrous lactose, L-cysteine ​​HCl, crospovidone, magnesium stearate, hypromellose, edetate disodium, lactose monohydrate, colloidal silicon dioxide, Opadry II Blue, and FD&C Blue #2 aluminum lake was taken with a high-fat meal, the AUC and C of naltrexone were significantly decreased. max 2.1-fold and 3.7-fold, respectively, and the AUC and Cmax At steady state, the food effect increases the AUC and C of naltrexone by 1.4-fold and 1.8-fold, respectively. max 1.7-fold and 1.9-fold, respectively, and increased the AUC and C of bupropion max Therefore, the label states that CONTRAVE should not be taken with a high-fat meal because this would significantly increase the systemic exposure of bupropion and naltrexone.

[0049] The topic combination can be used as an adjunctive treatment for major depressive disorder or depression.

[0050] In addition to major depressive disorder, the subject combinations can also be used to treat other diseases of the condition in the patient population or situation 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.

[0051] Affective disorders that may be treated by the subject combinations include, but are not limited to, depression, major depression, 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 dysfunction, pseudobulbar mood, and mood lability.

[0052] 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, worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-depreciation. 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 hormonal circadian rhythms.

[0053] Mental disorders that can be treated by the subject combination include, but are not limited to: anxiety disorders, 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 disorder, hypomania, unipolar depression, depression, stress disorder, somatoform disorder, personality disorder, psychosis, schizophrenia, paranoia, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's disease, agitation, and 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.

[0054] Agitation may occur in Alzheimer's disease as the disease progresses. Agitation may present itself as inappropriate verbal, emotional, and / or physical behavior. Inappropriate behavior may include, but is not limited to, incoherent babbling, inappropriate emotional responses, 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, aggressiveness, hyperactivity, and / or kicking.

[0055] 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 number 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 are characterized by emotional distress, aggressive behavior, destructive 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, early nursing home placement, and increased mortality. Currently, the FDA has not approved a therapy for the treatment of agitation in AD patients.

[0056] It is known that neurobehavioral symptoms may occur during dementia, and it can be treated by combination therapy. Compared to the patient's cognitive impairment, caregivers or family members may feel overwhelmed due to the patient's behavioral / psychological symptoms. Common forms of syndrome include Alzheimer's disease, vascular dementia, Lewy body (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 disorders. Neurobehavioral symptoms may also be found in other diseases (such as traumatic brain injury), such as disinhibition.

[0057] 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, hurting self or others, tearing objects or destroying property, making physical advances, pacing, wandering aimlessly, dressing inappropriately or undressing, trying to go to different places, intentionally falling down, eating / drinking inappropriate substances, handling objects inappropriately, hiding objects, hoarding objects, repetitive quirks, general irritability, screaming, making verbal advances, swearing or verbally aggression, repeating sentences or questions, strange noises (weird laughter or crying), whining, being defensive, and constantly asking for attention or help without reason.

[0058] 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.

[0059] The brain dysfunction that the subject combination can treat includes, but is not limited to, disorders involving intellectual impairment, such as Alzheimer's disease, Alzheimer's dementia, amnesia, amnesia / amnestic syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperactivity syndrome and schizophrenia. Brain dysfunction also includes disorders 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 and speech disorders.

[0060] Substance addictions that can be treated by the subject combination include, but are not limited to, drug dependence, cocaine addiction, psychostimulants (e.g., crack, cocaine, speed, methamphetamine), nicotine, alcohol, opioids, antianxiety 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, cigars and / or pipes, e-cigarettes or vaping, and chewing cigarette addiction.

[0061] 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, Tourette's syndrome, and Wilson's disease.

[0062] 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.

[0063] 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, Sandoff disease, and hereditary spastic paraplegia.

[0064] Neurodegenerative diseases that may be treated by the subject combinations include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CHD), and schizophrenia. disease, CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0065] 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.

[0066] Headache types that may be treated by the subject combination include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0067] 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, musculartension 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.

[0068] 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.

[0069] In some embodiments, the subject combinations may be administered orally to relieve musculoskeletal pain, including low back pain, and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, periarticular disorders, axial spondyloarthritis (including ankylosing spondylitis), Paget's disease, fibrous dysplasia, SAPHO syndrome, transient hip osteoarthritis, vertebral compression fractures, osteoporosis, and the like.

[0070] In some embodiments, the subject combinations may be administered to relieve inflammatory pain, including musculoskeletal pain, arthritic pain, and complex regional pain syndrome.

[0071] 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.

[0072] In some embodiments, the subject combinations are used to treat chronic musculoskeletal pain.

[0073] In some embodiments, the subject compositions may be administered to relieve complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is an inflammatory pain. CRPS may 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.

[0074] In some embodiments, the subject compositions may be administered orally to relieve neuropathic pain.

[0075] 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, etc.

[0076] In some embodiments, the subject compositions may be administered to relieve fibromyalgia.

[0077] The term "treatment" includes the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals, or activities that otherwise affect the structure or any function of the body of humans or other animals.

[0078] The subject combination may be used to treat any disease or condition identified in the following U.S. Patents as treatable by a combination of bupropion and dextromethorphan: 8,569,328, 9,168,234, 9,189,905, 9,205,083, 9,238,032, 9,278,095, 9,314,462, 9,370,513, 9,375,429, 9,408,815, 9,421,176, 9, 457,023、9,457,025、9,474,731、9,486,450、9,700,528、9,700,553、9,707,191、9,763,932、9,861,595、9,867,819、9,968,568、10,058,518、10,064,857、10,080,727、10,092,560、10,092,56 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 diseases that may be treated by a combination of bupropion and dextromethorphan, including the specific embodiments and combinations described therein.

[0079] As shown in the Examples below, the subject combination has no dose dumping of bupropion in vitro in the presence of ethanol. Thus, patients can drink alcohol as long as it is minimized or limited. For example, adult females can drink one serving of alcohol per day or less (such as one serving per day, 4 servings or less per week, 3 servings or less per week, 1 serving or less per week, 1 serving or less per month, 1 serving or less per year, etc.), or adult males can drink two servings of alcohol per day or less (such as two servings per day, one serving per day, 4 servings or less per week, 3 servings or less per week, 1 serving or less per week, 1 serving or less per month, 1 serving or less per year, etc.).

[0080] Example 1

[0081] As described above, a two-layer dosage form as described above having layer 1 and layer 2 was tested for ethanol dose dumping. No dose dumping of bupropion in the presence of ethanol in vitro was observed.

[0082] Example 2

[0083] The two-layer dosage form having layer 1 and layer 2 as described above was administered to human subjects with a high fat meal and the AUC and C were compared with those administered to fasting human subjects. max The AUC or C of bupropion or dextromethorphan was compared to test the food effect. max In this regard, no significant differences were observed between the two groups.

[0084] U.S. Provisional Patent Application No. 63 / 370,771, filed on August 8, 2022, is incorporated herein by reference in its entirety.

[0085] Unless otherwise indicated, all numbers used in the specification and claims to indicate quantities of components, properties such as amounts, percentages, etc. should be understood in all cases 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 attached claims are approximate values, which may vary depending on the desired properties to be obtained. At the very least, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be interpreted in accordance with the number of reported significant digits and applying customary rounding techniques.

[0086] The use of the term "comprising" herein also encompasses the use of "consisting essentially of" or "consisting of" as an alternative.

[0087] The affirmative recitation of elements anywhere herein should be understood to contemplate both the inclusion of the elements and the exclusion of the elements.

[0088] Unless otherwise indicated herein or clearly contradicted by context, the use of unspecified articles, "said" and similar references in the context of describing embodiments (especially in the context of the following claims) should be interpreted as covering singular and plural references. Unless otherwise indicated herein or clearly contradicted by 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 embodiments 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 for practicing the claims.

[0089] 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 accelerating the application process, it is contemplated that one or more members in 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, so as to satisfy the written description of all Markush groups used in the appended claims.

[0090] Certain embodiments are described herein, including the best mode known to the inventors for implementing the claimed embodiments. Of course, variations of these described embodiments will become apparent to those of ordinary skill in the art upon reading the above description. The inventors expect that the skilled person will adopt such variations as appropriate, and the inventors expect that the claimed embodiments can be practiced in ways other than those specifically described herein. Therefore, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. In addition, any combination of the above elements in all possible variations is covered unless otherwise indicated herein or clearly contradicted by the context.

[0091] 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. 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 embodiments exactly shown and described.

Claims

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

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

3. The dosage form of claim 1 or 2, wherein the dextromethorphan is in the form of an immediate release formulation and the bupropion is in the form of an extended release formulation.

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

5. A method of treating a nervous system disorder, the method comprising administering a dosage form to a human patient in need thereof twice daily, wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer, and wherein the patient consumes alcohol on the day the dosage form is administered.

6. A method of treating a neurological disorder in a human patient who drinks alcohol, the method comprising administering a dosage form to a human patient in need thereof twice daily, and limiting but not stopping the human patient's alcohol consumption, wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer.

7. A method of treating a neurological disorder in a human patient who drinks alcohol, the method comprising administering a dosage form to a human patient in need thereof twice daily, and reducing but not stopping the human patient's alcohol consumption, wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer.

8. A method of treating a neurological disorder in a human patient who drinks alcohol, the method comprising administering a dosage form to a human patient in need thereof twice daily and minimizing but not stopping the human patient's alcohol consumption, wherein the dosage form comprises 105 mg bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer.

9. A method of treating a neurological disorder in an adult patient who drinks alcohol, the method comprising administering to a human patient in need thereof twice daily a dosage form, wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer; in, If the human patient is a male, the human patient consumes two or fewer servings of alcohol per day; and If the human patient is female, the human patient consumes one serving of alcohol per day or less.

10. The method of claim 4, 5, 6, 7, 8 or 9, wherein the polymer comprises poly(acrylic acid), poly(alkylacrylic acid), or a combination or copolymer thereof.

11. The method of claim 4, 5, 6, 7, 8, 9 or 10, wherein the dextromethorphan is in the form of an immediate release formulation and the bupropion is in the form of an extended release formulation.

12. The method of claim 4, 5, 6, 7, 8, 9, 10 or 11, wherein the human patient is an adult male and the human patient consumes two or fewer servings of alcohol per day.

13. The method of claim 4, 5, 6, 7, 8, 9, 10 or 11, wherein the human patient is an adult female and the human patient consumes one serving or less of alcohol per day.

14. A method of treating a nervous system disorder, the method comprising administering a dosage form to a human in need thereof, wherein the dosage form is taken by the human in conjunction with a high fat meal, wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of bupropion in another salt form or bupropion in free base form, 45 mg of dextromethorphan hydrobromide or a molar equivalent of dextromethorphan in another salt form or dextromethorphan in free base form, and a polymer.

15. The method of claim 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein the neurological disorder is major depressive disorder.

16. The method of claim 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein the neurological disorder is agitation associated with Alzheimer's disease.

17. The method of claim 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein the nervous system disorder is neuropathic pain.

18. The method of claim 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein the nervous system disorder is anxiety.

19. The dosage form of claim 1, 2 or 3, wherein the dosage form does not exhibit significant dose dumping of bupropion in vitro in the presence of ethanol.

20. The dosage form of claim 1, 2, 3 or 19, wherein the dosage form has no food effect on bupropion when taken with a high fat meal in a human subject.

21. The dosage form of claim 1, 2, 3, 19, or 20, wherein the dosage form has no food effect on dextromethorphan when taken with a high fat meal in a human subject.

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