Particles containing bupropion

Abstract

The present disclosure relates to microparticles comprising bupropion, for example, microparticles having a particle diameter of from about 50 μm to about 100 μm. These microparticles can be included in pharmaceutical compositions and / or dosage forms for the treatment of various diseases such as depression.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 357,355, filed June 30, 2022, U.S. Provisional Application No. 63 / 370,572, filed August 5, 2022, and U.S. Provisional Application No. 63 / 370,778, filed August 8, 2022, the entire disclosures of which are incorporated herein by reference. [Background technology]

[0002] Bupropion is FDA-approved for the treatment of depression and smoking cessation. Summary of the Invention [Means for solving the problem]

[0003] The present disclosure relates to microparticles containing bupropion. It has been found that the particle size of the microparticles containing bupropion can affect the dissolution profile of the bupropion within the microparticles, which can also affect the pharmacokinetics of the bupropion.

[0004] Some embodiments include microparticles comprising bupropion hydrochloride, the microparticles having a particle size of about 50 μm to about 100 μm, which may be determined by laser diffraction or other suitable techniques.

[0005] Some embodiments include a dosage form comprising microparticles comprising bupropion, wherein at least 80% of the microparticles have a particle size of about 1 μm to about 300 μm as measured by laser diffraction.

[0006] Some embodiments include a pharmaceutical composition comprising microparticles comprising bupropion, wherein at least 80% of the microparticles have a particle size of about 1 μm to about 300 μm, where the particle size can be determined by laser diffraction or other suitable technique. DETAILED DESCRIPTION OF THE INVENTION

[0007] The microparticles containing bupropion may contain bupropion in any suitable form, such as the salt form, for example, the hydrochloride form of bupropion, the free base form, the hydrate form, the solvate form, the polymorphic form, or other solid forms, or can be prepared from them. In some embodiments, the microparticles, or the dosage form or pharmaceutical composition containing the microparticles, do not contain any other active pharmaceutical agent. In some embodiments, the microparticles may be present as a dosage form containing dextromethorphan in any suitable form, such as the hydrobromide form of dextromethorphan, the free base form, the hydrate form, the solvate form, the polymorphic form, or other solid forms.

[0008] The microparticles may contain any suitable amount of bupropion. For example, bupropion, such as bupropion hydrochloride, can account for about 1 - 20%, about 20 - 40%, about 10 - 20%, about 15 - 20%, about 20 - 25%, about 25 - 30%, about 30 - 35%, about 35 - 40%, about 40 - 60%, about 60 - 80%, about 80 - 100%, about 20 - 30%, about 30 - 33%, or about 31 - 32% of the weight of the microparticles.

[0009] When prepared by a specific method, the microparticles can exist in a distribution of various sizes. This size distribution can be described in various ways, but one convenient way is to specify the 10th percentile of the particle diameter, the median of the particle diameter, and the 90th percentile of the particle diameter.

[0010] The 10th percentile of the particle diameter is the size at which 10% of the microparticles are smaller than that diameter. In some embodiments, the 10th percentile of the particle diameter is about 1 - 30 μm, about 1 - 3 μm, about 3 - 5 μm, about 5 - 10 μm, about 10 - 15 μm, about 15 - 20 μm, about 20 - 25 μm, or about 25 - 30 μm, and the particle diameter can be determined by laser diffraction or other suitable techniques.

[0011] The median particle size is the diameter at which the number of particles smaller than the median particle size is equal to the number of particles larger than the median particle size. In some embodiments, the median particle size is about 50 - 100 μm, about 50 - 55 μm, about 55 - 60 μm, about 60 - 65 μm, about 65 - 70 μm, about 70 - 75 μm, about 75 - 80 μm, about 80 - 85 μm, about 85 - 90 μm, about 90 - 95 μm, about 95 - 100 μm, about 50 - 60 μm, about 60 - 70 μm, about 70 - 80 μm, about 80 - 90 μm, about 90 - 100 μm, about 50 - 75 μm, or about 75 - 100 μm, and the particle size can be determined by laser diffraction or other suitable techniques.

[0012] The 90th percentile of the particle diameter is the size at which 90% of the particles are smaller than that diameter. In some embodiments, the 90th percentile of the particle diameter is about 200 - 300 μm, about 200 - 210 μm, about 210 - 220 μm, about 220 - 230 μm, about 230 - 240 μm, about 240 - 250 μm, about 250 - 260 μm, about 260 - 270 μm, about 270 - 280 μm, about 280 - 290 μm, about 290 - 300 μm, about 200 - 240 μm, about 240 - 270 μm, or about 270 - 300 μm, and the particle diameter can be determined by laser diffraction or other suitable techniques.

[0013] The particle size distribution can also be characterized as a range of particle sizes, such as the particle diameter within which at least about 80% of the particles (e.g., at least the particles from the 10th percentile to the 90th percentile) will be included. In some embodiments, at least about 80% of the particle sizes of the particles are about 1 - 300 μm, about 2 - 260 μm, or about 20 - 230 μm, and the particle size can be determined by laser diffraction or other suitable techniques.

[0014] The particle size distribution can further be characterized by the ratio of the particle size of the 90th percentile of the particle diameter to the median particle size, the ratio of the median particle size to the particle size of the 10th percentile, and the ratio of the 90th percentile of the particle diameter to the 10th percentile of the particle diameter.

[0015] In some embodiments, the ratio of the 90th percentile of the particle size to the median of the particle size is about 2 to 10 (for example, if the 90th percentile value has a diameter twice that of the median, the ratio is 2), about 2 to 3, about 3 to 4, about 4 to 5, about 5 to 6, about 6 to 7, about 7 to 8, about 8 to 9, about 9 to 10, about 2 to 4, about 4 to 6, about 6 to 8, about 8 to 10, about 2 to 6, or about 6 to 10.

[0016] In some embodiments, the ratio of the median of the particle size to the 10th percentile of the particle size is about 2 to 50, about 2 to 6, about 6 to 10, about 10 to 15, about 15 to 20, about 20 to 25, about 25 to 30, about 30 to 35, about 35 to 40, about 40 to 45, about 45 to 50, about 2 to 10, about 10 to 20, about 20 to 30, about 30 to 40, about 40 to 50, about 2 to 20, or about 20 to 50.

[0017] In some embodiments, the ratio of the 90th percentile of the particle size to the 10th percentile of the particle size is about 5 to 200, about 5 to 20, about 20 to 40, about 40 to 60, about 60 to 80, about 80 to 100, about 100 to 120, about 120 to 140, about 140 to 160, about 160 to 180, about 180 to 200, about 5 to 50, about 50 to 120, or about 120 to 200.

[0018] The microparticles can be formulated into a pharmaceutical composition or dosage form. In some embodiments, the microparticles, pharmaceutical composition, or dosage form can include a stabilizer such as cysteine. The pharmaceutical composition can include the stabilizer in any suitable amount, for example, an amount of about 1 to 30 mg, 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, or about 65 to 70 mg.

[0019] The microparticles, pharmaceutical composition, or dosage form can further comprise a sustained- 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, etc. In some embodiments, the controlled-release polymer is 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.

[0020] The microparticles, pharmaceutical composition, or dosage form can further comprise a filler, such as microcrystalline cellulose, hi some embodiments, the filler can 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.

[0021] The microparticles, pharmaceutical composition, or dosage form can further comprise a lubricant, such as magnesium stearate, hi 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.

[0022] Dosage forms may be formulated for a suitable route of administration, such as oral administration.

[0023] 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 non-toxic in the amounts used.

[0024] 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 no others.

[0025] 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.

[0026] Examples of the composition of microparticles containing bupropion are shown below.

[0027] (Composition 1)

Table 1

[0028] The microparticles as described above can be formed in tablets or layers within dosage forms, for example, by pressing. They can also be encapsulated.

[0029] In some embodiments, the dosage form can include microparticles containing bupropion and a second therapeutic agent such as dextromethorphan. In some embodiments, such dosage forms do not include other therapeutic agents other than bupropion and dextromethorphan.

[0030] In dosage forms containing dextromethorphan, dextromethorphan can be incorporated into Composition 2.

[0031] (Composition 2) [Table 2]

[0032] Composition 1 and Composition 2 can be, for example, in two separate layers within a tablet or two separate powders contained within a capsule. Other types of dosage forms can be formed from Composition 1 and Composition 2.

[0033] The microparticles described herein can be prepared, for example, by sieving (e.g., through a 20-mesh sieve), mixing, spray granulating, drying, and pulverizing the dried mixture of bupropion, cysteine, carbopol 971, and microcrystalline cellulose from Composition 1. The resulting particle size distribution can be determined by laser diffraction.

[0034] The microparticles, pharmaceutical compositions, or dosage forms described herein can 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 agitated excitement associated with Alzheimer's disease, and addictions such as nicotine addiction.

[0035] The combination of the subject matter can be used for the adjunctive treatment of major depressive disorder or depression.

[0036] In addition to major depressive disorder, the combination of the subject matter can be used to treat other diseases of symptoms in the patient populations or situations described herein. For example, the combination of the subject matter can be used to treat pain and neuropathy. Examples of neurological diseases treated with the combination of the subject matter include, but are not limited to, affective disorders, mental disorders, brain function disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, headaches, etc.

[0037] Affective disorders that can be treated by the combination of the subject matter 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 addiction, psychotic dysfunction, emotional regulation disorder, emotional instability.

[0038] Depression can be manifested by depressive symptoms. These symptoms may include, for example, mood changes, intense feelings of sadness, despair, decreased mental activity, decreased concentration, pessimistic worry, excitement, anxiety, hyperexcitability, guilt, anger, worthlessness, reckless behavior, suicidal thoughts or attempts, and / or inferiority. Physical symptoms of depression may include insomnia, anorexia nervosa, 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.

[0039] The mental disorders treated with the combination of the subject matter 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 include disinhibition and apathy.

[0040] Agitation in Alzheimer's disease occurs as the disease progresses. Agitation may manifest as inappropriate words, emotions, and / or physical behaviors. Inappropriate behaviors include incoherent muttering, inappropriate emotional responses, demands for attention, threats, hyper-excitability, frustration, wailing, repeating questions, mood swings, scolding, swear words, physical outbursts, emotional distress, restlessness, breaking things, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, incessant searching, repeating body movements, huddling, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and / or kicking, but are not limited thereto.

[0041] 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 hyper-excitability, 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 a nursing facility, and increased mortality. Currently, there is no FDA-approved treatment for agitation in AD patients.

[0042] It is known that neurobehavioral symptoms appear during dementia and may be treated 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 groups 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, impulsive-compulsive behavior, hypersexuality, and personality disorders. Neurobehavioral symptoms such as disinhibition may also be seen in other conditions such as brain injury.

[0043] Agitated excitement in Alzheimer's disease patients can be evaluated using the Cohen-Mansfield Agitation Inventory or 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 breaking utensils, initiating physical sexual proximity, pacing, aimless wandering, inappropriate dressing or undressing, attempting to go to another place, deliberately falling, eating or drinking inappropriate substances, handling things inappropriately, hiding objects, hoarding objects, repeating a habit many times, overall restlessness, shouting, verbal sexual solicitation, cursing or verbal aggression, repeating statements or questions, making strange sounds (strange laughter or crying sounds), complaining, refusal, constantly seeking inappropriate attention or help, etc.

[0044] 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.

[0045] Brain dysfunctions that can be treated by the combination of the subject matter include, but are not limited to, dysfunctions associated with intellectual disabilities such as senile dementia, Alzheimer's dementia, memory loss, amnesia / amnesia syndrome, epilepsy, disturbance of consciousness, coma, decreased attention, language disorder, voice tremor, Parkinson's disease, Lennox-Gastaut syndrome, autism, attention deficit hyperactivity disorder, schizophrenia, etc. Brain dysfunctions also include dysfunctions 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 language disorder.

[0046] Substance abuse addictions that can be treated by the combination of the subject matter include drug dependence, cocaine intoxication, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, antianxiety drugs and hypnotics, marijuana (cannabis), amphetamines, hallucinogens, fenethylline, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction such as smoking tobacco, cigars and / or pipes, e-cigarettes and vaping, and addiction to chewing tobacco.

[0047] Movement disorders that can be treated by the combination of the subject matter include, but are not limited to, akathisia, akinesia, associated movement, athetoid, 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.

[0048] Dementias that can be treated 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.

[0049] Motor neuron diseases that can be treated by the combination of the subject matters 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.

[0050] Neurodegenerative diseases that can be treated by the combination of the subject matters 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.

[0051] Seizure disorders that can be treated by the combination of the subject matters 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 seizures including generalized tonic-clonic seizures - absence seizures - atonic seizures - myoclonic seizures - juvenile myoclonic seizures - infantile spasms, and status epilepticus.

[0052] Types of headaches that can be treated by the combination of the subject matters include, but are not limited to, migraine, tension, and cluster headache.

[0053] 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, and vocal tremor, diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity, incontinence including stress urinary incontinence, urge urinary incontinence, fecal incontinence, and erectile dysfunction.

[0054] 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.

[0055] 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 diseases such as 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 coxarthrosis, vertebral compression fractures, osteoporosis, etc.

[0056] 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.

[0057] 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-rheumatoid) arthropathy, non-articular rheumatism, periarticular disorders, neuropathic arthropathy such as Charcot foot, axial spondyloarthritis such as ankylosing spondylitis, and pain associated with SAPHO syndrome.

[0058] In some embodiments, the combination of the subject matter is used to treat chronic musculoskeletal pain.

[0059] In some embodiments, the composition of the subject matter 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 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.

[0060] In some embodiments, the composition of the subject matter may be orally administered to reduce neuropathic pain.

[0061] 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.

[0062] In some embodiments, the composition of the subject matter may be administered to reduce fibromyalgia.

[0063] 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.

[0064] 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.

[0065] The following documents are hereby incorporated by reference in their entirety: the AUVELITY (trademark) Medication Guide (axsome.com / auvelity-medication-guide.pdf), and the AUVELITY (trademark) Prescribing Information Highlights (axsome.com / auvelity-prescribing-information.pdf).

[0066] Unless otherwise indicated, all numerical values expressing quantities, amounts, percentages, and other properties of the components used in the specification and claims are to be understood as referring to both the exact value shown and the value modified by the term "about" in all instances. Accordingly, unless otherwise indicated, the numerical parameters set forth in the specification and the appended claims are approximations that may vary depending upon the desired property sought to be obtained. At a minimum, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the reported significant digits and by applying ordinary rounding techniques.

[0067] The use of the terms "comprising" or "comprises" in this specification is also contemplated to be replaced by the use of "consisting essentially of," "consists essentially of," "consisting of," or "consists of."

[0068] Any affirmative statement of an element anywhere in this specification is to be understood as intending to encompass both the inclusion and the exclusion of that element.

[0069] 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 specified herein or clearly contradicted by the context. All methods described herein can be performed in any suitable order, unless otherwise specified 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.

[0070] 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 a 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 all descriptions of the markush groups used in the appended claims.

[0071] 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 skilled 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 are intended to cover all modifications and equivalents of the subject matter recited therein to the extent permitted by applicable law. Further, unless otherwise specified herein or clearly contradicted by context, any combination of any possible variations of the above-described elements is contemplated.

[0072] 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 herein, but are not limited thereto. Thus, the claims are not strictly limited to the embodiments as illustrated and described.

[0073] (Appendix) (Appendix 1) Particles containing bupropion, wherein the particle size of the particles is from about 50 μm to about 100 μm.

[0074] (Appendix 2) The particle size is measured by laser diffraction, the particles according to Appendix 1.

[0075] (Appendix 3) The bupropion accounts for about 30% to about 35% of the weight of the particles, the particles according to Appendix 1 or 2.

[0076] (Appendix 4) A dosage form containing particles containing bupropion, wherein at least about 80% of the particle size of the particles is from about 1 μm to about 300 μm.

[0077] (Appendix 5) The particle size is the dosage form described in Appendix 4, measured by laser diffraction.

[0078] (Appendix 6) The median of the fine particle size is about 50 μm to about 100 μm when measured by laser diffraction, which is the dosage form described in Appendix 4 or 5.

[0079] (Appendix 7) The 10th percentile of the fine particle size is about 1 μm to about 30 μm when measured by laser diffraction, which is the dosage form described in Appendix 6.

[0080] (Appendix 8) The 90th percentile of the fine particle size is about 200 μm to about 300 μm when measured by laser diffraction, which is the dosage form described in Appendix 6.

[0081] (Appendix 9) The 90th percentile of the fine particle size is about 2 to about 6 times the median of the fine particle size when measured by laser diffraction, which is the dosage form described in Appendix 6.

[0082] (Appendix 10) The median of the fine particle size is about 2 to about 50 times the 10th percentile of the fine particle size when measured by laser diffraction, which is the dosage form described in Appendix 6.

[0083] (Appendix 11) The 90th percentile of the fine particle size is about 10 to about 200 times the 10th percentile of the fine particle size when measured by laser diffraction, which is the dosage form described in Appendix 6.

[0084] (Appendix 12) The dosage form according to any one of Appendices 6 to 11, further comprising microcrystalline cellulose.

[0085] (Appendix 13) A pharmaceutical composition comprising microparticles containing bupropion, wherein at least 80% of the particle diameters of the microparticles are from about 1 μm to about 300 μm.

[0086] (Appendix 14) The pharmaceutical composition according to Appendix 13, wherein the particle diameter is measured by laser diffraction.

[0087] (Appendix 15) The pharmaceutical composition according to Appendix 13 or 14, wherein the median particle diameter of the microparticles containing bupropion is from about 50 μm to about 100 μm when measured by laser diffraction.

[0088] (Appendix 16) The pharmaceutical composition according to Appendix 13, wherein the diameter of the microparticles at the 10th percentile based on the particle diameter is from about 1 μm to about 30 μm when measured by laser diffraction.

[0089] (Appendix 17) The pharmaceutical composition according to Appendix 13, wherein the diameter of the microparticles at the 90th percentile based on the particle diameter is from about 200 μm to about 300 μm when measured by laser diffraction.

[0090] (Appendix 18) The pharmaceutical composition according to Appendix 13, wherein the 90th percentile of the particle diameter is from about 2 to about 6 times the median of the particle diameter when measured by laser diffraction.

[0091] (Appendix 19) The pharmaceutical composition according to Appendix 13, wherein the median of the particle diameter is from about 2 to about 50 times the 10th percentile of the particle diameter when measured by laser diffraction.

[0092] (Appendix 20) The pharmaceutical composition according to Appendix 13, wherein the 90th percentile of the particle diameter is from about 10 to about 200 times the 10th percentile of the particle diameter when measured by laser diffraction.

[0093] (Appendix 21) The pharmaceutical composition according to any one of Appendices 13, 14, 25, 26, 17 to 20, further comprising a sustained-release or controlled-release polymer.

[0094] (Appendix 22) The pharmaceutical composition according to any one of Appendices 13, 14, 25, 26, 17 to 21, further comprising magnesium stearate.

[0095] (Appendix 23) The fine particles according to Appendix 1, wherein the bupropion is bupropion hydrochloride.

[0096] (Appendix 24) The dosage form according to Appendix 4, wherein the bupropion is bupropion hydrochloride.

[0097] (Appendix 25) The pharmaceutical composition according to Appendix 13, wherein the bupropion is bupropion hydrochloride.

Claims

1. Particles containing bupropion, wherein the particle size of the particles is from about 50 μm to about 100 μm.

2. The particle size is measured by laser diffraction, and the particles according to Claim 1.

3. The bupropion accounts for about 30% to about 35% of the weight of the particles, and the particles according to Claim 1 or 2.

4. A dosage form containing particles containing bupropion, wherein at least about 80% of the particle size of the particles is from about 1 μm to about 300 μm.

5. The particle size is measured by laser diffraction, and the dosage form according to Claim 4.

6. When measured by laser diffraction, the median particle size is from about 50 μm to about 100 μm, and the dosage form according to Claim 4 or 5.

7. When measured by laser diffraction, the 10th percentile of the particle size is from about 1 μm to about 30 μm, and the dosage form according to Claim 6.

8. When measured by laser diffraction, the 90th percentile of the particle size is from about 200 μm to about 300 μm, and the dosage form according to Claim 6.

9. When measured by laser diffraction, the 90th percentile of the particle size is about 2 to about 6 times the median of the particle size, and the dosage form according to Claim 6.

10. When measured by laser diffraction, the median of the particle size is about 2 to about 50 times the 10th percentile of the particle size, and the dosage form according to Claim 6.

11. When measured by laser diffraction, the 90th percentile of the particle size is about 10 to about 200 times the 10th percentile of the particle size, and the dosage form according to Claim 6.

12. Further comprising microcrystalline cellulose, and the dosage form according to any one of Claims 6 to 11.

13. A pharmaceutical composition containing particles containing bupropion, wherein at least 80% of the particle size of the particles is from about 1 μm to about 300 μm.

14. The particle size is measured by laser diffraction, and the pharmaceutical composition according to Claim 13.

15. When measured by laser diffraction, the median of the particle size of the particles containing bupropion is from about 50 μm to about 100 μm, and the pharmaceutical composition according to Claim 13 or 14.

16. When measured by laser diffraction, the diameter of the particles at the 10th percentile based on the particle size is from about 1 μm to about 30 μm, and the pharmaceutical composition according to Claim 13.

17. The pharmaceutical composition according to claim 13, wherein the diameter of 90 percentile of the fine particles based on the particle diameter is about 200 μm to about 300 μm when measured by laser diffraction.

18. The pharmaceutical composition according to claim 13, wherein the 90 percentile of the fine particle diameter is about 2 to about 6 times the median value of the fine particle diameter when measured by laser diffraction.

19. The pharmaceutical composition according to claim 13, wherein the median value of the particle diameter is about 2 to about 50 times the 10 percentile of the fine particle diameter when measured by laser diffraction.

20. The pharmaceutical composition according to claim 13, wherein the 90 percentile of the fine particle diameter is about 10 to about 200 times the 10 percentile of the fine particle diameter when measured by laser diffraction.

21. The pharmaceutical composition according to any one of claims 13, 14, 25, 26, 17 to 20, further comprising a sustained release or controlled release polymer.

22. The pharmaceutical composition according to any one of claims 13, 14, 25, 26, 17 to 21, further comprising magnesium stearate.

23. The fine particles according to claim 1, wherein the bupropion is bupropion hydrochloride.

24. The dosage form according to claim 4, wherein the bupropion is bupropion hydrochloride.

25. The pharmaceutical composition according to claim 13, wherein the bupropion is bupropion hydrochloride.

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