Treatment and prevention of cerebral atrophy

Abstract

This disclosure provides methods and kits for treating or preventing brain atrophy in subjects. The methods involve the administration of a sigma-1 receptor agonist and / or a dual modulator of the sigma-1 receptor and muscarinic receptor. Brain atrophy may be associated with, or can be associated with, neurological impairment.

Description

Technical Field

[0001] Cross-Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 581,517, filed September 8, 2023, entitled "TREATMENT AND PREVENTION OF BRAIN ATROPHY", the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to methods for treating or preventing brain atrophy related or associated with neurological disorders.

Background Art

[0003] Brain atrophy, or cerebral atrophy, refers to the loss of brain cells (neurons), connections between brain cells, and / or loss of brain volume, and when accelerated beyond the normal brain atrophy that occurs with aging, it is associated with many different diseases that can affect the brain. Brain atrophy can occur in a systemic form throughout the entire brain, or can be more localized to one part of the brain. Depending on the region and extent of tissue loss and atrophy, it can affect various brain functions including executive functions. Symptoms of brain atrophy can include seizures, dementia, memory loss, and aphasia.

[0004] Brain diseases and conditions that may be accompanied by brain atrophy include, inter alia, Alzheimer's disease, stroke, traumatic brain injury, Pick's disease, frontotemporal dementia, cerebral palsy, Huntington's disease, leukodystrophy, mitochondrial encephalomyopathy, multiple sclerosis, and infectious diseases such as encephalitis, neurosyphilis, and AIDS.

[0005] Brain atrophy can be detected and monitored using various non-invasive or minimally invasive brain imaging techniques, such as magnetic resonance imaging (MRI). However, treatments for brain atrophy are limited. Blood thinners, cholesterol-lowering agents such as statins, and certain antihypertensive drugs are used to address brain atrophy. Drugs used to treat Alzheimer's disease, such as Aricept (donepezil) and Namenda (memantine), are also used to slow atrophy. However, these drugs are not suitable for all individuals and may have limited or no effect in reducing or preventing abnormal brain atrophy. Therefore, in aging populations, there is an urgent need for novel approaches to prevent, slow, reduce, or halt brain atrophy. [Overview of the Initiative] [Means for solving the problem]

[0006] One aspect of the present disclosure comprises a method for treating or preventing brain atrophy in a human subject, comprising administering a therapeutically effective amount of a therapeutic agent that modulates both sigma-1 receptors and muscarinic acetylcholine receptors to the subject. In one aspect, the therapeutic agent is selected from tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine (A2-73 free base), 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine (A19-144 free base), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine (A1-41 free base), their enantiomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable crystals, their pharmaceutically acceptable cocrystals, and any combination thereof. In another embodiment, pharmaceutically acceptable salts are selected from hydrochlorides, hydrobroms, fumarates, sulfates, dihydrogen phosphates, benzoates, maleates, mesilates, edysilates, or oxalates. In yet another embodiment, pharmaceutically acceptable salts are hydrochlorides, and the drugs are selected from the group consisting of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride (A2-73), 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine hydrochloride (A19-144), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine hydrochloride (A1-41), their enantiomers, their pharmaceutically acceptable crystals, their pharmaceutically acceptable cocrystals, and any combination thereof. In one embodiment, a pharmaceutically acceptable cocrystal is formed between (i) a crystal of A2-73 free base, A2-73, A19-144 free base, A19-144, A1-41 free base, A1-41, and thus their enantiomers, and (ii) an acid or ionic salt. In one embodiment, the acid is selected from fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, benzoic acid, salicylic acid, oxalic acid, ethanedisulfonic acid, tartaric acid, citric acid, maleic acid, and any combination thereof. The ionic salt may be selected from quaternary ammonium cationic salts, transition metal salts, alkaline earth metal salts, or alkali metal salts.In one embodiment, the ionic salt is selected from lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, iron(II) chloride, iron(III) chloride, titanium chloride, chromium(III) chloride, scandium(III) chloride, manganese(II) chloride, copper(I) chloride, copper(II) chloride, nickel chloride, or aluminum chloride. In another embodiment, the therapeutic agent is selected from A2-73 free base, its crystals, its enantiomers, its enantiomer crystals, a pharmaceutically acceptable salt thereof, an enantiomer of a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt crystal thereof, or a cocrystal thereof. In yet another embodiment, the therapeutic agent is selected from A2-73, its crystals, its enantiomers, its enantiomer crystals, and its cocrystals. In various forms, the therapeutic agent includes amorphous A2-73 free base, crystalline form I A2-73 free base, amorphous A2-73, crystalline form I A2-73, crystalline form II A2-73, crystalline form III A2-73 enantiomer, (-) A2-73 enantiomer, amorphous A2-73 free base fumarate, crystalline form I A2-73 free base hydrogen fumarate, crystalline form II A2-73 free base hydrogen fumarate, crystalline form III A2-73 free base hydrogen fumarate, crystalline form IV A2-73 free base hydrogen fumarate, crystalline form V A2-73 free base mesylate form I, A2-73 free base sulfate form I, and A2-73 free base sulfate form II The following forms are selected: A2-73 free base oxalate form I, A2-73 free base oxalate form II, A2-73 free base oxalate form III, A2-73 free base dihydrogen phosphate form I, A2-73 free base edisylate form I, A2-73 free base benzoate form I, A2-73 free base hydrobromide crystal form A, A2-73 free base hydrobromide crystal form B, A2-73 free base maleate crystal form S5, A2-73 free base maleate crystal form S6, A2-73 cocrystal with tartaric acid cocrystal form CSII, A2-73 cocrystal with citric acid cocrystal form CSIII, or A2-73 cocrystal with malic acid cocrystal form CSIV, A2-73 and zinc chloride cocrystal, or combinations thereof.In yet another embodiment, the therapeutic agent is selected from A2-73 crystalline form I, A2-73 form II, A2-73 form III, and any combination thereof. Alternatively, the therapeutic agent is selected from (-)A2-73 enantiomer, (+)A2-73 enantiomer, (-)A2-73 enantiomer crystal, (+)A2-73 enantiomer crystal, (-)A2-73 enantiomer cocrystal, (+)A2-73 enantiomer cocrystal, and any combination thereof. In one embodiment, the therapeutic agent is selected from A2-73 crystalline form I, A2-73 crystalline form III, (-)A2-73 enantiomer, (-)A2-73 enantiomer crystal, (-)A2-73 enantiomer cocrystal, and any combination thereof. In another embodiment, the therapeutic agent is a cocrystal of zinc chloride and (-)A2-73 enantiomers in a molar ratio of approximately 1:1 to approximately 2:1.

[0007] In various embodiments of the method, the therapeutic dose may include approximately 0.5 mg to 100 mg per day, such as approximately 1 mg to 60 mg per day, or selected from approximately 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, or 60 mg per day. In one embodiment, the therapeutic dose is approximately 10 mg to 50 mg per day. The therapeutic dose can be administered through a dosage form selected from oral, intravenous, and transdermal forms. In one embodiment, the dosage form is a capsule formulated for oral administration. In another embodiment, the administration is daily administration for at least approximately 30 days, or up to approximately 96 weeks. In one embodiment, the administration comprises an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period in which the therapeutic dose of the drug is administered to the target, and the following (b) a rest period. The dosing period and the rest period may have the same duration or different durations. In one embodiment, the administration period is at least about 10, 11, 12, 13, and 14 days. In another embodiment, the rest period is about 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, or 14 days.

[0008] In various embodiments of this disclosure, the subject exhibits amyloid plaques or depositions in the brain. In one embodiment, the subject is suffering from or suspected to be suffering from a neurological disorder. The neurological disorders may be selected from cognitive impairment, Lewy body dementia, stroke, traumatic brain injury, infection, spinal cord injury, Alzheimer's disease, Parkinson's disease, dementia, Huntington's disease, amyotrophic lateral sclerosis, prion disease, Rett syndrome, fragile X syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith-Magenis syndrome, multiple sclerosis, frontotemporal dementia, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), and any combination thereof.

[0009] Another aspect of this disclosure comprises a method for preventing brain atrophy in subjects at risk of developing brain atrophy by administering a prophylactic effective dose of an agent that modulates both sigma-1 receptors and muscarinic acetylcholine receptors to the subject. In one aspect, brain atrophy manifests as a reduction or loss of brain tissue volume in at least one brain region compared to the brain tissue volume in a control sample, the brain region being selected from the frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, whole brain white matter, and whole brain gray matter, and the control sample being obtained from a healthy individual or a previous sample from the subject. In another aspect, brain atrophy is associated with or suspected to be associated with a brain infection, brain inflammation, neurological disorder, or any combination thereof. Neurological disorders may be selected from cognitive impairment, Lewy body dementia, stroke, traumatic brain injury, spinal cord injury, infection, Alzheimer's disease, Parkinson's disease, dementia, Huntington's disease, amyotrophic lateral sclerosis, prion disease, Rett syndrome, fragile X syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith-Magenis syndrome, multiple sclerosis, frontotemporal dementia, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), and any combination thereof. In one embodiment, the risk of developing brain atrophy is associated with one or more symptoms in the subject, selected from amnesia, difficulty speaking, difficulty writing, loss of language, inability to understand language, memory impairment, cognitive dysfunction, hallucinations, mood and personality changes, irrational judgment, seizures, loss of consciousness, spasms, teeth clenching, or any combination thereof.In yet another aspect, the risk of developing brain atrophy is associated with one or more disorders selected from cerebral palsy, Lewy body dementia, encephalitis, HIV, AIDS, cognitive impairment, stroke, traumatic brain injury, spinal cord injury, infection, Alzheimer's disease, Parkinson's disease, dementia, Huntington's disease, amyotrophic lateral sclerosis, prion disease, Rett syndrome, fragile X syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith-Magenis syndrome, multiple sclerosis, frontotemporal dementia, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), and any combination thereof.

[0010] In various embodiments, a method for preventing brain atrophy in subjects requiring prevention of brain atrophy comprises administering a prophylactic effective amount of a prophylactic agent to the subject that modulates both sigma-1 receptors and muscarinic acetylcholine receptors, the prophylactic agent being selected from tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine (A2-73 free base), 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine (A19-144 free base), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine (A1-41 free base), their enantiomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable crystals, their pharmaceutically acceptable cocrystals, and any combination thereof. In another embodiment, the pharmaceutically acceptable salts are selected from hydrochloride, hydrobromide, fumarate, sulfate, dihydrogen phosphate, benzoate, maleate, mesylate, edisylate, or oxalate. In yet another embodiment, the pharmaceutically acceptable salt is a hydrochloride salt, and the prophylactic agent is selected from the group consisting of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride (A2-73), 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine hydrochloride (A19-144), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine hydrochloride (A1-41), their enantiomers, their pharmaceutically acceptable crystals, their pharmaceutically acceptable cocrystals, and any combination thereof. In one embodiment, the pharmaceutically acceptable cocrystal is formed between (i) a compound selected from A2-73 free base, A2-73, A19-144 free base, A19-144, A1-41 free base, A1-41, and thus their enantiomers, crystals, and (ii) an acid or ionic salt. In one embodiment, the acid is selected from fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, benzoic acid, salicylic acid, oxalic acid, ethanedisulfonic acid, tartaric acid, citric acid, maleic acid, and any combination thereof. Furthermore, the ionic salt is selected from quaternary ammonium cationic salts, transition metal salts, alkaline earth metal salts, or alkali metal salts.In one embodiment, the ionic salt is selected from lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, iron(II) chloride, iron(III) chloride, titanium chloride, chromium(III) chloride, scandium(III) chloride, manganese(II) chloride, copper(I) chloride, copper(II) chloride, nickel chloride, or aluminum chloride. In another embodiment, the preventive agent is selected from A2-73 free base, its crystals, its enantiomers, its enantiomer crystals, a pharmaceutically acceptable salt thereof, an enantiomer of a pharmaceutically acceptable salt, a pharmaceutically acceptable salt crystal, or a cocrystal thereof. In one embodiment, the preventive agent is selected from A2-73, its crystals, its enantiomers, its enantiomer crystals, and its cocrystals. In various aspects, the prophylactic agent includes amorphous A2-73 free base, crystalline form I A2-73 free base, amorphous A2-73, crystalline form I A2-73, crystalline form II A2-73, crystalline form III A2-73 enantiomer, (-) A2-73 enantiomer, amorphous A2-73 free base fumarate, crystalline form I A2-73 free base hydrogen fumarate, crystalline form II A2-73 free base hydrogen fumarate, crystalline form III A2-73 free base hydrogen fumarate, crystalline form IV A2-73 free base hydrogen fumarate, crystalline form V A2-73 free base mesylate form I, A2-73 free base sulfate form I, and A2-73 free base sulfate form II The following forms are selected: A2-73 free base oxalate form I, A2-73 free base oxalate form II, A2-73 free base oxalate form III, A2-73 free base dihydrogen phosphate form I, A2-73 free base edisylate form I, A2-73 free base benzoate form I, A2-73 free base hydrobromide crystal form A, A2-73 free base hydrobromide crystal form B, A2-73 free base maleate crystal form S5, A2-73 free base maleate crystal form S6, A2-73 cocrystal with tartaric acid cocrystal form CSII, A2-73 cocrystal with citric acid cocrystal form CSIII, or A2-73 cocrystal with malic acid cocrystal form CSIV, A2-73 and zinc chloride cocrystal, or combinations thereof.In yet another embodiment, the preventive agent is selected from A2-73 crystalline form I, A2-73 form II, A2-73 form III, and any combination thereof. Alternatively, the preventive agent is selected from (-)A2-73 enantiomer, (+)A2-73 enantiomer, (-)A2-73 enantiomer crystal, (+)A2-73 enantiomer crystal, (-)A2-73 enantiomer cocrystal, (+)A2-73 enantiomer cocrystal, and any combination thereof. In one embodiment, the preventive agent is selected from A2-73 crystalline form I, A2-73 crystalline form III, (-)A2-73 enantiomer, (-)A2-73 enantiomer crystal, (-)A2-73 enantiomer cocrystal, and any combination thereof. In another embodiment, the preventive agent is a cocrystal of zinc chloride and (-)A2-73 enantiomers in a molar ratio of approximately 1:1 to approximately 2:1.

[0011] In various embodiments of this disclosure, the method comprises administering a prophylactic effective dose to a subject, the prophylactic effective dose being approximately 0.5 mg to approximately 100 mg per day, such as approximately 1 mg to approximately 60 mg per day, or selected from approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, or approximately 60 mg per day. In one embodiment, the prophylactic effective dose is approximately 10 mg to approximately 50 mg per day. The prophylactic effective dose may be administered to the subject via a dosage form selected from oral, intravenous, and transdermal dosage forms. In one embodiment, the dosage form is a capsule formulated for oral administration. The administration may be daily for at least approximately 30 days, or up to approximately 96 weeks. In one embodiment, the administration comprises an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period in which a prophylactic effective dose of the prosperant is administered to the subject, and the following (b) a rest period. The dosing period and the rest period may have the same duration or different durations. In one embodiment, the administration period is at least about 10, 11, 12, 13, and 14 days. In another embodiment, the rest period is about 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, or 14 days.

[0012] Color drawing reference The application file shall include at least one drawing drawn in color. A copy of the publication of this patent application containing the color drawing shall be provided by the Patent Office after the application and payment of the required fees. [Brief explanation of the drawing]

[0013] [Figure 1] The graphs depict the changes in the percentage volume of different brain regions before and after treatment with ANAVEX® 2-73 at week 48. Statistical significance is indicated by asterisks [*, **, ***, ****] when the p-values ​​are <0.05, 0.01, 0.001, or 0.0001, respectively, determined by a two-tailed unpaired t-test (*~****). [Figure 2] This diagram depicts the mean changes in brain volume before and after treatment with ANAVEX® 2-73 at 48 weeks. [Modes for carrying out the invention]

[0014] This disclosure is based in part on the finding that dual modulators of sigma-1 receptors and muscarinic receptors, such as ANAVEX® 2-73, are useful in treating and / or preventing brain atrophy. As used herein, treating brain atrophy means reducing or reversing existing brain atrophy. Preventing brain atrophy means blocking the formation or onset of brain atrophy and / or slowing its progression.

[0015] This disclosure encompasses a method for treating or preventing brain atrophy by administering a therapeutically effective dose of a dual modifier to a subject in need of treatment or prevention of brain atrophy. The therapeutically effective dose is an amount effective in treating and / or preventing brain atrophy in a human subject. In one embodiment, brain atrophy manifests as a reduction or loss of brain volume in at least one brain region selected from the group consisting of the whole gray matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, and whole white matter.

[0016] In various embodiments, brain atrophy is associated with, or linked to, cognitive impairment, stroke, Alzheimer's disease, Parkinson's disease, traumatic brain injury, multiple sclerosis, or infection. A method may include the step of detecting brain atrophy in a subject and administering the dual modifier described herein to the subject. Methods described herein may further include monitoring changes in brain atrophy before and after administration. Methods may also include other steps or methods for promoting and / or enhancing the treatment and / or prevention of brain atrophy.

[0017] In another embodiment, brain atrophy is used to determine or diagnose whether a subject has or is suspected of having a brain infection, brain inflammation, neurodegenerative disorder, neurodevelopmental disorder, or any combination thereof. In yet another embodiment, changes in brain atrophy are used to determine whether a disease underlying or associated with brain atrophy is worsening or improving, such diseases include brain infection, brain inflammation, neurodegenerative disorder, neurodevelopmental disorder, or any combination thereof.

[0018] I. Brain atrophy One aspect of this disclosure encompasses the treatment and / or prevention of brain atrophy. Brain atrophy can be observed and monitored using magnetic resonance imaging (MRI) or other imaging tools such as computed tomography (CT), positron emission tomography (PET), or single-photon emission computed tomography (SPECT) scans, each of which can produce objective measurements of atrophy by brain mass, size, volume, density, connectivity, hydration levels, and / or neuron count.

[0019] In one embodiment, brain atrophy in a test subject can be determined by determining the subject's whole brain volume using any imaging method and comparing the change in volume to a control or reference volume for the subject, or to a control value for brain volume obtained from a healthy age-matched population of subjects. Alternatively, brain atrophy in a test subject can be determined by determining the brain volume in a selected brain region of the subject and comparing it to a control or reference volume for the brain region of the subject, or to a control value for brain region obtained from a healthy age-matched population of subjects. Brain volume can be determined by measuring the volume of whole gray matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, and whole white matter.

[0020] Brain atrophy can be observed in the entire brain structure, including the gray matter and white matter, and in parts of the brain, most frequently in the frontal lobe, insular cortex, limbic lobe, parietal lobe, hippocampus, and temporal lobe regions. The symptoms of brain atrophy vary depending on which areas of the brain are affected and / or the underlying disease or disorder causing the atrophy. Typical symptoms of brain atrophy include dementia, memory loss, and difficulty performing daily tasks. Brain atrophy can lead to a loss of executive functions, such as the ability to eat and reason.

[0021] Naturally, the volume of the human brain changes with age and the stage of physical development. By the age of 6, the human brain has reached about 90% of its adult volume. Starting somewhere in the 40 years of life, the human brain begins to shrink, and by around age 40, the rate of shrinkage increases to about 5% per year. Therefore, some degree of atrophy is a normal and expected part of human aging. On the other hand, abnormally rapid or substantial brain shrinkage of the brain or brain region may be associated with brain disease or disorder, or brain injury.

[0022] Certain specific progressive neurological diseases, such as those affecting the central nervous system, are associated with brain atrophy caused by degeneration of specific cells in the brain. These diseases include, but are not necessarily limited to, dementia with Lewy bodies, stroke, neuroinfectious diseases, Alzheimer's disease, Parkinson's disease, dementia, Huntington's disease, prion disease, Rett syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith-Magenis syndrome, multiple sclerosis, motor neuron diseases (MND) such as amyotrophic lateral sclerosis, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, cerebral palsy, Rett syndrome, Angelman syndrome, Williams syndrome, multiple sclerosis, fragile X, infantile spasms and Smith-Magenis syndrome, schizophrenia, post-traumatic stress disorder (PTSD), any neuron damage including damage resulting from stroke, traumatic brain injury, and spinal cord injury, and frontotemporal dementia. Acquired diseases such as AIDS or Wernicke-Korsakoff syndrome can also cause progressive brain atrophy. Congenital conditions such as cerebral palsy can cause brain atrophy. Brain atrophy can occur resulting from acute brain injury from stroke, head trauma, CNS infection (e.g., encephalitis), or brain tumor.

[0023] The methods disclosed herein explicitly encompass treatment of other neurological diseases or disorders that may be accompanied by abnormal or accelerated brain atrophy, including but not necessarily limited to prion disease, motor neuron diseases (MND) such as amyotrophic lateral sclerosis, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), dementia, autism spectrum disorder, Rett syndrome, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), multiple sclerosis, childhood disintegrative disorder, fragile X, infantile spasms and Smith-Magenis syndrome, schizophrenia, post-traumatic stress disorder (PTSD), and any neuron damage including damage resulting from traumatic brain injury or spinal cord injury.

[0024] The present disclosure also encompasses methods for preventing brain atrophy in a subject, such as blocking, arresting, delaying, slowing the progression of, or avoiding the onset of brain atrophy in the subject. In another aspect, the subject is at risk of developing brain atrophy. In another aspect, such risk is manifested by one or more symptoms including amnesia, difficulty speaking, difficulty writing, loss of language, inability to understand language, memory impairment, cognitive dysfunction, hallucinations, changes in mood and personality, impaired judgment, convulsions, loss of consciousness, spasms, teeth clenching, or any combination thereof. In another aspect, such risk is associated with one or more disorders afflicting the subject, including cerebral palsy, encephalitis, HIV, AIDS, Huntington's disease, leukodystrophy, multiple sclerosis, stroke, syphilis, traumatic brain injury, Alzheimer's disease, infectious disorders, alcohol use disorder, physical brain injury, or any combination thereof.

[0025] II. Treatment of Neurological Diseases and Disorders Another aspect of the present invention provides a method for treating and / or preventing brain atrophy associated with or caused by a neurological disease or disorder described herein.

[0026] In one embodiment, this disclosure encompasses methods for treating and / or preventing brain atrophy associated with or related to Alzheimer's disease (AD). The most definitive feature of AD pathology is the progressive loss of brain tissue or brain volume, i.e., brain atrophy. While we do not wish to be bound by theory, brain atrophy commonly observed in patients with Alzheimer's disease may be associated with the formation of Aβ plaques. Specifically, the amyloid theory hypothesizes that amyloid beta may appear in the progressive stages of AD, which may go beyond the range of existing anti-Alzheimer's drugs such as inhibitors of β-site amyloid precursor protein cleavage enzymes (anti-BACE) or tau expression blockers. Due to the lack of reliable genomic markers that may be prognostic for the onset of AD, it has also been difficult to capture the disease in its early stages. Several biomarkers have become essential components of AD research. Due to the prevalence of AD pathology in the elderly, the same biomarkers are used in cognitive aging research. An unbiased descriptive classification scheme for these biomarkers is the "A / T / N" system, in which major AD biomarkers are divided into three binary categories based on their pathophysiological nature. "A" refers to the value of the β-amyloid biomarker (e.g., Ab42 / 40 ratio), "T" refers to the value of the tau biomarker (e.g., p-tau), and "N" refers to biomarkers of neurodegeneration or neuronal damage (e.g., structural MRI). To date, the only therapeutic intervention with proven efficacy is anti-beta-amyloid monoclonal antibodies (mAbs) targeting the "A" category. It is necessary to halt or slow the progression of brain atrophy in patients with Alzheimer's disease. Non-invasive brain imaging techniques such as MRI can be used to measure the level of atrophy in the brain.

[0027] Additionally, monitoring changes in brain atrophy can be used to evaluate the therapeutic effect of potential AD drug interventions. Stages of AD include early-onset AD, early-onset AD, or late-onset Alzheimer's disease. Early-onset Alzheimer's disease (EOAD) refers to the onset of AD at an age of 65 or younger. EOAD is often diagnosed late and is overshadowed by the more common late-onset AD (LOAD). EOAD accounts for about 5% of AD cases and differs significantly from LOAD, including its rapid course and the need for age-related psychosocial support. A significant percentage of EOAD are phenotypic variants that differ from the typical presentation of memory impairment in typical AD. Patients with EOAD often have greater parietal lobe atrophy, more white matter abnormalities, and less hippocampal volume loss compared to patients with LOAD. Phenotypic variants also have atrophy and white matter changes that anatomically correspond to cognitive changes and appear to involve alternative neural networks compared to typical AD. The management of EOAD is similar to the management of LOAD, but it needs to target specific cognitive domains involved and place particular emphasis on more age-appropriate psychosocial support and education. In one embodiment, this disclosure provides therapies for both EOAD and LOAD. In another embodiment, this disclosure provides therapies specifically for the early signs of EOAD or AD.

[0028] In another embodiment, the present disclosure provides a method for treating and / or preventing brain atrophy associated with and / or Rett syndrome (RSS), also known as cerebral atrophic hyperammonemia. RSS is a progressive disorder predominantly occurring in women and associated with cortical atrophy, stereotypic hand movements mimicking handwashing, severe mental deficits, and cortical and extrapyramidal dysfunction. The clinical progression of RSS is consistent with stunted neuronal development, which may result from either impaired cell differentiation or a lack of adequate trophic factors. Neuropathological studies of RS patients have confirmed (1) generalized brain atrophy involving the cerebrum and cerebellum, (2) decreased neuronal cell size and increased cell density throughout the brain, (3) decreased number of basal forebrain cholinergic neurons, and (4) decreased concentration of melanin-containing neurons in the substantia nigra. Additionally, biochemical studies have identified (1) decreased cholinergic markers in the neocortex, hippocampus, thalamus, and basal ganglia, (2) inconsistent and variable changes in bioamine biomarkers in postmortem tissue and cerebrospinal fluid (CSF), (3) elevated beta-endorphin levels in the thalamus and glutamate levels in CSF, and (4) no evidence of mitochondrial dysfunction. Taken together, these data suggest that RSS patients experience a primary deficit in brain neural activity, and that the formation and progression of brain atrophy may underlie some of the higher cognitive impairment and extrapyramidal dysfunction. Overall, the clinical, biochemical, and neuropathological data suggest that RSS is a neurodevelopmental disorder associated with or linked to brain atrophy. Genetically, Rett syndrome is most typically caused by mutations in the MECP2 gene located on the X chromosome. Mutations can arise sporadically or from germline mutations, but are typically not inherited. Mutations in the CDKL5 or FOXG1 genes have also been found in less than 10% of RSS cases. RSS is initially diagnosed by clinical observation, but the diagnosis is definitive if there is a gene deletion in the MECP2 gene. The onset and severity of RSS vary from person to person. Before the onset of symptoms, individuals generally appear to grow and develop normally. Early, subtle abnormalities in early infancy may include loss of muscle tone (hypotonia), difficulty feeding, and clumsiness of limb movement.Next, mental and physical symptoms gradually begin to appear. Individuals may experience other initial symptoms, including loss of the ability to use their hands intentionally and to speak, problems crawling or walking, and / or reduced eye contact. Following the loss of functional use of the hands, compulsive hand movements such as squeezing and washing may occur. Apraxia, the inability to perform motor functions, may interfere with all bodily movements, including gaze and speech. Children with RSS may also exhibit autism-like behaviors, such as incontinence, screaming seizures, uncomfortable crying, breath-holding, hyperventilation or air swallowing, avoidance of eye contact, lack of social / emotional reciprocity, marked impairment of the use of nonverbal behaviors to regulate social interaction, loss of speech, and paresthesia. Other symptoms include toe walking, sleep disturbances, strabismus, teeth grinding, difficulty chewing, growth retardation, seizures, cognitive impairment, and apnea (breath-holding), potential shortness of stature, hypotonia, delayed or absent walking ability, ataxia, microcephaly, gastrointestinal disorders, spasticity, chorea, and dystonia. Currently, there is no cure for RSS, but for example, MECP2 restoration using insulin-like growth factor-1 (IGF-1) has been shown to be promising in mouse models (Tropea, et al., Proc Natl Acad Sci USA., 106(6):2029-2034 (2009)). NMDA receptor antagonists have also been shown to be promising. Symptoms can also be treated with, for example, sleep aids, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (for self-injurious behavior), beta-blockers (for long QT syndrome), and medications to manage gastrointestinal dysfunction and malnutrition.

[0029] In another embodiment, this disclosure provides methods for treating and / or preventing brain atrophy associated with or linked to dementia. Dementia is a general term for severe cognitive impairment that interferes with daily activities. There is a link between brain atrophy and dementia. Studies have shown that dementia typically begins with a reduction in brain tissue, which may be limited to a specific part of the brain. For example, in frontotemporal dementia, the frontal and temporal lobes of the brain shrink. Gene mutations are linked to frontotemporal dementia. There is also Creutzfeldt-Jakob disease-associated dementia, which progresses abnormally rapidly. Other types of dementia, such as Alzheimer's disease or Lewy body dementia, may progress more slowly. Alzheimer's-associated dementia accounts for 60–80% of all dementia cases. Vascular dementia, caused by microhemorrhages and vascular occlusion in the brain, is the second most common cause of dementia. Individuals who experience brain changes caused by multiple types of dementia have mixed dementia. In short, dementia may be associated with, linked to, and caused by brain atrophy. The progression of brain atrophy further exacerbates dementia. This disclosure provides methods for treating and / or preventing dementia-related brain atrophy by reversing, reducing, slowing, stopping, and / or blocking brain cell loss, neuronal cytotoxicity, and / or brain shrinkage.

[0030] This disclosure also provides methods for modulating brain atrophy associated with, related to, and / or caused by Parkinson's disease (PD). PD is caused by the loss of nerve cells in a part of the brain called the substantia nigra. It is often age-related and characterized by brain cell degeneration. Such degeneration results in a decrease in dopamine in the brain. Because dopamine plays a crucial role in regulating bodily movement, PD is best known for causing slowed movement, tremors, and balance problems. Researchers have noted that many changes occur in the brains of people with Parkinson's disease, including the appearance and / or presence of Lewy bodies. Clumps of certain substances within brain cells are microscopic markers of Parkinson's disease. Cortical and subcortical atrophy is often seen in the early stages after the onset of PD and becomes more pronounced in the later stages of PD with the development of cognitive, non-motor, and mood dysfunction. Structural MRI may be used to monitor and / or predict the progression of PD. This disclosure provides methods for modulating PD-related brain atrophy by reversing, reducing, slowing, stopping, and / or blocking brain cell loss, neuronal cytotoxicity, and / or brain shrinkage.

[0031] III.How to use In one embodiment, brain atrophy in a test subject can be determined by assessing the subject's total brain volume and comparing the change in volume to a control or reference volume for the subject, or to a control value for brain volume obtained from a healthy age-matched population of subjects. Alternatively, brain atrophy in a test subject can be determined by assessing the brain volume in a selected brain region of the subject and comparing it to a control or reference volume for the brain region of the subject, or to a control value for the brain region obtained from a healthy age-matched population of subjects. Brain volume can be determined by measuring the volume of the whole brain gray matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, and whole brain white matter.

[0032] In one embodiment, the disclosure relates to a method for treating brain atrophy after it has been detected in a subject. Such treatments include, but are not limited to, reducing or reversing brain shrinkage; stopping, slowing, improving or reversing brain volume loss or brain cell loss; and stopping, slowing or reversing brain cell death. Such treatments may be achieved by administering one or more therapeutic activators to the subject, such as sigma-1 receptor agonists and / or dual modulators of sigma-1 receptors and muscarinic receptors.

[0033] This disclosure also encompasses methods for preventing brain atrophy. In one embodiment, such prevention includes blocking, inhibiting, delaying, slowing, or avoiding the onset of brain atrophy in a subject. In another embodiment, a subject is at risk of developing brain atrophy. Such prevention methods may be achieved by administering one or more prophylactic activators to a subject, such as sigma-1 receptor agonists and / or dual modulators of sigma-1 receptors and muscarinic receptors.

[0034] The modulating methods of this disclosure also include any suitable and available tools, instruments, apparatus, and / or techniques for monitoring or detecting brain features in various parts of the brain. Such brain features may include measurements of brain mass, size, volume, density, hydration levels, neuronal number, and / or neuronal connectivity. Such tools may include structural MRI.

[0035] IV. Therapeutic and / or prophylactic agents Sigma-1 receptor expression or activity is linked to neuronal activity in neurodevelopment / neurodegeneration, and sigma-1 receptor activation is associated with neuroprotection in human subjects and different in vitro and in vivo models. Such neuroprotection may be required in subjects diagnosed with or suspected of having neurological disorders such as neurodegeneration or neurodevelopmental disorders. Accordingly, one aspect of the present disclosure includes using therapeutic or prophylactic agents that are sigma-1 receptor agonists or dual modulators of sigma-1 receptors and muscarinic receptors to restore brain volume, halt and / or improve neuronal loss, and / or reduce or reverse brain atrophy in such subjects.

[0036] Non-exclusive examples of therapeutic or prophylactic agents include, but are not limited to, entacapone, nevicapone, nitecapone, opicapone, tolcapone, tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine (Anavex 2-73 free base), tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride (ANAVEX® 2-73, AV2-73, A2-73, or brarcamecin), 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine (ANAVEX 19-144 free base), 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine hydrochloride (ANAVEX® 19-144 or A19-144), tetrahydro-N,N-dimethyl-5 Examples include ,5-diphenyl-3-furamethaneamine (ANAVEX 1-41 free base), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine hydrochloride (ANAVEX® 1-41 or A1-41), 1-(3-4(((1R,3S,5S)-adamantan-1-yl)(phenyl)methyl)propyl)-4-methylpiperazine (ANAVEX® 1066 or "AV1066"), (1-(2,8-dimethyl-l-thia-3,8-diazaspiro(4,5)deca-3-yl)-3-(lH-indole-3-yl)propan-l-one) (also known as ANAVEX 3-71, AF710B), PRE-084, donepezil, fluvoxamine, amitriptyline, L-687, 384, and combinations thereof. Such enumerated therapeutic agents also encompass their enantiomers, stereoisomers, crystalline forms, salt forms, and cocrystal forms, and can therefore be administered in therapeutically effective doses to the target of need. In one embodiment, sigma-1 receptor agonists are A2-73, A2-73 free base, or their enantiomers, crystalline forms, pharmaceutically acceptable salts, analogs, or metabolites. A2-73, A2-73 free base, or salts thereof may be in racemic, stereoisomer, enantiomer, polymorph, or cocrystal forms. In one embodiment, enantiomers may be (+) or (-) rotations, or may be represented as (R) or (S) forms.In one embodiment, pharmaceutically acceptable cocrystals are formed between (i) free bases A2-73, A2-73, A19-144, A19-144, A1-41, and thus their enantiomers, polymorphs, and (ii) an acid or ionic salt. In another embodiment, the acid includes fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, benzoic acid, salicylic acid, oxalic acid, ethanedisulfonic acid, tartaric acid, citric acid, maleic acid, or combinations thereof. The ionic salt includes quaternary ammonium cationic salts, transition metal salts, alkaline earth metal salts, or alkali metal salts. In one embodiment, the ionic salt includes lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, iron(II) chloride, iron(III) chloride, titanium chloride, chromium(III) chloride, scandium(III) chloride, manganese(II) chloride, copper(I) chloride, copper(II) chloride, nickel chloride, or aluminum chloride.

[0037] In one embodiment, the therapeutic or prophylactic agent comprises tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine (A2-73 free base), its polymorphs, its enantiomers, its enantiomer polymorphs, a pharmaceutically acceptable salt thereof, an enantiomer of a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt polymorph thereof, or a cocrystal thereof. In another embodiment, the drug comprises tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride (A2-73), its polymorphs, its enantiomers, its enantiomer polymorphs, or a cocrystal thereof. In yet another embodiment, the drug comprises A2-73 free base in amorphous form, A2-73 free base in crystalline form I, A2-73 in amorphous form, A2-73 crystalline form I, A2-73 crystalline form II, A2-73 crystalline form III, (+) A2-73 enantiomer, and (-) A2-73 enantiomer. A2-73 free base in crystalline form I is disclosed and characterized in WO2019 / 200345A1, which is incorporated herein by reference in its entirety. Specifically, A2-73 free base in crystalline form I is substantially characterized by the XRPD pattern shown in Figure 16 and the particle shape depicted in Figure 15. In one embodiment, the A2-73 crystals are morph I, morph II, and / or morph III crystals disclosed and characterized in WO2017 / 013498A2, which is incorporated herein by reference in its entirety. Specifically, A2-73 crystalline form I is substantially characterized by the XRPD pattern shown in Figure 1 and the particle shape depicted in Figures 2 and 3. A2-73 crystalline form II is substantially characterized by the XRPD pattern shown in Figure 4, the particle shape depicted in Figure 7, and the FTIR spectrum shown in Figure 5. A2-73 crystalline form III is substantially characterized by the XRPD pattern shown in Figure 8, the particle shape depicted in Figure 11, and the FTIR spectrum shown in Figure 9. Analogues of A2-73 may include A1-41. Metabolites of A2-73 may include A19-144. In one embodiment, pharmaceutically acceptable salts include hydrochloride, hydrobromide, fumarate, sulfate, dihydrogen phosphate, benzoate, mesylate, edisylate, or oxalate.In another embodiment, the cocrystal comprises a pharmaceutically acceptable salt of A2-73 with an organic acid, including tartaric acid, citric acid, maleic acid, or a combination thereof. In another embodiment, A2-73 is an amorphous form of A2-73, a free base crystal form I of A2-73, a crystal form I of A2-73, a crystal form II of A2-73, a crystal form III of A2-73, a (+) enantiomer of A2-73, and a (-) enantiomer of A2-73. In one embodiment, the activator is an amorphous form of A2-73 free base fumarate, A2-73 free base hydrogen fumarate crystal form I, A2-73 free base hydrogen fumarate crystal form II, A2-73 free base hydrogen fumarate crystal form III, A2-73 free base hydrogen fumarate crystal form IV, A2-73 free base hydrogen fumarate crystal form V, and / or crystals thereof, all of which are disclosed and characterized in WO2019 / 200345A1, including XRPD patterns shown in Figures 29, 30, 32, 33, and 34, respectively. In another embodiment, A2-73 is other salt crystals such as A2-73 free base mesylate form I, A2-73 free base sulfate form I, A2-73 free base sulfate form II, A2-73 free base oxalate form I, A2-73 free base oxalate form II, A2-73 free base oxalate form III, A2-73 free base dihydrogen phosphate form I, A2-73 free base edisylate form I, A2-73 free base benzoate form I, all of which are disclosed and characterized in WO2019 / 200345A1, respectively, as shown in Figures 18-23 and 25-27, including XRPD patterns. In yet another embodiment, the activator is A2-73 free base hydrobromide crystal form A, A2-73 free base hydrobromide crystal form B, A2-73 maleate crystal form S5, or A2-73 maleate crystal form S6. These are disclosed and characterized in WO2021 / 158586A1, the disclosure of which is incorporated herein by reference in whole. In yet another embodiment, the activators are co-crystalline forms CSII of A2-73 co-crystal with tartaric acid, co-crystalline form CSIII of A2-73 co-crystal with citric acid, or co-crystalline form CSIV of A2-73 co-crystal with malic acid. These are disclosed and characterized in WO2023 / 208133A1, the disclosure of which is incorporated herein by reference in whole.In yet another embodiment, the activator is a cocrystal of A2-73 disclosed in U.S. Patent No. 12,018,005B1 and zinc chloride, the whole of which is incorporated by reference.

[0038] When the therapeutic or prophylactic agent is A2-73 or A2-73 free base, or their salts, enantiomers, polymorphs, or cocrystals, the therapeutic or prophylactic effective dose of A2-73 may be in the range of approximately 0.5 mg to approximately 100 mg, approximately 1 mg to approximately 80 mg, approximately 10 mg to approximately 70 mg, approximately 15 mg to approximately 55 mg, approximately 30 mg to approximately 50 mg, or approximately 3 mg to approximately 5 mg. When the therapeutic agent is A2-73, the therapeutic effective dose may be in the range of 0.5 mg to 100 mg, 1 mg to 80 mg, 10 mg to 70 mg, 15 mg to 55 mg, 30 mg to 50 mg, or 3 mg to 5 mg. If the drug is A2-73, the therapeutically effective dose may be approximately 0.5 mg, 1.0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg. In one embodiment, when the drug is A2-73, the therapeutic or prophylactic effective dose may be 0.5 mg, 1.0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg. In yet another embodiment, the therapeutic agent is A2-73 crystalline form I, A2-73 crystalline form II, or A2-73 crystalline form III, and their therapeutic or prophylactic effective doses may be in the range of approximately 0.5 mg to approximately 100 mg, approximately 1 mg to approximately 60 mg, approximately 30 mg to approximately 50 mg, or approximately 3 mg to approximately 5 mg.

[0039] When the therapeutic or prophylactic agent is 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine hydrochloride (A19-144), or 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine (A19-144 free base), or their salts, enantiomers, polymorphs, or cocrystals, the therapeutic or prophylactic effective dose may be in the range of approximately 0.5 mg to approximately 200 mg, approximately 1 mg to approximately 180 mg, approximately 10 mg to approximately 170 mg, approximately 15 mg to approximately 155 mg, approximately 30 mg to approximately 150 mg, approximately 40 mg to approximately 130 mg, approximately 50 mg to approximately 110 mg, approximately 60 mg to approximately 100 mg, approximately 70 mg to approximately 90 mg, approximately 80 mg to approximately 85 mg, or approximately 3 mg to approximately 5 mg. If the drug is A19-144, the therapeutically effective dose may be in the range of 0.5mg-200mg, 1mg-180mg, 10mg-170mg, 15mg-155mg, 30mg-150mg, 40mg-130mg, 50mg-110mg, 60mg-100mg, 70mg-90mg, 80mg-85mg, or 3mg-5mg. According to one theory, if the drug is A19-144, the effective therapeutic dose is approximately 0.5 mg, 1.0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg, It may be 95 mg, approximately 100 mg, approximately 110 mg, approximately 115 mg, approximately 120 mg, approximately 122 mg, approximately 125 mg, approximately 130 mg, approximately 132 mg, approximately 135 mg, approximately 138 mg, approximately 140 mg, approximately 145 mg, approximately 150 mg, approximately 155 mg, approximately 158 mg, approximately 160 mg, approximately 165 mg, approximately 168 mg, approximately 170 mg, approximately 172 mg, approximately 175 mg, approximately 180 mg, approximately 185 mg, approximately 190 mg, approximately 195 mg, or approximately 200 mg.In one embodiment, if the therapeutic agent is A19-144, the therapeutic or prophylactic effective dose is 0.5 mg, 1.0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg The dosage may be mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 122 mg, 125 mg, 130 mg, 132 mg, 135 mg, 138 mg, 140 mg, 145 mg, 150 mg, 155 mg, 158 mg, 160 mg, 165 mg, 168 mg, 170 mg, 172 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.

[0040] When the therapeutic or prophylactic agent is tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine hydrochloride (A1-41), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine (A1-41 free base), or its salts, enantiomers, polymorphs, or cocrystals, the therapeutic or prophylactic effective dose may be in the range of approximately 0.5 mg to approximately 200 mg, approximately 1 mg to approximately 180 mg, approximately 10 mg to approximately 170 mg, approximately 15 mg to approximately 155 mg, approximately 30 mg to approximately 150 mg, approximately 40 mg to approximately 130 mg, approximately 50 mg to approximately 110 mg, approximately 60 mg to approximately 100 mg, approximately 70 mg to approximately 90 mg, approximately 80 mg to approximately 85 mg, or approximately 3 mg to approximately 5 mg. If the therapeutic agent is A1-41, the therapeutic or prophylactic effective dose may be in the range of 0.5 mg to 200 mg, 1 mg to 180 mg, 10 mg to 170 mg, 15 mg to 155 mg, 30 mg to 150 mg, 40 mg to 130 mg, 50 mg to 110 mg, 60 mg to 100 mg, 70 mg to 90 mg, 80 mg to 85 mg, or 3 mg to 5 mg. According to one method, when the therapeutic agent is A1-41, the therapeutic or prophylactic effective dose is approximately 0.5 mg, 1.0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, and 90 mg. g may be approximately 95 mg, approximately 100 mg, approximately 110 mg, approximately 115 mg, approximately 120 mg, approximately 122 mg, approximately 125 mg, approximately 130 mg, approximately 132 mg, approximately 135 mg, approximately 138 mg, approximately 140 mg, approximately 145 mg, approximately 150 mg, approximately 155 mg, approximately 158 mg, approximately 160 mg, approximately 165 mg, approximately 168 mg, approximately 170 mg, approximately 172 mg, approximately 175 mg, approximately 180 mg, approximately 185 mg, approximately 190 mg, approximately 195 mg, or approximately 200 mg.In one embodiment, when the therapeutic or prophylactic agent is A1-41, the therapeutic or prophylactic effective dose is 0.5 mg, 1.0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, The dosage may be 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 122 mg, 125 mg, 130 mg, 132 mg, 135 mg, 138 mg, 140 mg, 145 mg, 150 mg, 155 mg, 158 mg, 160 mg, 165 mg, 168 mg, 170 mg, 172 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.

[0041] In one embodiment, the therapeutic or prophylactic agent is A2-73 and A2-73 free base, and the effective therapeutic dose includes a combination of amounts of approximately 0.5 mg to approximately 100 mg, approximately 1 mg to approximately 80 mg, approximately 10 mg to approximately 70 mg, approximately 15 mg to approximately 55 mg, approximately 30 mg to approximately 50 mg, or approximately 3 mg to approximately 5 mg. In another embodiment, the therapeutic agent is A2-73 and A19-144, and the therapeutically effective dose includes a combination of approximately 0.5 mg, approximately 1.0 mg, approximately 3 mg, approximately 5 mg, approximately 10 mg, 15 mg, approximately 20 mg, approximately 22 mg, approximately 25 mg, approximately 30 mg, approximately 32 mg, approximately 35 mg, approximately 38 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 58 mg, approximately 60 mg, approximately 65 mg, approximately 68 mg, approximately 70 mg, approximately 72 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, or approximately 100 mg. In another embodiment, the therapeutic agent is A2-73 and A1-41, and the therapeutically effective dose includes a combination of amounts of 0.5 mg, 1.0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg.

[0042] In one embodiment, the therapeutic or prophylactic agent is administered daily, every other day, three times a week, or once a week. In another embodiment, the agent is administered once a day, twice a day, or three times a day. In yet another embodiment, the therapeutically effective dose may be in the range of approximately 0.5 mg / day to approximately 100 mg / day, approximately 1 to approximately 60 mg / day, approximately 20 to approximately 50 mg / day, approximately 20 to approximately 30 mg / day, or approximately 15 to approximately 25 mg / day. In yet another embodiment, the therapeutically effective dose of A2-73 may be in the range of 0.5 mg / day to 100 mg / day, 1 to approximately 60 mg / day, 20 to approximately 50 mg / day, 20 to approximately 30 mg / day, or 15 to approximately 25 mg / day. In one embodiment, administering a therapeutic or prophylactically effective dose may provide a blood level of A2-73 of approximately 10 ng / ml to approximately 12 ng / ml. In one embodiment, administering a therapeutically effective dose of A2-73 can provide a blood level of A2-73 of 10 ng / ml to 12 ng / ml. In another embodiment, administering a therapeutically effective or prophylactically effective dose of A2-73 can provide a blood level of A2-73 of approximately 10 ng / ml, approximately 10.2 ng / ml, approximately 10.5 ng / ml, approximately 10.8 ng / ml, approximately 11 ng / ml, approximately 11.2 ng / ml, approximately 11.5 ng / ml, or approximately 12 ng / ml. In yet another embodiment, administering a therapeutically effective dose of A2-73 can provide a blood level of A2-73 of 10 ng / ml, 10.2 ng / ml, 10.5 ng / ml, 10.8 ng / ml, 11 ng / ml, 11.2 ng / ml, 11.5 ng / ml, or 12 ng / ml.

[0043] Therapeutic or prophylactic agents such as A2-73, A19-144, and A1-41, or their free bases, salts, or enantiomers, may be administered to the subject daily or every other day during the course of treatment or according to an intermittent dosing regimen. For example, A2-73 may be administered every 2, 3, 4, 5, 6, 7, 14, or 30 days. The frequency of administration may be once, twice, or three times on the day of administration. Therapeutic agents such as A2-73 may be administered over periods ranging from about 1 day to about 1 year, about 1 day to about 1 week, about 3 days to about 1 month, about 2 weeks to about 6 months, or about 2 months to about 4 months. Therapeutic agents may be administered over periods of about 1 day, about 7 days, about 30 days, about 60 days, about 120 days, or about 180 days or more. In some embodiments, the therapeutic agent A2-73 is administered over a period of approximately 12 weeks, approximately 24 weeks, approximately 36 weeks, approximately 48 weeks, approximately 57 weeks, approximately 96 weeks, or approximately 148 weeks, or approximately 208 weeks, indefinitely, or until the condition being treated is resolved. Furthermore, the administration regimen may include administering to the subject as a pharmaceutical composition or dosage form containing a therapeutically effective amount of the agent. In one embodiment, such administration follows an intermittent administration regimen of at least two cycles, each cycle comprising (a) an administration period in which a therapeutically effective amount of the pharmaceutical composition is administered to the patient, and (b) a subsequent rest period. In some embodiments, the administration period and the rest period may be the same or different in duration. Attention should be paid to administration and rest periods ranging from the lower limit of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 days (longer) to the upper limit of approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, and 14 days (shorter). Furthermore, administration periods of approximately 1 to 12 days and rest periods of approximately 1 to 12 days should be noted. In one embodiment, the administration period is 12 days, and the rest period is 12 days. Such regimens, particularly for oral dosage forms, are useful in which the therapeutically effective dose of the therapeutic agent or its pharmaceutical composition is approximately 1 mg to approximately 100 mg, especially approximately 30 mg to approximately 50 mg. Furthermore, an A2-73 dosage of approximately 3 mg to 5 mg administered intravenously is intended.

[0044] Other methods for administering therapeutic or prophylactic agents such as A2-73 free base, A19-144, A19-144 free base, A1-41, or A1-41 free base can be found, for example, in U.S. Patent No. 9,750,746, U.S. Patent Publication No. 2017 / 0360,798, U.S. Patent Publication No. 2019 / 0022052, U.S. Patent Publication No. 2018 / 0360,796, U.S. Patent Publication No. 2018 / 0169,059, U.S. Patent Publication No. 2018 / 0177,756, U.S. Patent Publication No. 2018 / 0169,060, and U.S. Patent Publication No. 2019 / 011,7615. The disclosures of each of the above patents and applications are expressly incorporated herein in their entirety.

[0045] V. Pharmaceutical Compositions One aspect of this disclosure encompasses pharmaceutical compositions, also called pharmaceutical formulations, for the delivery of therapeutic agents, such as sigma-1 receptor agonists, or dual modulators of sigma-1 receptors and muscarinic receptors. A pharmaceutical formulation includes a therapeutic agent and pharmaceutically acceptable excipients or carriers. Another aspect of this disclosure encompasses dosage forms (also referred to as "unit doses"). It encompasses a pharmaceutical composition and refers to the final product that is marketed and packaged in a form suitable for use. Depending on the method / route of administration, dosage forms may be in liquid, solid, or semi-solid form. This disclosure provides dosage forms suitable for the delivery of therapeutic agents, among many others, such as pills, tablets, capsules, beverages, and injections.

[0046] One aspect of this disclosure encompasses a pharmaceutical composition or dosage form comprising a therapeutic dose of a therapeutic agent. The therapeutic agent may be in the form of a free base or a pharmaceutically acceptable salt thereof. This includes pharmaceutically acceptable salts of compounds, including organic and inorganic salts such as acetates, aspartates, benzoates, tartrates, citrates, formates, glucons, glucurons, glutamates, fumarates, hydrochlorides, hydrobroms, hydroiodides, hypophosphates, isobutyrates, isocitrates, lactates, malates, maleates, meconates, methyl bromides, methanesulfons, monohydrates, mucinates, nitrates, oxalates, phenylpropionates, phosphates, phthalates, propions, pyruvates, salicylates, stearates, succinates, sulfates, tannates, tartrates, terephthalates, and valersates.

[0047] When the therapeutic or prophylactic agent is A2-73, A2-73 free base, or a salt thereof, the pharmaceutical composition may contain approximately 1 mg to 50 g, approximately 0.1 to 5 g, approximately 0.5 g to 3 g, approximately 1 mg to 55 mg, approximately 40 mg to 60 mg, approximately 80 mg to 120 mg, approximately 180 mg to 220 mg, approximately 0.1 g to 5 g, or approximately 0.5 g to 3 g of A2-73. Compositions or formulations containing A2-73 can be found, for example, in U.S. Patent No. 9,750,746, U.S. Patent Publication No. 2017 / 0360,798, U.S. Patent Publication No. 2019 / 0022052, U.S. Patent Publication No. 2018 / 0360,796, U.S. Patent Publication No. 2018 / 0169,059, U.S. Patent Publication No. 2018 / 0177,756, U.S. Patent Publication No. 2018 / 0169,060, and U.S. Patent Publication No. 2019 / 011,7615, each of which disclosures are incorporated herein by reference in whole.

[0048] If the therapeutic or prophylactic agent is A2-73, A2-73 free base, or a salt thereof, the composition or formulation may contain A2-73 in amounts of approximately 0.5 mg to approximately 100 mg, approximately 1 mg to approximately 80 mg, approximately 10 mg to approximately 70 mg, approximately 15 mg to approximately 55 mg, approximately 30 mg to approximately 50 mg, or approximately 3 mg to approximately 5 mg. If the therapeutic agent is A2-73, the formulation may contain A2-73 in amounts of 0.5 mg to approximately 100 mg, 1 mg to approximately 80 mg, 10 mg to approximately 70 mg, 15 mg to approximately 55 mg, 30 mg to approximately 50 mg, or 3 mg to approximately 5 mg. If the therapeutic agent is A2-73, the formulation may contain A2-73 in amounts of approximately 0.5 mg, approximately 1.0 mg, approximately 3 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 22 mg, approximately 25 mg, approximately 30 mg, approximately 32 mg, approximately 35 mg, approximately 38 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 58 mg, approximately 60 mg, approximately 65 mg, approximately 68 mg, approximately 70 mg, approximately 72 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, or approximately 100 mg. In one embodiment, if the therapeutic agent is A2-73, the formulation may contain A2-73 in amounts of 0.5 mg, 1.0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg.

[0049] If the therapeutic or prophylactic agent is A19-144, A19-144 free base, or a salt thereof, the composition may contain A19-144 in the range of approximately 0.5 mg to approximately 200 mg, approximately 1 mg to approximately 180 mg, approximately 10 mg to approximately 170 mg, approximately 15 mg to approximately 155 mg, approximately 30 mg to approximately 150 mg, approximately 40 mg to approximately 130 mg, approximately 50 mg to approximately 110 mg, approximately 60 mg to approximately 100 mg, approximately 70 mg to approximately 90 mg, approximately 80 mg to approximately 85 mg, or approximately 3 mg to approximately 5 mg. If the therapeutic agent is A19-144, the composition may contain A19-144 in amounts ranging from 0.5 mg to 200 mg, 1 mg to 180 mg, 10 mg to 170 mg, 15 mg to 155 mg, 30 mg to 150 mg, 40 mg to 130 mg, 50 mg to 110 mg, 60 mg to 100 mg, 70 mg to 90 mg, 80 mg to 85 mg, or 3 mg to 5 mg. According to one method, if the therapeutic agent is A19-144, the formulation contains A19-144 in doses of approximately 0.5 mg, 1.0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, and 90 mg. It may contain g in amounts of approximately 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 122 mg, 125 mg, 130 mg, 132 mg, 135 mg, 138 mg, 140 mg, 145 mg, 150 mg, 155 mg, 158 mg, 160 mg, 165 mg, 168 mg, 170 mg, 172 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.In one embodiment, if the therapeutic agent is A19-144, the formulation contains A19-144 in doses of 0.5 mg, 1.0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, and 90 mg. It may contain g, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 122 mg, 125 mg, 130 mg, 132 mg, 135 mg, 138 mg, 140 mg, 145 mg, 150 mg, 155 mg, 158 mg, 160 mg, 165 mg, 168 mg, 170 mg, 172 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.

[0050] If the therapeutic or prophylactic agent is A1-41, A1-41 free base, or a salt thereof, the preparation may contain A1-41 in amounts ranging from approximately 0.5 mg to approximately 200 mg, approximately 1 mg to approximately 180 mg, approximately 10 mg to approximately 170 mg, approximately 15 mg to approximately 155 mg, approximately 30 mg to approximately 150 mg, approximately 40 mg to approximately 130 mg, approximately 50 mg to approximately 110 mg, approximately 60 mg to approximately 100 mg, approximately 70 mg to approximately 90 mg, approximately 80 mg to approximately 85 mg, or approximately 3 mg to approximately 5 mg. If the therapeutic or prophylactic agent is A1-41, the formulation may contain A1-41 in amounts ranging from 0.5 mg to 200 mg, 1 mg to 180 mg, 10 mg to 170 mg, 15 mg to 155 mg, 30 mg to 150 mg, 40 mg to 130 mg, 50 mg to 110 mg, 60 mg to 100 mg, 70 mg to 90 mg, 80 mg to 85 mg, or 3 mg to 5 mg. According to one method, if the therapeutic agent is A1-41, the formulation contains A1-41 in approximately 0.5 mg, 1.0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, and 90 mg. It may contain in amounts of approximately 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 122 mg, 125 mg, 130 mg, 132 mg, 135 mg, 138 mg, 140 mg, 145 mg, 150 mg, 155 mg, 158 mg, 160 mg, 165 mg, 168 mg, 170 mg, 172 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.In one embodiment, if the therapeutic or prophylactic agent is A1-41, the formulation contains A1-41 in doses of 0.5mg, 1.0mg, 3mg, 5mg, 10mg, 15mg, 20mg, 22mg, 25mg, 30mg, 32mg, 35mg, 38mg, 40mg, 45mg, 50mg, 55mg, 58mg, 60mg, 65mg, 68mg, 70mg, 72mg, 75mg, 80mg, 85mg, and 90mg. It may contain g, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 122 mg, 125 mg, 130 mg, 132 mg, 135 mg, 138 mg, 140 mg, 145 mg, 150 mg, 155 mg, 158 mg, 160 mg, 165 mg, 168 mg, 170 mg, 172 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.

[0051] In yet another embodiment, the therapeutic or prophylactic agent is A2-73 crystalline form I, A2-73 crystalline form II, or A2-73 crystalline form III, and their therapeutically effective doses may be in the range of 0.5 mg to 100 mg, 1 mg to 60 mg, 30 mg to 50 mg, or 3 mg to 5 mg. When the agonist is A2-73, the therapeutic or prophylactic effective dose of A2-73 may be in the range of approximately 0.5 mg to approximately 100 mg, approximately 1 mg to approximately 60 mg, approximately 30 mg to approximately 50 mg, or approximately 3 mg to approximately 5 mg. In yet another embodiment, the therapeutic or prophylactic effective dose of A2-73 may be in the range of approximately 0.5 mg / day to approximately 100 mg / day, approximately 1 to approximately 60 mg / day, approximately 20 to approximately 50 mg / day, approximately 20 to approximately 30 mg / day, or approximately 15 to approximately 25 mg / day. In another embodiment, a therapeutically effective dose of A2-73 may range from 0.5 mg / day to 100 mg / day, 1 to 60 mg / day, 20 to 50 mg / day, 20 to 30 mg / day, or 15 to 25 mg / day. Administering a therapeutically effective or prophylactically effective dose of A2-73 can provide a blood level of approximately 10 ng / ml to approximately 12 ng / ml of A2-73. In one embodiment, administering a therapeutically effective dose of A2-73 can provide a blood level of 10 ng / ml to approximately 12 ng / ml of A2-73. In another embodiment, administering a therapeutically effective dose of A2-73 can provide a blood level of approximately 10 ng / ml, approximately 10.2 ng / ml, approximately 10.5 ng / ml, approximately 10.8 ng / ml, approximately 11 ng / ml, approximately 11.2 ng / ml, approximately 11.5 ng / ml, or approximately 12 ng / ml of A2-73. In another embodiment, administering a therapeutically effective or prophylactically effective dose of A2-73 can provide blood levels of A2-73 of 10 ng / ml, 10.2 ng / ml, 10.5 ng / ml, 10.8 ng / ml, 11 ng / ml, 11.2 ng / ml, 11.5 ng / ml, or 12 ng / ml.

[0052] Therapeutic or prophylactic agents can be formulated and administered to subjects by several different means. For example, compositions can generally be administered parenterally, intraperitoneally, intravascularly, transdermally, subcutaneously, or intrapulmonaryly in dosage units containing, as desired, conventional non-toxic, pharmaceutically acceptable adjuvants, carriers, excipients, and vehicles.

[0053] As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intrathecal, or intrasternal injection or infusion techniques. The formulation of pharmaceutical compositions is discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975) and Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY (1980).

[0054] In another embodiment, the therapeutic agent may be formulated to be suitable for administration to specific types of subjects, such as elderly or pediatric subjects, subjects with difficulty swallowing, subjects prone to seizures, or subjects prone to vomiting or nausea. As used herein, elderly refers to persons aged 65 years or older. For persons over 79 years, aged may also be used. Children include infants (0–2 years), children (2–12 years), or adolescents (13–18 years). For example, to facilitate the administration of the therapeutic agent to pediatric subjects, the formulation may contain excipients desirable for pediatric subjects, such as flavored oral suspensions, flavored caplets, or flavored capsules. Such flavors may be strawberry, apple, bubblegum, grape, or orange, and such formulations meet all the criteria necessary for pediatric use.

[0055] A pharmaceutical formulation comprises one or more pharmaceutically acceptable excipients or carriers. Non-limiting examples of excipients or carriers include chemical enhancers, wetting agents, pressure-sensitive adhesives, antioxidants, solubilizers, thickeners, plasticizers, adjuvants, carriers, excipients, vehicles, coatings, and any combination thereof. One or more excipients may be selected for oral, transdermal, parenteral, intraperitoneal, intravascular, subcutaneous, inhalation spray, rectal, or intrapulmonary administration.

[0056] In another embodiment, therapeutic agents may generally be formulated to improve patient compliance and prevent the subject from removing the drug delivery device. For example, therapeutic agents may be formulated to improve patient compliance and prevent removal of the drug delivery device by providing formulations for extended delivery. Extended delivery may range in duration from more than one day to several months. This may be particularly relevant to patients with impaired cognitive and / or motor control abilities. Extended delivery in terms of duration may range from about one day to about one year, about one day to about one week, about three days to about one month, about two weeks to about six months, or about two months to about four months.

[0057] Extended-release formulations can be used for substantially continuous delivery of a drug at a pre-selected rate. For example, with respect to the crystallinity of A2-73, the drug can be delivered at a rate of about 0.5 mg to about 100 mg / day, about 40 to about 60 g / day, or about 10 to about 30 g / day. An appropriate amount of crystalline A2-73 can be readily determined by those skilled in the art, for example, based on the intended duration of drug administration by the extended-release formulation, the delivery mechanism, the formulation, and the relative potency of the drug, among other factors.

[0058] i. Binder Non-limiting examples of binders suitable for various formulations include starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxoazolidone, polyvinyl alcohol, C 12 -C 18 Examples include fatty acid alcohols, polyethylene glycol, polyols, sugars, oligosaccharides, polypeptides, oligopeptides, and combinations thereof. Polypeptides can be any sequence of amino acids ranging from approximately 100 to approximately 300,000 daltons.

[0059] The binder may be introduced into a mixture to be granulated in solid form, including, but not limited to, crystals, particles, powders, or any other finely divided solid form known in the art. Alternatively, the binder may be dissolved or suspended in a solvent and sprayed onto the mixture in the granulating device as a binder fluid during granulation.

[0060] ii. Diluent Non-limiting examples of diluents (also called "fillers" or "diluents") include carbohydrates, inorganic compounds, and biocompatible polymers such as polyvinylpyrrolidone (PVP). Other non-limiting examples of diluents include dicalcium sulfate, tricalcium sulfate, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starch, sugars such as sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, and sorbitol, polyhydric alcohols, starch, pre-made direct compression diluents, and mixtures of any of the above.

[0061] iii. Disintegrant Disintegrants may be effervescent or non-effervescent. Non-limiting examples of non-effervescent disintegrants include starches such as corn starch, potato starch, and their gelatinized and modified forms; sweeteners; clays such as bentonite; microcrystalline cellulose; alginates; sodium starch glycolate; agar; guar; carob; karaya; pectin; and gums such as tragacanth. Preferred effervescent disintegrants, but not limited to, include sodium bicarbonate in combination with citric acid and sodium bicarbonate in combination with tartaric acid.

[0062] iv. Preservatives Non-exclusive examples of preservatives include, but are not limited to, ascorbic acid and its salts, ascorbyl palmitate, ascorbyl stearate, anoxomer, N-acetylcysteine, isothiocyanate benzyl, m-aminobenzoic acid, o-aminobenzoic acid, p-aminobenzoic acid (PABA), butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), caffeic acid, canthaxanthin, alpha-carotene, beta-carotene, beta-apocarotenic acid, carnosol, Carvacrol, catechin, cetyl gallate, chlorogenic acid, citric acid and its salts, clove extract, coffee bean extract, p-coumaric acid, 3,4-dihydroxybenzoic acid, N,N'-diphenyl-p-phenylenediamine (DPPD), dilauryl thiodipropionate, distearyl thiodipropionate, 2,6-di-tert-butylphenol, dodecyl gallate, edetate, elaginate, erythorbic acid, sodium erythorbate, esculetin, esculin, 6-ethoxy-1,2-dihydro-2,24-Trimethylquinoline, ethyl gallate, ethyl maltol, ethylenediaminetetraacetic acid (EDTA), eucalyptus extract, eugenol, ferric acid, flavonoids (e.g., catechin, epicatechin, epicatechin gallate, epigallocatechin (EGC), epigallocatechin gallate (EGCG), polyphenol epigallocatechin-3-gallate), flavones (e.g., apigenin, chrysin, luteolin), flavonols (e.g., dachicetin, myricetin, dendrobium), flavanones, flaxetin, fumaric acid, gallic acid, gentian extract, gluconic acid, glycine, gum (gum) Guaiacum), hesperetin, alpha-hydroxybenzylphosphinic acid, hydroxycinnamic acid, hydroxyglutaric acid, hydroquinone, N-hydroxysuccinic acid, hydroxytrilosol, hydroxyurea, rice bran extract, lactic acid and its salts, lecithin, lecithin citrate, R-alpha-lipoic acid, lutein, lycopene, malic acid, maltol, 5-methoxytryptamine, methyl gallate, monoglyceride citrate, monoisopropyl citrate, morin, beta-naphthoflavone, nordihydroguaretic acid (NDGA), octyl gallate, oxalic acid, palmityl citrate, phenothiazine, phosphatidylcholine, phosphoric acid, phosphate, phytic acid, phytyl biclomenol, pimento extract, methyl phosphate Propyl phosphate, polyphosphate, quercetin, trans-resveratrol, rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin, sinapic acid, succinic acid, stearyl citrate, syringic acid, tartaric acid, thymol, tocopherol (i.e., alpha-, beta-, gamma-, and delta-tocopherol), tocotrienol (i.e., alpha-, beta-, gamma-, and delta-tocotrienol), tyrosol, vanillic acid, 2,6-di-tert-butyl-4-hydroxymethylphenol (i.e., Ionox100), 2,4-(tris-3',5'-bi-tert-butyl-4'-hydroxybenzyl)-mesitylene (i.e., Ionox330), 2,4,Examples include 5-trihydroxybutyrophenone, ubiquinone, tertiary butylhydroquinone (TBHQ), thiodipropionic acid, trihydroxybutyrophenone, tryptamine, tyramine, uric acid, vitamin K and its derivatives, vitamin Q10, wheat germ oil, zeaxanthin, or combinations thereof.

[0063] v. Flavoring modifiers Suitable flavor modifiers include fragrances, flavor enhancers, and sweeteners. Fragrances include, but are not limited to, synthetic flavor oils, flavor aromatics, and / or natural oils, extracts from plants, leaves, flowers, and fruits, and combinations thereof. Other non-limited examples of flavors include citrus oils such as cinnamon oil, wintergreen oil, peppermint oil, clover oil, hay oil, anise oil, eucalyptus, vanilla, lemon oil, orange oil, grape and grapefruit oil, and fruit essential oils including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0064] As flavoring agents, but not limited to, cellulose hydroxypropyl ethers (HPCs) such as Klucel®, Nisswo HPC, and PrimaFlo HP22, low-substituted hydroxypropyl ethers (L-HPCs), cellulose hydroxypropyl methyl ethers (HPMCs) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel® and Metolose®, ethylcellulose (EC) such as E461, Ethocel®, Aqualon®-EC, Surelease and mixtures thereof, polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcellulose such as Natrosol®, carboxymethylcellulose and carboxymethylcellulose salts (CMCs) such as Aualon®-CMC, Kollicoat Examples include polyvinyl alcohol and polyethyl glycol copolymers such as IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic polymers such as Eudragit® EPO, Eudragit® RD100, and Eudragit® E100 and mixtures of acrylic polymers with cellulose ethers, sepifilms such as cellulose phthalate acetate, HPMC and stearic acid mixtures, cyclodextrins, and mixtures of these materials. In other embodiments, additional flavoring agents intended are described in U.S. Patents 4,851,226, 5,075,114, and 5,876,759, each of which is incorporated herein by reference in whole.

[0065] Non-limiting examples of sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier), saccharin and various salts thereof such as sodium salts, dipeptide sweeteners such as aspartame, dihydrochalcone compounds, glycyrrhizine, Stevia rebaudiana (stevioside), chloro derivatives of sucrose such as sucralose, sugar alcohols such as sorbitol, mannitol, and silitol, hydrolyzed starch hydrolysates, and synthetic sweeteners such as 3,6-dihydro-6-methyl-1,2,3-oxathiadin-4-one-2,2-dioxide, particularly potassium salts (acesulfame-K), and their sodium and calcium salts.

[0066] vi. Lubricants and flow enhancers Lubricant compositions may be used to lubricate the components forming a pharmaceutical composition. As flow enhancers, lubricants facilitate the removal of solid dosage forms during the manufacturing process. Non-limiting examples of lubricants and flow enhancers include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, Sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. A pharmaceutical composition will generally contain about 0.01% to about 10% by weight of lubricant. In some embodiments, a pharmaceutical composition will contain about 0.1% to about 5% by weight of lubricant. In further embodiments, a pharmaceutical composition will contain about 0.5% to about 2% by weight of lubricant.

[0067] vii. Dispersant The dispersants may include, but are not limited to, starch, alginic acid, polyvinylpyrrolidone, guar gum, kaolin, bentonite, refined woody cellulose, sodium starch glycolate, isomorphosilicate, and microcrystalline cellulose as a highly hydrophilic-lipophilic balance (HLB) emulsifying surfactant.

[0068] viii. Colorants Depending on the aspect of this disclosure, it may be desirable to include colorants. Suitable colorants include, but are not limited to, food, drug, and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext.D&C). These colors or dyes, along with their corresponding lakes and certain natural and derived colorants, may be suitable for use in various aspects of this disclosure.

[0069] ix. Backside modifier Non-exclusive examples of pH modifiers include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate, and sodium bicarbonate.

[0070] x. Chelating agents Chelating agents may be included as excipients to immobilize metal ion-containing oxidizing groups, but are not limited to those used to inhibit the oxidative degradation of morphinanes by these oxidizing groups. Non-limited examples of chelating agents include lysine, methionine, glycine, gluconates, polysaccharides, glutamates, aspartates, and disodium ethylenediaminetetraacetate (Na2EDTA).

[0071] xi. Antibacterial agents Antimicrobial agents may be included as excipients to minimize the degradation of the compounds by microbial agents, including bacteria and fungi, as described herein. Non-limiting examples of antimicrobial agents include parabens, chlorobutanol, phenol, calcium propionate, sodium nitrate, sodium nitrite, Na2EDTA, and sulfites, including, but not limited to, sulfur dioxide, sodium bisulfite, and potassium bisulfite.

[0072] xii. Release-controlled polymers Release-controlled polymers may be included in various solid-dose pharmaceutical compositions incorporating the compounds according to this disclosure. In one embodiment, the release-controlled polymer may be used as a tablet coating. In other embodiments, including, but not limited to, two-layer tablets, the release-controlled polymer may be mixed with granules and other excipients before forming the tablet by known processes, including, but not limited to, compression in a tablet mold. Suitable release-controlled polymers include, but not limited to, hydrophilic and hydrophobic polymers.

[0073] Suitable hydrophilic release-controlled polymers include, but are not limited to, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ether, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, nitrocellulose, cross-linked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides, ammonium alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, sodium carmellose alginate, carmellose calcium, carrageenan, fucoidan, ferceleran, gum arabic, carrageenan gum, ghati gum, guar gum, karaya gum, and carob gum. Examples include okra gum, tragacanth gum, scleroglucan gum, xanthan gum, hypnea, laminaran, acrylic polymers, acrylate polymers, carboxyvinyl polymers, copolymers of maleic anhydride and styrene, copolymers of maleic anhydride and ethylene, copolymers of propylene maleate anhydride or copolymers of isobutylene maleate anhydride), crosslinked polyvinyl alcohol and poly-N-vinyl-2-pyrrolidone, polyglucan diesters, polyacrylamide, polyacrylic acid, polyamide, polyethylene glycol, polyethylene oxide, poly(hydroxyalkyl methacrylate), polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polystyrene, polyvinylpyrrolidone, anionic and cationic hydrogels, and combinations thereof.

[0074] xiii. Coating Solid dosages containing the compounds according to this disclosure may include coatings that can control the release of the compounds, function as a moisture barrier or buffer, or modify the pH. As used herein, “control releasing coat” or “controlled release coat” is defined to mean a functional coating that may include, for example, at least one pH-independent polymer, a pH-dependent polymer (e.g., enteric or reverse enteric polymer), a soluble polymer, an insoluble polymer, a lipid, a lipid material, or a combination thereof. When applied to a dosage form, the coating may modify the release rate of the compounds according to this disclosure, either slower (e.g., when applied to a normal-release matrix dosage form), even slower (e.g., when applied to a controlled-release matrix dosage form), or when applied to an uncoated dosage form. For example, a controlled-release coating may be designed such that, when the controlled-release coating is applied to a dosage form, the combined dosage form with the controlled-release coating may exhibit a release of the compounds according to this disclosure such as “modified release,” “controlled release,” “sustained release,” “extended release,” “delayed release,” “long-term release,” or a combination thereof. The "controlled emission coating" may optionally include additional materials that can alter the function of the controlled emission coating.

[0075] As used herein, the term “moisture barrier” refers to a substance that inhibits or delays the absorption of moisture. The compounds according to this disclosure may be hygroscopic and therefore prone to degradation over time under high humidity conditions. The proportion of moisture barrier components and the amount of moisture barrier applied optionally to a controlled-release coating or core are typically such that the moisture barrier does not fall within the USP definition and the requirements of enteric coatings. Preferably, the moisture barrier may comprise an enteric and / or acrylic polymer, preferably an acrylic polymer, optionally a plasticizer, and a permeation enhancer. The permeation enhancer is a hydrophilic substance that allows water to enter without physically damaging the coating. The moisture barrier may further comprise other conventional inert excipients, which may improve the handling of extended-release formulations.

[0076] Coating and matrix materials that can be used in accordance with the present invention include polyvinyl-type synthetic polymers, e.g., polyvinyl chloride, polyvinyl acetate and its copolymers, polyvinyl alcohol, and polyvinylpyrrolidone; polyethylene-type synthetic polymers, e.g., polyethylene and polystyrene; acrylic acid polymers; biopolymers or modified biopolymers, e.g., cellulose polymers, shellac, and gelatin; fats, oils, higher fatty acids, and higher alcohols (i.e., acids and alcohols containing alkyl chains of at least 10 carbon atoms), e.g., aluminum monostearate, cetyl alcohol, hydrogenated beef tallow, hydrogenated castor oil, 12-hydroxystearyl alcohol, mono- or dipalmitate glyceryl; mono, di, or tristearate glyceryl; myristyl alcohol, stearic acid, stearyl alcohol, and polyethylene glycol; waxes; sugars and sugar alcohols, which are known in the art for use in controlled-release formulations.

[0077] The pH buffering properties of the coating are due to the group of compounds commonly used in antacid formulations, such as magnesium oxide, hydroxide, or carbonate; aluminum hydroxide, carbonic acid, or calcium silicate; and composite aluminum / magnesium compounds, such as Al2O3·6MgO·CO2·12H2O, (Mg6Al2(OH) 16 The coating material may be enhanced by introducing a selection of the following into the coating material: CO3·4H2O), MgO·Al2O3·2SiO2.nH2O, aluminum bicarbonate coprecipitate, or similar compounds; or other pharmaceutically acceptable pH buffering compounds, such as sodium, potassium, calcium, magnesium, and aluminum salts of phosphoric acid, carbonic acid, citrate, or other suitable weak acids, inorganic acids, or organic acids; or suitable organic bases, including basic amino acids; and salts or combinations thereof.

[0078] pH-dependent coatings perform the function of releasing a drug to a desired region of the gastrointestinal (GI) tract, such as the stomach or small intestine. When a pH-independent coating is desired, the coating is designed to achieve optimal release regardless of changes in the pH of the ambient fluid, such as the GI tract. When a coating is formulated to release the compound according to this disclosure into the intestines (particularly the upper small intestine), the coating is often referred to as an "enteric coating." pH-dependent coatings may include, but are not limited to, acrylic acid polymers and copolymers, such as polymers formed from acrylic acid, methacrylic acid, methyl acrylate, methyl acrylate, aminomethyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate (e.g., Eudragit®); cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate, cellulose phthalate acetate (CAP), cellulose trimellitic acetate, cellulose hydroxypropyl methylphthalate, cellulose hydroxypropyl methylsuccinate, and sodium carboxymethylcellulose; vinyl polymers and copolymers such as shellac (purified shellac), polyvinylpyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate (PVAP), vinyl chlorophosphate acetate copolymer, and ethylene vinyl acetate copolymer; zein; and salts and combinations thereof.

[0079] VI. Dosage form One aspect of this disclosure encompasses dosage forms of sigma-1 receptor agonists (also called "unit doses"), or dual regulators of sigma-1 receptors and muscarinic receptors. It encompasses pharmaceutical compositions and refers to end products that are commercially available and packaged in a form suitable for use. Depending on the method / route of administration, the dosage form may be in liquid, solid, or semi-solid form. This disclosure provides dosage forms suitable for the delivery of therapeutic agents, among many others, such as pills, tablets, capsules, beverages, and injections. This disclosure provides dosage forms suitable for the delivery of therapeutic agents to designated patient groups, such as elderly patients and pediatric patients, or in forms suitable for administration by healthcare providers and / or caregivers.

[0080] Another aspect of the present disclosure includes dosage forms of sigma-1 receptor agonists, or dual modifiers of sigma-1 receptors and muscarinic receptors, in either a therapeutically effective or prophylactically effective dose. Specifically, if such agonists are A2-73 or A2-73 free base, the dosage forms may include A2-73 in amounts of approximately 1 mg to approximately 50 g, approximately 1 mg to approximately 500 mg, approximately 1 mg to approximately 100 mg, approximately 1 mg to approximately 500 mg, approximately 50 to approximately 400 mg, approximately 75 to approximately 150 mg, approximately 150 to approximately 200 mg, approximately 40 mg to approximately 60 mg, approximately 80 mg to approximately 120 mg, or approximately 180 mg to approximately 220 mg. For example, the dosage form may include A2-73 in doses of 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, or 300 mg or more. In some embodiments, the dosage form may include A2-73 in doses of approximately 1 mg to approximately 500 mg, or approximately 1 mg to approximately 100 mg.

[0081] Dosage forms include those formulated for extended or sustained release, and those formulated for immediate release. For example, immediate-release dosage forms may include crystalline forms of A2-73 free base, A2-73, and A2-73 free base salt, as disclosed herein. For example, fast-degrading oral dosage forms may include, for example, A2-73 crystalline form I. Alternatively, dosage forms may include crystalline form I of A2-73 free base, or crystalline form I of A2-73 free base fumarate, formulated for inhalation drug delivery, either as a dry powder or an aerosol spray.

[0082] Dosage forms also include those formulated for topical administration. For example, a dosage form can be formulated as one or more of the following: gel, ointment, emulsion, microemulsion, solution, suspension, paste, gel, foam, spray, lotion, or cream. In one embodiment, the topical dosage form is a transdermal patch. When the dosage form is formulated as a transdermal patch, the transdermal patch may contain about 40 mg to about 60 mg, about 80 mg to about 120 mg, or about 180 mg to about 220 mg of A2-73 free base in crystalline form.

[0083] The dosage form can alternatively be formulated for oral administration. Orally formulated dosage forms may include tablets, capsules and chewable capsules, powders, granules, teas, drops, or liquid medications or syrups that are swallowed, chewed, or dissolved in water or sublingually. In some embodiments, the dosage form is an enteric-coated oral formulation.

[0084] If the dosage form is an enteric-coated oral formulation, the formulation may contain about 0.1 mg to about 60 mg of A2-73 free base, preferably about 1 mg to about 50 mg of A2-73 free base.

[0085] Enteric-coated oral formulations may also contain A2-73 free base salts in crystalline form. A2-73 free base salts may be fumarate, sulfate, mesylate, dihydrogen phosphate, edisylate, benzoate, hydrochloride, and oxalate. In one embodiment, the A2-73 salt is a fumarate. When the A2-73 salt is a fumarate, the enteric-coated oral formulation may contain about 0.1 to about 100 mg of A2-73 fumarate, preferably about 1 mg to about 55 mg of A2-73 fumarate.

[0086] Dosage forms also include those formulated for subcutaneous and / or intramuscular injection. For example, an intramuscular dosage form may comprise A2-73 in free base form, dissolved in an oil matrix for intramuscular injection, or alternatively, prepared as a suspension of free base for intramuscular injection. Dosage forms formulated for subcutaneous or intramuscular injection may comprise A2-73 in the salt or free base form disclosed herein, prepared as microspheres using methods known in the art. Alternatively, A2-73 in free base or salt form may be coated with a thin-layer coating, such as a zinc oxide coating, using, for example, atomic layer deposition (ALD) techniques, and used in formulations for subcutaneous or intramuscular injection. Alternatively, A2-73 free base may be dissolved in a biodegradable polymer matrix and then subcutaneously implanted (or used in transdermal patches, as further detailed below).

[0087] VII. Kit In one embodiment, the Disclosure provides a kit for practicing the methods disclosed herein. The kit may include one or more therapeutic agents, pharmaceutically acceptable carriers, solvents, buffers, etc. The kit may also include instructions for practicing the methods. Instructions included in the kit may be affixed to the packaging material or included as accompanying documentation. Instructions are typically, but not limited to, written or printed materials. Any medium capable of storing such instructions and communicating them to end users is contemplated by the Disclosure. Such media include, but are not limited to, electronic storage media (e.g., magnetic disks, tapes, cartridges, chips) and optical media (e.g., CD-ROMs). As used herein, the term “instructions” may include the address of an internet site providing the instructions.

[0088] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings generally understood by those skilled in the art in the field to which this invention pertains. The following references provide general definitions of many of the terms used herein: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994), The Cambridge Dictionary of Science and Technology (Walker ed., 1988), The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). Where used herein, the following terms have the meanings attributed to them unless otherwise specified.

[0089] When introducing elements of this disclosure or preferred embodiments thereof, the articles “a,” “an,” “the,” and “said” are intended to mean that one or more of the elements are present. The terms “comprising,” “including,” and “having” are intended to be comprehensive and mean that additional elements other than those listed may be present.

[0090] As used herein, the term "or" may be conjugated or separable.

[0091] The term “comprising” means “including, but not necessarily limited to,” and specifically indicates an open-ended inclusion or membership in a combination, group, series, etc., described in this specification. As used herein, the terms “comprising” and “including” are inclusive and / or open-ended and do not exclude additional, unlisted elements or method processes. The term “essentially consisting of” is more restrictive than “including,” but less restrictive than “consisting of.” Specifically, the term “essentially consisting of” limits membership to certain materials or steps and materials or steps that do not substantially affect the essential features of the claimed invention.

[0092] As used herein, terms such as “include,” “including,” “contain,” “containing,” and “having” mean “comprising.” This disclosure also intends other embodiments that “include,” “consist of,” and “essentially consist of,” the embodiments or elements presented herein, whether expressly described herein or otherwise.

[0093] As used herein, the term “substantially” means to a great or significant degree, but not to the same extent as “complete.”

[0094] As used herein, the terms “about” or “approximately,” when applied to one or more values ​​of interest, mean a value that is similar to the given reference value or within an acceptable margin of error for a particular value determined by those skilled in the art, which in part depends on how the value is measured or determined, such as the limitations of the measuring system. In one embodiment, the term “about” means any value, including both integer and fractional components, that is within a variation of up to ±10% of the value modified by the term “about.” Alternatively, “about” can mean within three or more standard deviations, according to the practice of the art. Alternatively, for example, with respect to biological systems or processes, the term “about” can mean within a number of digits of the value, within five times in some embodiments, and within two times in some embodiments. As used herein, the symbol “ ~ " means "about" or "approximately".

[0095] All ranges disclosed herein include both endpoints as distinct values, as well as all integers and fractions specified within the range. For example, the range 0.1 to 2.0 includes 0.1, 0.2, 0.3, 0.4...2.0. Where an endpoint is modified by the term "approximately", the specified range is extended by a variation of up to ±10% of any value within the range containing the endpoint, or by a variation within three or more standard deviations.

[0096] As used herein, the terms “active ingredient” or “active pharmaceutical ingredient” refer to a drug, active ingredient, compound, or substance, composition, or mixture thereof that provides a pharmacological, often beneficial, effect.

[0097] Where used herein, the terms “control” and “reference” are used interchangeably. A “reference” or “control” level may be a predetermined value or range used as a baseline or benchmark for evaluating measured results. “Control” also refers to a control experiment or control cells.

[0098] As used herein, the term “dose” refers to any form of active ingredient preparation or composition containing cells that contains an amount sufficient to initiate or produce a therapeutic effect with at least one dose. “Preparation” and “composition” are used interchangeably herein.

[0099] As used herein, the term “prevention” means preventing or reducing the progression of a disability to a statistically significant extent or to an extent detectable by a person skilled in the art.

[0100] As used herein, the term “gene” means a segment of DNA containing all the information necessary for the regulated biosynthesis of an RNA product, including promoters, exons, introns, and other untranslated regions that control expression.

[0101] As used herein, the terms “disorder,” “disease,” “condition,” and “dysfunction” are interchangeable and not limited to encompass abnormal conditions that adversely affect all or part of the structure or function of an organism. Diseases can be caused by external factors such as pathogens or by internal dysfunction. For example, internal dysfunction of the immune system can produce a variety of different diseases, including various forms of immunodeficiency, hypersensitivity, allergies, and autoimmune diseases. In humans, disease often refers to any injury, disability, disorder, syndrome, infection, deviant behavior, or atypical variation in structural and functional states that causes pain, dysfunction, suffering, social problems, or death in the affected person. Diseases can affect a person not only physically but also mentally, because suffering from a disease and living with a disease can change the affected person’s view of life. Diseases often present with or are associated with specific signs and symptoms. Interventions or treatments are often desired to eliminate, reduce, and / or reverse the course of the disease, and / or to alleviate or improve the physical and / or psychological symptoms therein.

[0102] As used herein, the terms “polymorph,” “polymorphic form,” “crystal,” and “crystalline” are used interchangeably and refer to ordered solid forms in which atoms, ions, and / or molecules are arranged and patterned in a particular manner, resulting in a specific and unique three-dimensional format. A single molecule may exist in multiple crystalline forms that may possess different physicochemical or biological properties. Different polymorphic forms of the same active pharmaceutical ingredient (API) can result in changes to the API’s solubility, dissolution rate, pharmacokinetics, and ultimately its bioavailability and efficacy in therapeutic use. Developing polymorphic forms and identifying which polymorphic form is most stable and / or most preferable is important in drug design and manufacture.

[0103] As used herein, the terms “co-crystal” and “cocrystal” are used interchangeably and generally refer to a solid that is a crystalline single-phase material composed of two or more different molecules or ionic compounds in a specific stoichiometric ratio. Essentially, a cocrystal consists of two or more components that form their own crystalline structure and have their own properties. Cocrystals may include organic compounds having acids or ionic salts. Commonly encountered cocrystals include hydrates, solvates, and inclusion compounds. Cocrystals are often stable and possess their own physicochemical and / or biological properties distinct from the individual components that make up the cocrystal.

[0104] As used herein, the terms “enantiomer,” “optical isomer,” or “optical counter” are used interchangeably and refer to one of two stereoisomers that, due to the chirality of the carbon atoms, cannot be superimposed on their own mirror image. Even a rearrangement or change in stereostructure of a molecule as a whole does not convert one chemical substance to its enantiomer. A chiral chemical structure rotates plane-polarized light. Therefore, enantiomers can be represented in (-) or (+) form, indicating the direction of optical rotation. There are three common nomenclature rules for specifying one of the two enantiomers (absolute configurations) of a given chiral molecule: the R / S system is based on the molecular geometry; the (+)- and (-)- systems are based on its optical rotational properties; and the D / L system is based on the molecule’s relationship to its enantiomers, such as glyceraldehyde. When a molecule is described as dextrorotatory, it rotates the plane of polarization clockwise and can also be represented as (+). When it is expressed as levorotatory, it rotates the plane of polarization counterclockwise and can also be expressed as (-). A mixture of equal amounts of each enantiomer, called a "racemic mixture" or "racemate," does not rotate light. Two enantiomers of the same molecule may have different physicochemical or biological properties, conferring differences in solubility, dissolution rate, pharmacokinetics, and ultimately bioavailability. In addition, a single enantiomer may have different crystalline structures, i.e., polymorphs. A single enantiomer may form cocrystals with other compounds or molecules. Stereoiomers include both enantiomers and diastereomers. Diastereomers, like enantiomers, share the same molecular formula and cannot be superimposed on each other, but they are not mirror images of each other.

[0105] As used herein, the term “polypeptide” means any polypeptide comprising two or more amino acids linked to one another by peptide bonds or modified peptide bonds, i.e., peptide isosteres. Polypeptides include both short chains commonly referred to as peptides, glycopeptides, or oligomers, and long chains commonly referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-coding amino acids. Polypeptides include amino acid sequences modified by either natural processes such as post-translational processing or by chemical modification techniques well known in the art. Such modifications are well described in basic texts and more detailed monographs, as well as in voluminous research literature.

[0106] As used herein, the terms “inhibit,” “suppress,” and “suppress” mean reducing or inhibiting a given biological process, condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0107] As used herein, the terms “treatment” and “to treat” mean the prevention, suppression, inhibition, reversal, mitigation, improvement, or inhibition of the progression of a biological process, including a disorder or disease, or the elimination of the disease. Treatment may be carried out in either an acute or chronic manner. The term “treatment” also means reducing the severity of a disease or symptom associated with such a disease before the disease develops. To “suppress” or “improve” a disease, disorder, or its symptoms involves administering the cells, compositions, or compounds described herein to a target after the clinical manifestation of such disease, disorder, or its symptoms. To “prevent” or “prevent” a disease, disorder, or its symptoms involves administering the cells, compositions, or compounds described herein to a target before the onset of the disease, disorder, or its symptoms. To “suppress” a disease or disorder involves administering the cells, compositions, or compounds described herein to a target after the induction of the disease or disorder, but before its clinical manifestation or the appearance of its symptoms.

[0108] As used herein, the terms “treatment,” “therapy,” and “therapy regimen” also refer to clinical interventions performed in response to a disease, disorder, or physiological condition that is present in or to which a patient may be susceptible. The goals of treatment include the relief or prevention of symptoms, the slowing or cessation of the progression or worsening of a disease, disorder, or condition, and / or the remission of a disease, disorder, or condition (e.g., a depressive disorder).

[0109] The terms "effective dose" and "therapeutic effective dose" refer to an amount sufficient to produce a beneficial or desirable biological and / or clinical outcome.

[0110] As used herein, the term “administer” to an animal or cell, such as a therapeutic entity for treating a depressive disorder, is intended to mean distributing, delivering, or applying the substance to an intended target. With respect to therapeutic agents, the term “administer” is intended to mean bringing the therapeutic agent into contact with, distributing, delivering, or applying the therapeutic agent to a subject by any preferred route for delivering the therapeutic agent to a desired location in the animal, including parenteral or oral delivery, intramuscular injection, subcutaneous / intradermal injection, intravenous injection, subarachnoid administration, oral administration, transdermal delivery, topical administration, and administration via an intranasal or respiratory route. The term “administer” includes self-administration and administration to a subject by another person.

[0111] As used herein, the terms “prevent” and “prevention” mean preventing or reducing the likelihood of developing a disease, disorder, or condition in a person who does not have the disease, disorder, or condition but is at risk of developing it or is likely to develop it.

[0112] As used herein, the term “subject” refers to an animal. Typically, subjects are mammals and may include primates (e.g., humans, male or female, infants, adolescents, or adults), non-human primates, rats, mice, rabbits, pigs, cattle, sheep, goats, horses, dogs, cats, fish, birds, etc. In one embodiment, a subject is a human. A subject may be an experimental animal (e.g., cynomolgus macaques, rats, mice, guinea pigs, etc.). Human subjects expressly encompass any age, size, sex, and race, including infants, children, teenagers, adults, or seniors (over 65 years of age).

[0113] It should also be understood that the various modes of treatment or prevention of medical conditions described herein include, but are less than, complete treatment or prevention, and are intended to mean “substantial” in that a detectable biological or medically relevant outcome is achieved.

[0114] Since various modifications can be made to the cells and methods described above without departing from the scope of the present invention, all matters contained in the above description and the examples given below should be interpreted as illustrative rather than restrictive. [Examples]

[0115] The above disclosures are provided only with respect to disclosures prior to the filing date of this application. Nothing in this specification should be construed as acknowledging that the present invention does not have prior rights to such disclosures for the sake of prior art.

[0116] The following examples are included to demonstrate the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that the inventors have found to work well in the practice of the present disclosure. However, those skilled in the art should understand that many modifications can be made in light of the present disclosure without departing from the spirit and scope of the present disclosure, and that similar or comparable results can still be obtained, and therefore all matters described herein should be construed as illustrative and not restrictive.

[0117] Example 1: Study design for brain atrophy associated with Alzheimer's disease patients ANAVEX® 2-73 (as used herein interchangeably with "A2-73" or "brarcamesin") was evaluated in a multicenter (52 medical research centers / hospitals in 5 countries), randomized, double-blind, placebo-controlled, 48-week Phase 2b / 3 trial (ANAVEX2-73-AD-004). This trial enrolled 508 participants with early-symptomatic Alzheimer's disease (mild cognitive impairment / mild dementia) from July 2018 to June 2021 (last patient visit for primary outcome was June 2022). The trial results showed favorable outcomes for cognitive and functional endpoints with brarcamesin at doses ranging from 10 mg to a maximum of 50 mg per day (patients were given A2-73 at daily doses of approximately 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg).

[0118] Example 2: Changes in brain atrophy in Alzheimer's patients Changes in the level of brain atrophy were monitored using structural MRI by comparing MRI at baseline with MRI obtained at the end of the study at week 48. The comparison showed that brarcamesin slowed, and in some cases reversed, brain atrophy in major regions of the whole brain. Such effects were not observed in the placebo group. A significant reduction in atrophy was observed in patients treated with brarcamesin compared to placebo (see Table 1 and Figure 1). The percentage changes in volume of the whole brain, whole gray matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, and temporal lobe regions were significantly reduced in the treatment group compared to the placebo group (p<0.005), and hippocampal and whole white matter volumes demonstrated a trend toward atrophy reduction without reaching statistical significance. [Table 1-1] [Table 1-2]

[0119] Example 3. Considerations regarding the treatment of brain atrophy associated with Alzheimer's disease. The clinical results described above, in an analysis of the intention-to-treat (ITT) population, showed that ANAVEX® 2-73 treatment met the primary endpoint and reduced clinical decline in overall cognitive and functional scales over 48 weeks. ANAVEX® 2-73 demonstrated a visible improvement in patients with Alzheimer's disease. Patients treated with ANAVEX® 2-73 were 84% more likely than placebo patients to have cognitive improvement of -0.50 points or more from baseline to the end of treatment in ADAS-Cog scores, with an odds ratio of 1.84 (p=0.015). On average, patients who showed cognitive improvement with ANAVEX® 2-73 treatment had an ADAS-Cog cognitive score improvement of -4.03 points. Treatment with ANAVEX® 2-73 was 167% more likely to improve function compared to placebo in terms of clinically meaningful improvement in ADCS-ADL score change of +3.5 points or more, with an odds ratio of 2.67 (p=0.0255). These data reflected significant improvement compared to the placebo group. The data also demonstrated clinically meaningful outcomes in cognition and function from baseline. In addition, treatment with ANAVEX® 2-73 statistically and significantly reduced cognitive decline as measured by ADAS-Cog by 45% compared to placebo at the end of treatment. These data represented a treatment difference of -1.85 points in mean score change (p=0.033).

[0120] ANAVEX® 2-73 treatment also met the secondary endpoint of reduction of clinical decline in cognitive and functional impairment as assessed by the Clinical Dementia Rating Scale Box Sum (CDR-SB) compared to placebo, with a treatment difference of -0.42 points (p=0.040) in mean score change, representing a 27% reduction in the ITT population.

[0121] ANAVEX® 2-73 was generally safe and well-tolerated. The incidence of therapeutic adverse events (TEAEs) during treatment was similar in the active and placebo groups, with dizziness being the most common TEAE. TEAEs with a threshold of 7.5% were mainly mild or moderate. No clinically significant changes in vital signs, laboratory values, or ECG parameters were observed in the active or placebo groups. The safety findings in the study were consistent with the known safety profile of ANAVEX® 2-73. In addition to the safety and efficacy demonstrated in the primary and key secondary endpoints, a pre-specified analysis of patients without SIGMAR1 gene mutations provides further confidence in the robustness of SIGMAR1 activation in the treatment of neurodegenerative diseases. Approximately 80% of the global population lacks SIGMAR1 gene mutations. ANAVEX® 2-73 was more effective in this pre-specified population. This effect was consistent with observations from previous clinical trials of ANAVEX® 2-73.

[0122] In addition to the results and observations described above, changes in brain atrophy were correlated with the therapeutic effect in the treatment group. This indicated a statistically significant reduction in brain atrophy in the treatment group compared to the placebo group. The reduction included a decrease in atrophy volume in the whole brain, whole gray matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, and temporal lobe regions. This was the first reported reduction or reversal of brain atrophy by pharmacotherapy. Therefore, ANAVEX® 2-73 was effective in reducing and reversing brain atrophy.

[0123] Example 4: Treatment of brain atrophy associated with Rett syndrome An 8-year-old girl has been diagnosed with Rett syndrome. Her neuropathological examination reveals generalized brain atrophy involving the cerebrum and cerebellum. The examination also shows a decrease in neuronal size and an increase in cell density throughout the brain. The girl was given 20 mg of ANAVEX® 2-73 oral capsules once daily for 16 weeks, and a reduction and reversal of brain atrophy was detected.

[0124] Example 5: Treatment of Parkinson's disease-related brain atrophy A 68-year-old man has been diagnosed with Parkinson's disease with dementia. MRI scans reveal cortical and subcortical atrophy. He has been treated with oral ANAVEX® 2-73 at a dose of 30 mg once daily for 48 weeks, and the progression of atrophy has slowed in the cortical and subcortical regions.

[0125] Example 6: Treatment of brain atrophy associated with dementia A 72-year-old man has been diagnosed with idiopathic dementia. MRI scans reveal brain shrinkage in the frontal and temporal lobes. He has been treated with oral ANAVEX® 2-73 at a dose of 35 mg once daily for 48 weeks, and the brain shrinkage has been controlled, limited, and no further shrinkage has been observed.

[0126] Example 7: Prevention of brain atrophy Two 67-year-old men experienced similar amnesia over a two-month period, starting with forgetting the location of their car keys and progressing to forgetting how to drive home. MRI scans did not reveal any observable brain shrinkage in either man. One man was given oral Anavex® 2-73 at a daily dose of 20 mg for eight weeks. His memory improved, he no longer forgot where he lived or his car keys, and his MRI showed no brain shrinkage. The other man did not take Anavex® 2-73 or any other medication. His amnesia worsened to the point where he was no longer able to drive. His MRI revealed significant brain shrinkage. In conclusion, Anavex® 2-73 is effective in preventing the onset of brain atrophy.

Claims

1. A method for treating brain atrophy in a subject requiring treatment for brain atrophy, comprising administering to the subject a therapeutically effective amount of a therapeutic agent that modulates both sigma-1 receptors and muscarinic acetylcholine receptors.

2. The aforementioned therapeutic agent, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine, 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine, Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine, The method according to claim 1, selected from their enantiomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable crystals, their pharmaceutically acceptable cocrystals, and any combination thereof.

3. The method according to claim 2, wherein the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, fumarate, sulfate, dihydrogen phosphate, benzoate, maleate, mesylate, edysilate, or oxalate.

4. The aforementioned therapeutic agent, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine hydrochloride, Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine hydrochloride, The method according to claim 2 or 3, selected from those enantiomers, those pharmaceutically acceptable crystals, those pharmaceutically acceptable cocrystals, and any combination thereof.

5. The aforementioned pharmaceutically acceptable cocrystal is (i) Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine, 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine, Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine hydrochloride, Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine hydrochloride, Compounds selected from those enantiomers, or their crystals, (ii) The method according to any one of claims 2 to 4, wherein a bond is formed between (ii) an acid or an ionic salt.

6. The method according to claim 5, wherein the acid is selected from fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, benzoic acid, salicylic acid, oxalic acid, ethanedisulfonic acid, tartaric acid, citric acid, maleic acid, and any combination thereof.

7. The method according to claim 5 or 6, wherein the ionic salt is selected from a quaternary ammonium cationic salt, a transition metal salt, an alkaline earth metal salt, or an alkali metal salt.

8. The method according to any one of claims 5 to 7, wherein the ionic salt is selected from lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, iron(II) chloride, iron(III) chloride, titanium chloride, chromium(III) chloride, scandium(III) chloride, manganese(II) chloride, copper(I) chloride, copper(II) chloride, nickel chloride, or aluminum chloride.

9. The method according to any one of claims 1 to 8, wherein the therapeutic agent is selected from tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine, its crystals, its enantiomers, crystals of its enantiomers, a pharmaceutically acceptable salt thereof, an enantiomer of the pharmaceutically acceptable salt thereof, crystals of the pharmaceutically acceptable salt thereof, and a cocrystal thereof.

10. The method according to any one of claims 1 to 9, wherein the therapeutic agent is selected from tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, its crystals, its enantiomers, the crystals of its enantiomers, and its cocrystals.

11. The aforementioned therapeutic agent, Amorphous form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride of crystalline form I (A2-73 crystalline form I), Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride of crystalline form II (A2-73 crystalline form II), Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride of crystalline form III (A2-73 crystalline form III), Amorphous form of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, Amorphous form of (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, Crystalline form of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride in crystalline form, Amorphous form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrogen fumarate, Hydrogen tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine fumarate in crystalline form I, Hydrogen tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine fumarate in crystalline form II, Hydrogen tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine fumarate of crystalline form III, Hydrogen tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine fumarate of crystalline form IV, Hydrogen tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine fumarate in crystalline form V, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine mesylate of crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine sulfate in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine sulfate in crystalline form II, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine oxalate in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine oxalate in crystalline form II, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine phosphate dihydrogen of crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine edisylate in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine benzoate in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrobromide in crystalline form A, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrobromide in crystalline form B, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine maleate with crystalline form S5, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine maleate in crystalline form S6, Cocrystal form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and tartaric acid. Cocrystal form CSIIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and citric acid. Cocrystal form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and malic acid. Cocrystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and zinc chloride. (-) Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and zinc chloride cocrystal, (+) Cocrystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and zinc chloride, and The method according to any one of claims 1 to 10, selected from any combination thereof.

12. The aforementioned therapeutic agent, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride in crystalline form II, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride of crystalline form III, Any of those cocrystals, and The method according to any one of claims 1 to 11, selected from any combination thereof.

13. The aforementioned therapeutic agent, Amorphous form of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, Amorphous form of (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, Crystalline form of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride in crystalline form, Those cocrystals, and The method according to any one of claims 1 to 11, selected from any combination thereof.

14. The aforementioned therapeutic agent, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride of crystalline form I (A2-73 crystalline form I), Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride of crystalline form III (A2-73 crystalline form III), Amorphous form of (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride in crystalline form, Those cocrystals, and The method according to any one of claims 1 to 11, selected from any combination thereof.

15. The method according to any one of claims 1 to 11, wherein the therapeutic agent is a cocrystal of (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and zinc chloride in a molar ratio of about 1:1 to about 2:

1.

16. The method according to any one of claims 1 to 15, wherein the therapeutically effective dose comprises approximately 0.5 mg to approximately 100 mg per day.

17. The method according to any one of claims 1 to 16, wherein the therapeutically effective dose is approximately 1 mg to approximately 60 mg per day, or selected from approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, or approximately 60 mg per day.

18. The method according to any one of claims 1 to 17, wherein the therapeutically effective dose is approximately 10 mg to approximately 50 mg per day.

19. The method according to any one of claims 1 to 18, wherein the therapeutically effective dose is administered through a dosage form selected from oral, intravenous, and transdermal forms.

20. The method according to claim 19, wherein the dosage form is a capsule formulated for oral administration.

21. The method according to any one of claims 1 to 20, wherein the administration is daily administration for at least about 30 days.

22. The method according to any one of claims 1 to 21, wherein the administration is a daily administration for a maximum of approximately 96 weeks.

23. The method according to any one of claims 1 to 22, wherein the administration comprises an intermittent administration regimen of at least two cycles, each cycle comprising (a) an administration period in which the therapeutically effective amount of the drug is administered to the subject, and (b) a rest period thereafter.

24. The method according to claim 23, wherein the administration period and the rest period have the same duration.

25. The method according to claim 23, wherein the administration period and the rest period have different durations.

26. The method according to any one of claims 23 to 25, wherein the administration period is at least about 10, 11, 12, 13, and 14 days.

27. The method according to any one of claims 23 to 25, wherein the aforementioned rest period is shorter than approximately 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, or 14 days.

28. The method according to any one of claims 1 to 27, wherein the subject exhibits amyloid plaques or deposition in the brain.

29. The method according to any one of claims 1 to 28, wherein the subject is suffering from or suspected to be suffering from a neurological disorder.

30. The method according to claim 29, wherein the neurological disorder is selected from cognitive impairment, Lewy body dementia, stroke, traumatic brain injury, infection, spinal cord injury, Alzheimer's disease, Parkinson's disease, dementia, Huntington's disease, amyotrophic lateral sclerosis, prion disease, Rett syndrome, fragile X syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith-Magenis syndrome, multiple sclerosis, frontotemporal dementia, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), and any combination thereof.

31. A method for preventing brain atrophy in subjects at risk of developing brain atrophy by administering a prophylactically effective dose of a drug that modulates both sigma-1 receptors and muscarinic acetylcholine receptors to the subjects.

32. The method according to claim 31, wherein the brain atrophy manifests as a reduction or loss of brain tissue volume in at least one brain region compared to the brain tissue volume in a control sample, the brain region being selected from the frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, whole brain white matter, and whole brain gray matter, and the control sample is obtained from a healthy individual or is a previous sample from the subject.

33. The method according to claim 31 or 32, wherein the brain atrophy is associated with or suspected to be associated with a brain infection, brain inflammation, neurological disorder, or any combination thereof.

34. The method according to claim 33, wherein the neurological disorder is selected from cognitive impairment, Lewy body dementia, stroke, traumatic brain injury, spinal cord injury, infection, Alzheimer's disease, Parkinson's disease, dementia, Huntington's disease, amyotrophic lateral sclerosis, prion disease, Rett syndrome, fragile X syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith-Magenis syndrome, multiple sclerosis, frontotemporal dementia, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), and any combination thereof.

35. The method according to any one of claims 31 to 34, wherein the risk of developing the aforementioned brain atrophy is associated with one or more symptoms in the subject, selected from amnesia, difficulty speaking, difficulty writing, loss of language, inability to understand language, memory impairment, cognitive dysfunction, hallucinations, mood and personality changes, irrational judgment, seizures, loss of consciousness, spasms, teeth clenching, or any combination thereof.

36. The method according to any one of claims 31 to 35, wherein the risk of developing the brain atrophy is associated with one or more disorders selected from cerebral palsy, Lewy body dementia, encephalitis, HIV, AIDS, cognitive impairment, stroke, traumatic brain injury, spinal cord injury, infection, Alzheimer's disease, Parkinson's disease, dementia, Huntington's disease, amyotrophic lateral sclerosis, prion disease, Rett syndrome, fragile X syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith-Magenis syndrome, multiple sclerosis, frontotemporal dementia, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), and any combination thereof.

37. The aforementioned drug, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine, 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine, Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine, The method according to any one of claims 31 to 36, selected from their enantiomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable crystals, their pharmaceutically acceptable cocrystals, and any combination thereof.

38. The method according to claim 37, wherein the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, fumarate, sulfate, dihydrogen phosphate, benzoate, maleate, mesylate, edisylate, and oxalate.

39. The pharmaceutically acceptable salt is the hydrochloride salt, and the therapeutic agent is, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine hydrochloride, Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine hydrochloride, The method according to claim 37 or 38, selected from the group consisting of their enantiomers, their pharmaceutically acceptable crystals, their pharmaceutically acceptable cocrystals, and any combination thereof.

40. The aforementioned pharmaceutically acceptable cocrystal is (i) Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine, 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine, Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethaneamine hydrochloride, Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furamethaneamine hydrochloride, Compounds selected from those enantiomers, or their crystals, (ii) The method according to any one of claims 37 to 39, wherein a bond is formed between (ii) an acid or an ionic salt.

41. The method according to claim 40, wherein the acid is selected from fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, benzoic acid, salicylic acid, oxalic acid, ethanedisulfonic acid, tartaric acid, citric acid, maleic acid, and any combination thereof.

42. The method according to claim 40 or 41, wherein the ionic salt is selected from quaternary ammonium cationic salts, transition metal salts, alkaline earth metal salts, and alkali metal salts.

43. The method according to any one of claims 40 to 42, wherein the ionic salt is selected from lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, iron(II) chloride, iron(III) chloride, titanium chloride, chromium(III) chloride, scandium(III) chloride, manganese(II) chloride, copper(I) chloride, copper(II) chloride, nickel chloride, and aluminum chloride.

44. The method according to any one of claims 31 to 43, wherein the agent is selected from tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine, its crystals, its enantiomers, the crystals of the enantiomers, a pharmaceutically acceptable salt thereof, an enantiomer of the pharmaceutically acceptable salt thereof, a crystal of the pharmaceutically acceptable salt thereof, and a cocrystal thereof.

45. The method according to any one of claims 31 to 44, wherein the agent is selected from tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, its crystals, its enantiomers, the crystals of its enantiomers, and its cocrystals.

46. The aforementioned drug, Amorphous form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride of crystalline form I (A2-73 crystalline form I), Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride of crystalline form II (A2-73 crystalline form II), Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride of crystalline form III (A2-73 crystalline form III), Amorphous form of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, Amorphous form of (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, Crystalline form of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride in crystalline form, Amorphous form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrogen fumarate, Hydrogen tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine fumarate in crystalline form I, Hydrogen tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine fumarate in crystalline form II, Hydrogen tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine fumarate of crystalline form III, Hydrogen tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine fumarate of crystalline form IV, Hydrogen tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine fumarate in crystalline form V, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine mesylate of crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine sulfate in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine sulfate in crystalline form II, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine oxalate in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine oxalate in crystalline form II, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine phosphate dihydrogen of crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine edisylate in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine benzoate in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrobromide in crystalline form A, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrobromide in crystalline form B, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine maleate with crystalline form S5, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine maleate in crystalline form S6, Cocrystal form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and tartaric acid. Cocrystal form CSIIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and citric acid. Cocrystal form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and malic acid. Cocrystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and zinc chloride. (-) Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and zinc chloride cocrystal, (+) Cocrystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and zinc chloride, and The method according to any one of claims 31 to 45, selected from any combination thereof.

47. The aforementioned drug, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride in crystalline form II, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride of crystalline form III, Those cocrystals, and The method according to any one of claims 31 to 46, selected from any combination thereof.

48. The aforementioned drug, Amorphous form of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, Amorphous form of (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, Crystalline form of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride in crystalline form, Those cocrystals, and The method according to any one of claims 31 to 46, selected from any combination thereof.

49. The aforementioned drug, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride in crystalline form I, Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride of crystalline form III, Amorphous form of (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride, (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride in crystalline form, Those cocrystals, and The method according to any one of claims 31 to 46, selected from any combination thereof.

50. The method according to any one of claims 31 to 49, wherein the agent is a cocrystal of (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furamethaneamine hydrochloride and zinc chloride in a molar ratio of about 1:1 to about 2:

1.

51. The method according to any one of claims 31 to 50, wherein the effective preventive dose comprises approximately 0.5 mg to approximately 100 mg per day.

52. The method according to any one of claims 31 to 51, wherein the effective preventive dose is approximately 1 mg to approximately 60 mg per day, or selected from approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, or approximately 60 mg per day.

53. The method according to any one of claims 31 to 52, wherein the effective preventive dose is approximately 10 mg to approximately 50 mg per day.

54. The method according to any one of claims 31 to 53, wherein the prophylactic effective dose is administered through a dosage form selected from oral, intravenous, and transdermal forms.

55. The method according to claim 54, wherein the dosage form is an oral capsule.

56. The method according to any one of claims 31 to 55, wherein the administration is daily administration for at least about 30 days.

57. The method according to any one of claims 31 to 56, wherein the administration is a daily administration for a maximum of approximately 96 weeks.

58. The method according to any one of claims 31 to 57, wherein the administration comprises an intermittent administration regimen of at least two cycles, each cycle comprising (a) an administration period in which the prophylactic effective amount of the drug is administered to the subject, and (b) a rest period thereafter.

59. The method according to claim 58, wherein the administration period and the rest period have the same duration.

60. The method according to claim 58, wherein the administration period and the rest period have different durations.

61. The method according to any one of claims 58 to 60, wherein the administration period is at least about 10, 11, 12, 13, or 14 days.

62. The method according to any one of claims 58 to 60, wherein the aforementioned rest period is shorter than approximately 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, or 14 days.

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