Pharmaceutical composition containing bupropion and cysteine

Abstract

The present disclosure relates to a pharmaceutical composition comprising bupropion and cysteine, and a pharmaceutical dosage form comprising bupropion and cysteine. The present invention also relates to a molecular complex of bupropion and cysteine. These compositions and dosage forms can improve the stability of bupropion.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims priority to U.S. Provisional Application No. 63 / 357,318, filed on June 30, 2022, U.S. Provisional Application No. 63 / 370,554, filed on August 5, 2022, and U.S. Provisional Application No. 63 / 370,777, filed on August 8, 2022, the entire disclosures of which are incorporated herein by reference.

Background Art

[0002] Bupropion has received FDA approval for the treatment of depression and smoking cessation.

Summary of the Invention

Means for Solving the Problems

[0003] The present disclosure relates to pharmaceutical compositions, dosage forms, and the use of those compositions and dosage forms that contain bupropion and cysteine. The present disclosure also relates to molecular complexes of bupropion and cysteine.

[0004] Some embodiments include molecular complexes of bupropion and cysteine, and the molar ratio of bupropion to cysteine is from about 0.9:1 to about 1.1:1. These molecular complexes may be more stable than bupropion alone.

[0005] Some embodiments include pharmaceutical compositions that contain molecular complexes of bupropion and cysteine, and the molar ratio of bupropion to cysteine within the molecular complex is from about 0.5:1 to about 2:1 or from about 0.9:1 to about 1.1:1. These pharmaceutical compositions may be more stable than similar pharmaceutical compositions with bupropion without cysteine.

[0006] Some embodiments include pharmaceutical dosage forms that include bupropion and cysteine, can include a molecular complex of bupropion and cysteine, and the dosage form includes from about 90 mg to about 120 mg of bupropion and from about 30 mg to about 100 mg of cysteine.

Mode for Carrying Out the Invention

[0007] The present disclosure relates to pharmaceutical compositions that include bupropion and cysteine. The amounts of cysteine described herein have been found to be effective for stabilizing bupropion in the presence of common excipients such as calcium phosphate, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and the like.

[0008] The pharmaceutical composition, dosage form, or molecular complex can include or be prepared from bupropion in any suitable form, such as a salt form, for example, bupropion hydrochloride form, free base form, hydrate form, solvate form, polymorphic form, or other solid form. In some embodiments, the pharmaceutical composition does not include other active pharmaceutical agents.

[0009] The pharmaceutical dosage form can include bupropion in any suitable amount, such as from about 80 to 150 milligrams, from about 80 to 120 milligrams, from about 80 to 90 milligrams, from about 90 to 100 milligrams, from about 100 to 110 milligrams, from about 110 to 120 milligrams, from about 103 to 107 milligrams, or about 105 milligrams, of bupropion hydrochloride, another salt form of bupropion, or the free base form of bupropion.

[0010] The pharmaceutical composition, dosage form, or molecular complex can include or be prepared from cysteine in a suitable form, such as a neutral form, zwitterionic form, salt form, for example, cysteine hydrochloride form, hydrate form, solvate form, polymorphic form, or other solid form.

[0011] The pharmaceutical composition can contain an appropriate amount of cysteine (e.g., L-cysteine), such as about 30 to 100 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 65 to 70 mg, about 67 mg, etc., in the form of L-cysteine hydrochloride, another salt form of L-cysteine, the neutral form or zwitterionic form of L-cysteine. These amounts of cysteine can help stabilize bupropion in the presence of other excipients. Cysteine can be in the form of a hydrate of cysteine. For example, cysteine can be in the hydrated form. For example, cysteine can be in the form of cysteine hydrochloride monohydrate or L-cysteine hydrochloride monohydrate.

[0012] In some pharmaceutical compositions, bupropion and cysteine are in the form of a molecular complex or can associate non-covalently or with each other, and the molecular complex can include both salts and other forms of non-covalent interaction such as hydrogen bonding and van der Waals interactions.

[0013] One potential bupropion-cysteine molecular complex is represented by the following structure.

Chemical formula

[0014] In some embodiments, the molar ratio of bupropion to cysteine can be from about 0.2:1 (e.g., 0.2 moles of bupropion to 1 mole of cysteine) to about 4:1, from about 0.2:1 to about 0.5:1, from about 0.5:1 to about 0.7:1, from about 0.7:1 to about 0.9:1, from about 0.9:1 to about 1.1:1, from about 1.1:1 to about 1.3:1, from about 1.3:1 to about 1.5:1, from about 1.5:1 to about 2:1, from about 2:1 to about 3:1, from about 3:1 to about 4:1, from about 0.5 to about 1:1.

[0015] The pharmaceutical composition or dosage form can further include a sustained-release or controlled-release polymer such as a crosslinked or non-crosslinked acrylate polymer or copolymer (e.g., Carbomer copolymer type A such as Carbopol 971P), a cellulose derivative such as methylcellulose. In some embodiments, the controlled-release polymer 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.

[0016] The pharmaceutical composition or dosage form can further include a filler such as microcrystalline cellulose. In some embodiments, the filler can 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.

[0017] The pharmaceutical composition or dosage form can further include 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.

[0018] The dosage form can be formulated according to a suitable route of administration such as oral administration.

[0019] Dosage forms such as solid dosage forms such as capsules, tablets, or pills for oral administration may include 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 unit dosage form is a capsule, in addition to the materials of the above types, a liquid carrier may also 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 substantially non-toxic in the amounts used.

[0020] The dosage form can further include a second active pharmaceutical ingredient such as dextromethorphan, for example, dextromethorphan hydrochloride. In some embodiments, the dosage form can include bupropion and dextromethorphan and can contain 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 nothing else.

[0021] In some embodiments, the dosage form includes cysteine, carbopol 971P, microcrystalline cellulose, silicon dioxide, and magnesium. In some embodiments, the dosage form includes a first layer containing bupropion and cysteine and a second layer containing dextromethorphan, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0022] Examples of single-layer dosage forms are shown below.

[0023]

Table 1

[0024] The two-layer dosage form may include a first layer having the above composition and a second layer described in detail below.

[0025] (Layer 2)

Table 2

[0026] The pharmaceutical compositions, dosage forms, or molecular complexes described herein may be useful for the treatment of neurological or mental conditions such as depression, including major depressive disorder or treatment-resistant major depressive disorder, agitation such as the agitation associated with Alzheimer's disease, addictions such as nicotine addiction.

[0027] The subject combination may be used for the adjunctive treatment of major depressive disorder or depression.

[0028] In addition to major depressive disorder, the subject combination may be used to treat other diseases of symptoms in the patient populations or situations described herein. For example, the subject combination may 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.

[0029] Mood disorders that may 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 addiction or abuse, nicotine addiction, psychotic dysfunction, emotional regulation disorder, emotional instability.

[0030] 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, agitation, anxiety, hyperexcitability, guilt, anger, worthlessness, reckless behavior, suicidal thoughts or attempts, and / or submissiveness. 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.

[0031] The mental disorders treated with the combination of the subject matters 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, but are not limited thereto. 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.

[0032] 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 muttering, inappropriate emotional responses, demands for attention, threats, hyperexcitability, dissatisfaction, wailing, repetitive questioning, mood swings, scolding, scolding words, physical outbursts, emotional distress, restlessness, breaking, sleep disorders, delusions, hallucinations, pacing, wandering, searching, searching everywhere, repetitive body movements, brooding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and / or kicking, but are not limited thereto.

[0033] Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and behavioral and psychological symptoms including agitation. AD is the most common form of dementia, affecting 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.

[0034] Neurobehavioral symptoms are known to occur during dementia and may be treatable by this combination. Caregivers or family members may be overwhelmed by the patient's behavioral and psychological symptoms rather than the patient's cognitive impairment. The general forms of the syndrome are a group of diseases that contribute to Alzheimer's disease, vascular dementia, Lewy body dementia (abnormal aggregates of 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, agitation, disinhibition, hallucinations, delusions, psychosis, impulsivity, aggression, obsessive-compulsion, hypersexuality, and personality disorders. Neurobehavioral symptoms such as disinhibition may also be seen in other conditions such as brain injury.

[0035] Agitation in Alzheimer's 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 apart or causing property damage, initiating physical sexual advances, pacing, aimless wandering, inappropriate dressing or undressing, attempting to go to another place, deliberately falling, eating or drinking inappropriate substances, inappropriately handling things, hiding things, hoarding things, repeatedly performing mannerisms, overall restlessness, shouting, verbal sexual temptation, cursing or verbal attacks, repeating statements or questions, making strange sounds (strange laughter or crying sounds), complaining, refusal disorder, constantly seeking inappropriate attention or help, etc.

[0036] Schizophrenia can be treated in combinations that include positive and / or negative symptoms of schizophrenia, or residual symptoms of schizophrenia. Other treatable symptoms include intermittent explosive disorder.

[0037] Brain dysfunctions that can be treated by combinations of the subject matter include, but are not limited to, disorders associated with intellectual disabilities such as senile dementia, Alzheimer's type dementia, memory loss, amnesia / amnesia syndrome, epilepsy, disturbance of consciousness, coma, decreased attention, speech disorder, tremor of 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.

[0038] Substances abuse disorders treatable by the combination of the subject matter include drug dependence, cocaine intoxication, stimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, antianxiety and hypnotic drugs, marijuana (cannabis), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as tobacco, cigars and / or pipes, e-cigarettes and vaping, and addiction to chewing tobacco.

[0039] Movement disorders treatable by the combination of the subject matter include, but are not limited to, akathisia, akinesia, associated movement, athetosis, ataxia, ballism, hemiballism, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's chorea, rheumatic chorea, Sydenham 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.

[0040] 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, and the like.

[0041] 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, postpoliomyelitis syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] Other neurological disorders that can be treated by the combination of the subject matter include 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, and vocal tremors, diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity, incontinence including stress urinary incontinence, urge urinary incontinence, fecal incontinence, and erectile dysfunction.

[0046] 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.

[0047] 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 joint rheumatism, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, periarticular disorders, axial spondyloarthritis including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral compression fractures, osteoporosis, etc.

[0048] In some embodiments, the combination of the subject matter can be administered to reduce inflammatory pain such as musculoskeletal pain, arthritic pain, complex regional pain syndrome, etc.

[0049] Arthritis refers to inflammatory joint diseases that may be accompanied by pain. Examples of arthritic pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid 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.

[0050] In some embodiments, the combination of the subject matter is used to treat chronic musculoskeletal pain.

[0051] In some embodiments, the composition of the subject matter can 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 an element 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.

[0052] In some embodiments, the composition of the subject matter can be orally administered to reduce neuropathic pain.

[0053] 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 therapy or chemotherapy-related neuropathy, etc.

[0054] In some embodiments, the composition of the subject matter can be administered to reduce fibromyalgia.

[0055] 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.

[0056] The combination of the subject matter can be used for the treatment of any disease or condition 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 in their entirety for the disclosure of diseases treatable by the combination of bupropion and dextromethorphan, including the specific embodiments and combinations described therein.

[0057] The following documents are hereby incorporated by reference in their entirety: the AUVELITY (trademark) Medication Guide (www.axsome.com / auvelity - medication - guide.pdf) and the AUVELITY (trademark) Highlights of Prescribing Information (www.axsome.com / auvelity - prescribing - information.pdf).

[0058] Unless otherwise specified, all numerical values representing properties such as amounts, quantities, percentages, etc. of components used in the specification and claims are to be understood as indicating both the exact value shown and the value modified by the term "about" in all cases. Thus, unless otherwise specified, the numerical parameters set forth in the specification and the appended claims are approximations and may vary depending on the desired properties to be obtained. At a minimum, and not as an attempt to limit the scope of the claims to the application of the doctrine of equivalents, each numerical parameter should be construed in accordance with the normal rounding - off method, taking into account the number of significant digits reported.

[0059] 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.

[0060] Any affirmative recitation of an element anywhere in this specification should be understood to contemplate both the inclusion and the exclusion of that element.

[0061] The terms "a", "an", "the", and similar referents used in the context of describing embodiments (especially 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 only to better illustrate the embodiments and is not to be construed as limiting any claims. The language of the specification should not be construed as indicating any non-claimed elements essential to the practice of the claims.

[0062] 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 anticipated that one or more members of the group will be included in or deleted from the group. If such inclusion or deletion occurs, the specification is considered to include the modified group, thereby satisfying the description of all Markush groups used in the appended claims.

[0063] 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 employ such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced in a manner other than that specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited therein to the extent permitted by applicable law. Further, unless otherwise stated herein or clearly contradicted by context, any combination of any possible variations of the above-described elements is contemplated.

[0064] 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 can be utilized in accordance with the teachings herein, but are not limited thereto. Thus, the claims are not strictly limited to the embodiments as illustrated and described.

[0065] (Appendix) (Appendix 1) A molecular complex of bupropion and cysteine, wherein the molar ratio of bupropion to cysteine in the molecular complex is from about 0.9:1 to about 1.1:1.

[0066] (Appendix 2) The molecular complex according to Appendix 1, wherein the molar ratio of bupropion to cysteine is about 1:1.

[0067] (Appendix 3) A pharmaceutical composition comprising bupropion and cysteine, wherein the molar ratio of bupropion to cysteine is from about 0.5:1 to about 2:1.

[0068] (Appendix 4) The pharmaceutical composition according to Appendix 3, wherein the molar ratio of bupropion to cysteine is about 1:1.

[0069] (Supplementary Note 5) The pharmaceutical composition according to Supplementary Note 3 or 4, further comprising a sustained-release polymer

[0070] (Supplementary Note 6) The pharmaceutical composition according to Supplementary Note 5, wherein the sustained-release polymer is an acrylate polymer or copolymer, methylcellulose, or a combination thereof

[0071] (Supplementary Note 7) The pharmaceutical composition according to any one of Supplementary Notes 3 to 6, further comprising a filler

[0072] (Supplementary Note 8) The pharmaceutical composition according to Supplementary Note 7, wherein the filler is microcrystalline cellulose

[0073] (Supplementary Note 9) A pharmaceutical dosage form comprising bupropion and cysteine, comprising from about 90 mg to about 120 mg of bupropion and from about 30 mg to about 100 mg of cysteine

[0074] (Supplementary Note 10) The pharmaceutical dosage form according to Supplementary Note 9, wherein the molar ratio of bupropion to cysteine in the pharmaceutical dosage form is from about 0.5:1 to about 2:1

[0075] (Supplementary Note 11) The pharmaceutical dosage form according to Supplementary Note 9, wherein the molar ratio of bupropion to cysteine is about 1:1

[0076] (Supplementary Note 12) The pharmaceutical dosage form according to any one of Supplementary Notes 9 to 11, further comprising a sustained-release polymer

[0077] (Supplementary Note 13) The pharmaceutical dosage form according to Supplementary Note 12, wherein the sustained-release polymer is an acrylate polymer or copolymer, methylcellulose, or a combination thereof

[0078] (Supplementary Note 14) The pharmaceutical dosage form according to any one of Appendices 9 to 13, which is in the form of a capsule, tablet, or pill.

[0079] (Appendix 15) The pharmaceutical dosage form according to any one of Appendices 9 to 14, further comprising dextromethorphan.

[0080] (Appendix 16) The pharmaceutical dosage form according to Appendix 15, wherein the bupropion and the cysteine are in the first layer and the dextromethorphan is in the second layer.

[0081] (Appendix 17) The pharmaceutical dosage form according to any one of Appendices 9 to 16, further comprising a filler.

[0082] (Appendix 18) The pharmaceutical dosage form according to Appendix 17, wherein the filler is microcrystalline cellulose.

[0083] (Appendix 19) The pharmaceutical dosage form according to any one of Appendices 9 to 18, further comprising a lubricant.

[0084] (Appendix 20) The pharmaceutical dosage form according to Appendix 19, wherein the lubricant is magnesium stearate.

[0085] (Appendix 21) The pharmaceutical dosage form according to any one of Appendices 9 to 20, wherein the cysteine is L-cysteine hydrochloride monohydrate.

[0086] (Appendix 22) The molecular complex according to Appendix 1, wherein the bupropion is more stable than bupropion alone.

[0087] (Appendix 23) The pharmaceutical composition according to Appendix 3, wherein the bupropion is more stable than bupropion alone.

[0088] (Appendix 24) The bupropion is a pharmaceutical dosage form described in Supplementary Note 9, which is more stable than bupropion alone.

[0089] (Supplementary Note 25) A pharmaceutical composition comprising the molecular complex described in Supplementary Note 1.

[0090] (Supplementary Note 26) A pharmaceutical composition described in Supplementary Note 3, in which bupropion and cysteine form a molecular complex.

Claims

1. A molecular complex of bupropion and cysteine, wherein the molar ratio of bupropion to cysteine in the molecular complex is from about 0.9:1 to about 1.1:

1.

2. The molecular complex according to claim 1, wherein the molar ratio of bupropion to cysteine is about 1:

1.

3. A pharmaceutical composition comprising bupropion and cysteine, wherein the molar ratio of bupropion to cysteine is from about 0.5:1 to about 2:

1.

4. The pharmaceutical composition according to claim 3, wherein the molar ratio of bupropion to cysteine is about 1:

1.

5. The pharmaceutical composition according to claim 3 or 4, further comprising a sustained release polymer.

6. The pharmaceutical composition according to claim 5, wherein the sustained release polymer is an acrylate polymer or copolymer, methylcellulose, or a combination thereof.

7. The pharmaceutical composition according to any one of claims 3 to 6, further comprising a filler.

8. The pharmaceutical composition according to claim 7, wherein the filler is microcrystalline cellulose.

9. A pharmaceutical dosage form comprising bupropion and cysteine, comprising from about 90 mg to about 120 mg of bupropion and from about 30 mg to about 100 mg of cysteine.

10. The pharmaceutical dosage form according to claim 9, wherein the molar ratio of bupropion to cysteine in the pharmaceutical dosage form is from about 0.5:1 to about 2:

1.

11. The pharmaceutical dosage form according to claim 9, wherein the molar ratio of bupropion to cysteine is about 1:

1.

12. The pharmaceutical dosage form according to any one of claims 9 to 11, further comprising a sustained release polymer.

13. The pharmaceutical dosage form according to claim 12, wherein the sustained release polymer is an acrylate polymer or copolymer, methylcellulose, or a combination thereof.

14. The pharmaceutical dosage form according to any one of claims 9 to 13, which is in the form of a capsule, tablet, or pill.

15. The pharmaceutical dosage form according to any one of claims 9 to 14, further comprising dextromethorphan.

16. The pharmaceutical dosage form according to claim 15, wherein the bupropion and the cysteine are in a first layer and the dextromethorphan is in a second layer.

17. The pharmaceutical dosage form according to any one of claims 9 to 16, further comprising a filler.

18. The pharmaceutical dosage form according to claim 17, wherein the filler is microcrystalline cellulose.

19. The pharmaceutical dosage form according to any one of claims 9 to 18, further comprising a lubricant.

20. The pharmaceutical dosage form according to claim 19, wherein the lubricant is magnesium stearate.

21. The pharmaceutical dosage form according to any one of claims 9 to 20, wherein the cysteine is L-cysteine hydrochloride monohydrate.

22. The molecular complex according to claim 1, wherein the bupropion is more stable than bupropion alone.

23. The pharmaceutical composition according to claim 3, wherein the bupropion is more stable than bupropion alone.

24. The pharmaceutical dosage form according to claim 9, wherein the bupropion is more stable than bupropion alone.

25. A pharmaceutical composition comprising the molecular complex according to claim 1.

26. The pharmaceutical composition according to claim 3, wherein bupropion and cysteine form a molecular complex.

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