Treatment and prevention of brain atrophy

Abstract

The present disclosure provides methods and kits for treating or preventing brain atrophy in a subject. The methods involve administering a sigma-1 receptor agonist and / or a dual modulator of sigma-1 receptor and muscarinic receptor. The brain atrophy can be associated with or related to a neurological disorder.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application Serial 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. Technical Field

[0003] This disclosure relates to methods for treating or preventing brain atrophy that is associated with or related to neurological disorders. Background Technology

[0004] Brain atrophy (cerebral atrophy) refers to the loss of brain cells (neurons), the connections between brain cells, and / or the loss of brain volume. When brain atrophy accelerates beyond the normal rate of aging, it is associated with many different diseases that can affect the brain. Brain atrophy can manifest as a widespread form throughout the entire brain or it can be more localized to a specific part of the brain. Depending on the area and extent of tissue loss and atrophy, multiple brain functions, including executive functions, may be affected. Symptoms of brain atrophy can include seizures, dementia, memory loss, and aphasia.

[0005] Brain diseases and conditions that may involve brain atrophy include 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.

[0006] 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 have been used to combat brain atrophy. Drugs used to treat Alzheimer's disease, such as Aricept (donepezil) and Namenda (memantine), have also been used to slow the atrophy. However, these drugs are not suitable for everyone and may have limited to no significant effect in reducing or preventing abnormal brain atrophy. Therefore, in the context of an aging population, there is an urgent need for new methods to prevent, slow, reduce, or stop brain atrophy. Summary of the Invention

[0007] One aspect of this disclosure covers a method for treating or preventing brain atrophy in human subjects, the method comprising administering to the subject a therapeutically effective amount of a therapeutic agent that modulates both σ-1 receptors and muscarinic acetylcholine receptors. In one aspect, the therapeutic agent is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine (A2-73 free base); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethylamine (A19-144 free base); tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanylamine (A1-41 free base); its enantiomers, pharmaceutically acceptable salts, pharmaceutically acceptable crystals, pharmaceutically acceptable cocrystals, and any combination thereof. In another aspect, the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, fumarate, sulfate, dihydrogen phosphate, benzoate, maleate, methanesulfonate, edysilate, or oxalate. In yet another aspect, the pharmaceutically acceptable salt is a hydrochloride, and the reagent is selected from the group consisting of: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (A2-73); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethylamine hydrochloride (A19-144); tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethylamine hydrochloride (A1-41); its enantiomers, its pharmaceutically acceptable crystals, its pharmaceutically acceptable eutectics, and any combination thereof. In one aspect, a pharmaceutically acceptable eutectic is formed between (i) and (ii): (i) A2-73 free base, A2-73, A19-144 free base, A19-144, A1-41 free base, A1-41, its enantiomers, and their crystals; and (ii) an acid or ionic salt. In one aspect, the acid is selected from fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphoric acid, dihydrogen phosphoric acid, 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 cation salts, transition metal salts, alkaline earth metal salts, or alkali metal salts. In one aspect, the ionic salt is selected from lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, ferric chloride (II), ferric chloride (III), titanium chloride, chromium chloride (III), scandium chloride (III), manganese chloride (II), copper chloride (I), copper chloride (II), nickel chloride, or aluminum chloride. In another aspect, the therapeutic agent is selected from A2-73 free base, its crystals, its enantiomers, crystals of its enantiomers, its pharmaceutically acceptable salt, enantiomers of its pharmaceutically acceptable salt, crystals of its pharmaceutically acceptable salt, or eutectic thereof.In another respect, the therapeutic agent is selected from A2-73, its crystals, its enantiomers, crystals of its enantiomers, and their eutectics. In several respects, the therapeutic agent is selected from A2-73 free base in amorphous form, A2-73 free base in crystal form I, A2-73 in amorphous form, A2-73 crystal form I, A2-73 crystal form II, A2-73 crystal form III, (+)A2-73 enantiomer, (-)A2-73 enantiomer, A2-73 free base fumarate in amorphous form, A2-73 free base hydrogen fumarate in crystal form I, A2-73 free base hydrogen fumarate in crystal form II, A2-73 free base hydrogen fumarate in crystal form III, A2-73 free base hydrogen fumarate in crystal form IV, A2-73 free base hydrogen fumarate in crystal form V, A2-73 free base methanesulfonate type I, and A2-73 free base sulfate. Type I, A2-73 free base sulfate type II, A2-73 free base oxalate type I, A2-73 free base oxalate type II, A2-73 free base oxalate type III, A2-73 free base dihydrogen phosphate type I, A2-73 free base ethanedisulfonate type I, A2-73 free base benzoate type 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, eutectic form CSII of A2-73 eutectic with tartaric acid, eutectic form CSIII of A2-73 eutectic with citric acid, or eutectic form CSIV of A2-73 eutectic with malic acid, eutectic of A2-73 with zinc chloride, or combinations thereof. In another aspect, the therapeutic agent is selected from A2-73 crystal form I, A2-73 type II, A2-73 type III, and any combination thereof. Alternatively, the therapeutic agent is selected from (-) A2-73 enantiomers, (+) A2-73 enantiomers, crystals of (-) A2-73 enantiomers, crystals of (+) A2-73 enantiomers, eutectics of (-) A2-73 enantiomers, eutectics of (+) A2-73 enantiomers, and any combination thereof. In one aspect, the therapeutic agent is selected from A2-73 crystal form I, A2-73 crystal form III, (-) A2-73 enantiomers, crystals of (-) A2-73 enantiomers, eutectics of (-) A2-73 enantiomers, and any combination thereof. In another respect, the therapeutic agent is a eutectic of (-) A2-73 enantiomer and zinc chloride in a molar ratio of about 1:1 to about 2:1.

[0008] In several aspects of the method, the therapeutically effective dose includes about 0.5 mg to about 100 mg daily, such as about 1 mg to about 60 mg daily, or selected from about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg daily. In one aspect, the therapeutically effective dose is about 10 mg to about 50 mg daily. The therapeutically effective dose can be administered by a dosage form selected from oral, intravenous, and transdermal dosage forms. In one aspect, the dosage form is a capsule formulated for oral administration. In another aspect, the administration is daily administration for at least about 30 days or up to about 96 weeks. In one aspect, the administration comprises an intermittent dosing regimen of at least two cycles, each cycle comprising: (a) a dosing period during which the subject is administered a therapeutically effective dose of the drug; and thereafter (b) a rest period. The dosing period and the rest period may have the same duration or different durations. In one aspect, the dosing period is at least about 10 days, 11 days, 12 days, 13 days, and 14 days. On the other hand, the rest periods are approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, or 14 days.

[0009] In several aspects of this disclosure, the subject showed amyloid plaques or deposits in the brain. In one aspect, the subject had or was suspected of having a neurological disorder. The neurological disorder 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, prions, 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] Another aspect of this disclosure covers a method for preventing brain atrophy in subjects at risk of developing brain atrophy by administering to subjects a preventively effective amount of a drug, said drug modulating both σ-1 receptors and muscarinic acetylcholine receptors. In one aspect, brain atrophy is characterized by a reduction or loss of brain tissue volume in at least one brain region compared to the brain tissue volume in a control sample, wherein the brain region is selected from the frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, whole brain white matter, and whole brain gray matter, and wherein the control sample is obtained from a healthy individual or from a previous sample of the subject. In another aspect, brain atrophy is associated with or suspected of being associated with brain infection, brain inflammation, neurological disorders, or any combination thereof. Neurological disorders can 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, prions, Rett syndrome, Fragile X syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder unclassified (PDD-NOS), childhood disintegrative disorder, Smith-Magnanese 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 aspect, the risk of developing brain atrophy is associated with one or more of the following symptoms in the subject: amnesia, speech difficulties, writing difficulties, language loss, inability to understand words, memory impairment, cognitive impairment, hallucinations, mood and personality changes, irrational judgment, seizures, loss of consciousness, spasticity, clenching teeth, or any combination thereof. In another respect, the risk of developing brain atrophy is associated with one or more of the following disorders: 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, prions, Rett syndrome, Fragile X syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder unclassified (PDD-NOS), childhood disintegrative disorder, Smith-Magnanis 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.

[0011] In several respects, methods for preventing brain atrophy in subjects in need include administering to subjects a preventatively effective amount of a prophylactic agent that modulates both σ-1 receptors and muscarinic acetylcholine receptors, wherein the prophylactic agent is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine (A2-73 free base); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethylamine (A19-144 free base); tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanylamine (A1-41 free base); its enantiomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable crystals, its pharmaceutically acceptable cocrystals, and any combination thereof. In another respect, the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, fumarate, sulfate, dihydrogen phosphate, benzoate, maleate, methanesulfonate, ethanedisulfonate, or oxalate. In another aspect, 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-furanmethylamine hydrochloride (A2-73); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethylamine hydrochloride (A19-144); tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethylamine hydrochloride (A1-41); its enantiomers, its pharmaceutically acceptable crystals, its pharmaceutically acceptable eutectics, and any combination thereof. In one aspect, a pharmaceutically acceptable eutectic is formed between (i) and (ii): (i) is selected from the following compounds: A2-73 free base, A2-73, A19-144 free base, A19-144, A1-41 free base, A1-41, its enantiomers, its crystals; and (ii) an acid or ionic salt. In one aspect, the acid is selected from fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphoric acid, dihydrogen phosphoric acid, benzoic acid, salicylic acid, oxalic acid, ethanedisulfonic acid, tartaric acid, citric acid, maleic acid, and any combination thereof. And the ionic salt is selected from quaternary ammonium cation salts, transition metal salts, alkaline earth metal salts, or alkali metal salts. In one aspect, the ionic salt is selected from lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, ferric chloride (II), ferric chloride (III), titanium chloride, chromium chloride (III), scandium chloride (III), manganese chloride (II), copper chloride (I), copper chloride (II), nickel chloride, or aluminum chloride. In another aspect, the prophylactic agent is selected from A2-73 free base, its crystals, its enantiomers, crystals of its enantiomers, its pharmaceutically acceptable salt, enantiomers of its pharmaceutically acceptable salt, crystals of its pharmaceutically acceptable salt, or cocrystals thereof. In another aspect, the prophylactic agent is selected from A2-73, its crystals, its enantiomers, crystals of its enantiomers, or cocrystals thereof.In several aspects, the preventive agents are selected from 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 enantiomers, (-)A2-73 enantiomers, A2-73 free base fumarate in amorphous form, A2-73 free base hydrogen fumarate in crystalline form I, A2-73 free base hydrogen fumarate in crystalline form II, A2-73 free base hydrogen fumarate in crystalline form III, A2-73 free base hydrogen fumarate in crystalline form IV, A2-73 free base hydrogen fumarate in crystalline form V, A2-73 free base methanesulfonate type I, and A2-73 free base sulfate. Type I, A2-73 free base sulfate type II, A2-73 free base oxalate type I, A2-73 free base oxalate type II, A2-73 free base oxalate type III, A2-73 free base dihydrogen phosphate type I, A2-73 free base ethanedisulfonate type I, A2-73 free base benzoate type 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, eutectic form CSII of A2-73 eutectic with tartaric acid, eutectic form CSIII of A2-73 eutectic with citric acid, or eutectic form CSIV of A2-73 eutectic with malic acid, eutectic of A2-73 with zinc chloride, or combinations thereof. In another aspect, the prophylactic agent is selected from A2-73 crystal form I, A2-73 type II, A2-73 type III, and any combination thereof. Alternatively, the prophylactic agent is selected from (-) A2-73 enantiomers, (+) A2-73 enantiomers, crystals of (-) A2-73 enantiomers, crystals of (+) A2-73 enantiomers, eutectic crystals of (-) A2-73 enantiomers, eutectic crystals of (+) A2-73 enantiomers, and any combination thereof. In one aspect, the prophylactic agent is selected from A2-73 crystal form I, A2-73 crystal form III, (-) A2-73 enantiomers, crystals of (-) A2-73 enantiomers, eutectic crystals of (-) A2-73 enantiomers, and any combination thereof. In another aspect, the preventative agent is a eutectic of (-) A2-73 enantiomer and zinc chloride in a molar ratio of about 1:1 to about 2:1.

[0012] In several aspects of this disclosure, the method includes administering a prophylactic effective amount to a subject, wherein the prophylactic effective amount is about 0.5 mg to about 100 mg daily, such as about 1 mg to about 60 mg daily, or selected from about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg daily. In one aspect, the prophylactic effective amount is about 10 mg to about 50 mg daily. The prophylactic effective amount can be administered to the subject by a dosage form selected from oral, intravenous, and transdermal dosage forms. In one aspect, the dosage form is a capsule formulated for oral administration. Administration may be daily for at least about 30 days or up to about 96 weeks. In one aspect, administration comprises an intermittent dosing regimen of at least two cycles, each cycle comprising: (a) a dosing period during which the subject is administered a prophylactic effective amount of the agent; and thereafter (b) a rest period. The dosing period and the rest period may have the same duration or different durations. In one aspect, the dosing period is at least about 10 days, 11 days, 12 days, 13 days, and 14 days. On the other hand, the rest periods are approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, or 14 days.

[0013] Reference to color illustrations

[0014] This application contains at least one drawing in color. Upon request and payment of the necessary fees, the Patent Office will provide a copy of this patent application publication with the color drawings. Attached Figure Description

[0015] Figure 1 The changes in the percentage of brain volume in different regions before and after treatment with ANAVEX® 2-73 at week 48 were depicted. Statistical significance was indicated by an asterisk (p < 0.05, 0.01, 0.001, or 0.0001, respectively). , , , ]express.( - As determined by a two-tailed unpaired t-test.

[0016] Figure 2 The mean changes in brain volume before and after treatment with ANAVEX® 2-73 at week 48 were depicted. Detailed Implementation

[0017] This disclosure is partly based on the finding that dual modulators of σ-1 and muscarinic receptors, such as ANAVEX® 2-73, can be used to treat and / or prevent 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.

[0018] This disclosure covers methods for treating or preventing brain atrophy by administering a therapeutically effective amount of a dual modulator to a subject in need. A therapeutically effective amount is an amount that is effective in treating and / or preventing brain atrophy in human subjects. In one aspect, brain atrophy is characterized by a reduction or loss of brain volume in at least one brain region selected from the whole brain gray matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, and whole brain white matter.

[0019] Brain atrophy is associated with or related to cognitive impairment, stroke, Alzheimer's disease, Parkinson's disease, traumatic brain injury, multiple sclerosis, or infection in multiple ways. Methods may include steps of detecting brain atrophy in a subject and administering a dual modulator as described herein. The methods described herein may additionally include monitoring changes in brain atrophy before and after administration. Methods may also include other steps or approaches to promote and / or enhance the treatment and / or prevention of brain atrophy.

[0020] In another aspect, 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 aspect, changes in brain atrophy are used to determine the worsening or improvement of diseases that cause or are associated with brain atrophy, and such diseases include brain infections, brain inflammation, neurodegenerative disorders, neurodevelopmental disorders, or any combination thereof.

[0021] I. Brain atrophy

[0022] One aspect of this disclosure covers 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), each of which can produce objective measurements of atrophy in terms of brain mass, size, volume, density, connectivity, hydration level, and / or number of neurons.

[0023] In one aspect, brain atrophy in a tested subject can be determined by using any imaging method to determine the whole brain volume of the subject and comparing the volume change relative to a control or reference volume of the subject, or relative to a control value of brain volume obtained from a healthy, age-matched group of subjects. Alternatively, brain atrophy in a tested subject can be determined by determining the brain volume of selected brain regions of the subject and comparing it with a control or reference volume of the brain regions of those regions, or with a control value of brain regions obtained from a healthy, age-matched group of subjects. Brain volume can be determined by measuring the volume of whole-brain gray matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, and whole-brain white matter.

[0024] Brain atrophy occurs throughout the brain structure, including the gray matter, white matter, and certain parts of the brain, but is most common in the frontal lobe, insular cortex, limbic lobe, parietal lobe, hippocampus, and temporal lobe. Symptoms of brain atrophy vary depending on the affected brain region and / or the underlying disease or disorder causing it. Typical symptoms include dementia, memory loss, and behavioral impairments in daily tasks. Brain atrophy can lead to a loss of executive functions such as thinking and reasoning abilities.

[0025] Naturally, the volume of the human brain changes with age and stage of physical development. By age 6, the brain has reached approximately 90% of its adult volume. Starting sometime in the fourth decade of life, the brain begins to shrink, with the rate of shrinkage increasing to about 5% per year by age 40. Therefore, a certain degree of shrinkage is a normal and expected part of human aging. On the other hand, abnormally rapid or significant shrinkage of the brain or brain regions may be associated with brain diseases or disorders, or brain injury.

[0026] Certain progressive neurological disorders, such as those of the central nervous system, are associated with brain atrophy caused by the degeneration of certain cells in the brain. These disorders include, but are not necessarily limited to: Lewy body dementia, stroke, neurological infections, Alzheimer's disease, Parkinson's disease, dementia, Huntington's disease, prions, Rett syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder unclassified (PDD-NOS), childhood disintegrative disorder, Smith-Magnus syndrome, multiple sclerosis, motor neuron diseases (MND) such as amyotrophic lateral sclerosis, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorders, cerebral palsy, Rett syndrome, Angelman syndrome, Williams syndrome, multiple sclerosis, Fragile X, infantile spasms and Smith-Magnus syndrome, schizophrenia, post-traumatic stress disorder (PTSD), and any neuronal damage such as injury caused by stroke, traumatic brain injury, 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 also cause brain atrophy. Brain atrophy can occur due to acute brain injury from stroke, head trauma, CNS infections (such as encephalitis), or brain tumors.

[0027] The methods disclosed in this article explicitly consider treating other neurological diseases or disorders that may involve abnormalities or accelerate brain atrophy, including but not limited to prions, motor neuron diseases (MNDs) such as amyotrophic lateral sclerosis, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), dementia, autism spectrum disorders, Rett syndrome, Angelman syndrome, Williams syndrome, pervasive developmental disorder unclassified (PDD-NOS), multiple sclerosis, childhood disintegrative disorder, Fragile X, infantile spasms and Smith-Magnus syndrome, schizophrenia, post-traumatic stress disorder (PTSD), and any neuronal damage such as damage caused by traumatic brain injury or spinal cord injury.

[0028] This disclosure also covers methods for preventing brain atrophy, such as blocking, preventing, delaying, slowing, or avoiding the onset of brain atrophy in subjects. In another aspect, subjects are at risk of developing brain atrophy. In another aspect, such risk manifests as one or more symptoms, including amnesia, speech difficulties, writing difficulties, language loss, inability to understand words, memory impairment, cognitive impairment, hallucinations, mood and personality changes, irrational judgment, seizures, loss of consciousness, spasms, clenched teeth, or any combination thereof. In another aspect, such risk is associated with one or more disorders suffered by 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 disorders, physical brain injury, or any combination thereof.

[0029] II. Treatment of neurological disorders and disturbances

[0030] Another aspect of the invention provides methods for treating and / or preventing brain atrophy associated with or caused by neurological diseases or disorders as described herein.

[0031] In one aspect, this disclosure covers methods for treating and / or preventing brain atrophy associated with or related to Alzheimer's disease (AD). The most defining characteristic of AD pathology is the progressive loss of brain material or volume, i.e., brain atrophy. Without being bound by theory, the brain atrophy common in Alzheimer's patients may be related to the formation of Aβ plaques. Specifically, the amyloid theory posits that β-amyloid may appear late in AD, potentially beyond the reach of existing anti-Alzheimer's drugs such as β-site amyloid precursor protein lyase inhibitors (anti-BACE) or tau expression blockers. Capturing the disease at earlier stages has also been challenging due to the lack of reliable genomic biomarkers that can predict AD onset. Several biomarkers have become essential components of AD research. Due to the prevalence of AD pathology in older adults, the same biomarkers are used in cognitive aging research. One unbiased descriptive classification scheme for these biomarkers would be the "A / T / N" system, where major AD biomarkers are divided into three binary categories based on their pathophysiological characteristics. “A” refers to the value of a β-amyloid biomarker (e.g., Ab42 / 40 ratio); “T” refers to the value of a tau biomarker (e.g., p-tau); and “N” refers to a biomarker of neurodegeneration or neuronal damage (e.g., structural MRI). To date, the only proven therapeutic intervention is an anti-β-amyloid monoclonal antibody (mAb) targeting class “A”. There is a need to stop or slow the progression of brain atrophy in Alzheimer's disease patients. Non-invasive brain imaging techniques such as MRI can be used to measure the level of brain atrophy.

[0032] Additionally, monitoring changes in brain atrophy can be used to assess the therapeutic efficacy of potential AD pharmacological interventions. Stages of AD include early signs of AD, early-onset AD, and late-onset Alzheimer's disease (LOAD). Early-onset Alzheimer's disease (EOAD) refers to AD that begins at age 65 or younger. Diagnosis of EOAD is often delayed and masked by the more common late-onset AD (LOAD). EOAD accounts for approximately 5% of AD cases and differs significantly from LOAD, such as in its aggressive progression and the need for age-related psychosocial support. A large percentage of EOAD cases are phenotypic variants that differ from the common memory impairments present in typical AD. Compared to those with LOAD, patients with EOAD often have more severe parietal atrophy, more white matter abnormalities, and less hippocampal volume loss. These phenotypic variants also exhibit atrophy and white matter changes that anatomically correspond to cognitive changes and appear to involve alternative neural networks relative to typical AD. Management of EOAD is similar to that of LOAD, but particular emphasis should be placed on targeting the specific cognitive areas involved and providing more age-appropriate psychosocial support and education. In one aspect, this disclosure provides treatments for both EOAD and LOAD. In another aspect, this disclosure provides treatments specifically for early signs of EOAD or AD.

[0033] In another aspect, this disclosure provides methods for the treatment and / or prevention of brain atrophy associated with and / or related to Rett syndrome (RSS), also known as brain atrophy hyperammonemia. RSS is a progressive disorder predominantly in women and is associated with cortical atrophy, stereotyped hand movements mimicking handwashing, severe intellectual disability, and extracorporeal and extrapyramidal dysfunction. The clinical progression of RSS is consistent with the arrest of neuronal development, which may be due to impaired cell differentiation or lack of adequate trophic factors. Neuropathological studies in patients with RSS have confirmed: (1) widespread brain atrophy involving the cerebrum and cerebellum; (2) decreased neuronal cell size and increased cell packing density throughout the brain; (3) a reduced number of cholinergic neurons in the basal forebrain; and (4) a decreased concentration of melanin-containing neurons in the substantia nigra. In addition, biochemical studies have identified: (1) reduced cholinergic markers in the neocortex, hippocampus, thalamus, and basal ganglia; (2) inconsistent and variable changes in biogenic amine biomarkers in postmortem tissues and cerebrospinal fluid (CSF); (3) elevated β-endorphin levels in the thalamus and glutamate levels in the CSF; and (4) no evidence of mitochondrial dysfunction. In summary, these data suggest that patients with RSS experience primary deficits in brain activity, and that the formation and progression of brain atrophy may be a potential cause of some higher cognitive impairments and extrapyramidal dysfunction. Overall, clinical, biochemical, and neuropathological data indicate that RSS is a neurodevelopmental disorder associated with or related to brain atrophy. Genetically, Rette syndrome is most typically caused by a mutation in the MECP2 gene located on the X chromosome. This mutation can be sporadic or originate from germ cell mutations but is generally not heritable. Mutations in the CDKL5 or FOXG1 genes have also been found in less than 10% of RSS cases. RSS is initially diagnosed through clinical observation, but the diagnosis is definitive when a genetic defect is present in the MECP2 gene. The onset and severity of RSS vary from person to person. Before the onset of symptoms, the person often appears to be growing and developing normally. Even in early infancy, subtle abnormalities may include loss of muscle tone (hypotonia), feeding difficulties, and jerky limb movements. Subsequently, gradually, mental and physical symptoms begin to appear. The person loses the ability to use their hands purposefully and to speak, and may experience other early symptoms, including difficulty crawling or walking and / or reduced eye contact. Loss of functional use of the hands then manifests as compulsive hand movements such as wringing and washing. Apraxia, the inability to perform motor functions, can interfere with all bodily movements, including eye fixation and speech. Children with RSS may also exhibit autistic-like behaviors such as incontinence, screaming episodes, uncomfortably crying, breath-holding, hyperventilation or aerophagia, avoidance of eye contact, lack of social / emotional reciprocity, significantly impaired use of nonverbal behaviors to regulate social interaction, aphasia, and sensory problems.Other symptoms include gait on tiptoe, sleep problems, wide-based gait, teeth grinding, difficulty chewing, slow growth, seizures, cognitive impairment, and apnea (breath-holding), possible short stature, hypotonia, delayed or absent walking ability, ataxia, microcephaly, gastrointestinal problems, spasms, chorea, and dystonia. Currently, there is no cure for RSS, but restoring MECP2, for example using insulin-like growth factor-1 (IGF-1), has shown promise in mouse models (Tropea et al., Proc Natl Acad Sci USA., 106(6): 2029-2034 (2009)). NMDA receptor antagonists have also shown promise. In addition, symptoms can be treated with medications such as hypnotics, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (for self-harming behaviors), beta-blockers (for long QT syndrome), and agents used to manage gastrointestinal dysfunction and malnutrition.

[0034] In another aspect, this disclosure provides methods for treating and / or preventing brain atrophy associated with or related to dementia. Dementia is a general term for severe thinking problems that interfere with daily tasks. There is a link between brain atrophy and dementia. Studies show that dementia generally begins with shrinkage of brain tissue, which can be limited to certain parts of the brain. For example, in frontotemporal dementia, the frontal and temporal lobes of the brain shrink. Genetic mutations have been associated with frontotemporal dementia. In addition, there is dementia associated with Creutzfeldt-Jakob disease, which deteriorates unusually rapidly. Other types of dementia, such as Alzheimer's dementia or Lewy body dementia, can progress more slowly. Alzheimer's-related dementia accounts for 60-80% of all dementia cases. Vascular dementia, caused by microbleeds and vascular occlusion in the brain, is the second most common cause of dementia. Those who experience brain changes caused by multiple types of dementia have mixed-type dementia. In summary, dementia can be associated with, related to, and caused by brain atrophy. The progression of brain atrophy further worsens 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 cell poisoning, and / or brain shrinkage.

[0035] 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 leads to a decrease in dopamine in the brain. Because dopamine plays an essential role in regulating body movement, PD is best known for its bradykinesia, tremor, and balance problems. Researchers have noted many changes occurring in the brains of people with Parkinson's disease, such as the appearance and / or presence of Lewy bodies. Clots of specific 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 prominent in later stages of PD due to cognitive, nonmotor, and emotional dysfunction. Structural MRI can 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 cell poisoning, and / or brain shrinkage.

[0036] III. Usage Method

[0037] In one aspect, brain atrophy in a test subject can be determined by determining the subject's whole brain volume and comparing the change in volume relative to a control or reference volume for that subject, or relative to a control value of brain volume obtained from a healthy, age-matched group of subjects. Alternatively, brain atrophy in a test subject can be determined by measuring the brain volume of selected brain regions of the subject and comparing it to a control or reference volume of those regions, or relative to a control value of brain regions obtained from a healthy, age-matched group of subjects. Brain volume can be determined by measuring the volume of whole-brain gray matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, and whole-brain white matter.

[0038] In one aspect, this disclosure relates to methods for treating brain atrophy after it has been detected in a subject. Such treatment includes, but is 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 treatment can be achieved by administering to the subject one or more therapeutically active agents such as σ-1 receptor agonists and / or dual modulators of σ-1 receptors and muscarinic receptors.

[0039] This disclosure also covers methods for preventing brain atrophy. In one aspect, such prevention includes blocking, preventing, delaying, slowing, or avoiding the onset of brain atrophy in a subject. In another aspect, the subject is at risk of developing brain atrophy. Such prevention methods can be achieved by administering to the subject one or more prophylactic active agents such as σ-1 receptor agonists and / or dual modulators of σ-1 receptors and muscarinic receptors.

[0040] The modulation methods disclosed herein also include any suitable and available tools, instruments, devices, and / or techniques for monitoring or detecting brain characteristics of different parts of the brain. Such brain characteristics may include measurements of brain mass, size, volume, density, hydration level, number of neurons, and / or neuronal connections. Such tools may include structural MRI.

[0041] IV. Therapeutic and / or preventative medications

[0042] σ-1 receptor expression or activity is associated with neural activity in neurodevelopment / neurodegeneration, and σ-1 receptor activation is associated with neuroprotection in human subjects and in various in vitro and in vivo models. Such neuroprotection may be needed in subjects diagnosed with or suspected of having neurological disorders such as neurodegeneration or neurodevelopmental disorders. Therefore, one aspect of this disclosure covers the use of therapeutic or prophylactic agents in such subjects to restore brain volume, halt and / or improve neuronal loss and / or reduce or reverse brain atrophy, said therapeutic or prophylactic agents being σ-1 receptor agonists or dual modulators of σ-1 receptors and muscarinic receptors.

[0043] Non-limiting examples of therapeutic or prophylactic agents include, but are not limited to, entacapone, nalibappone, niticcapone, opicapone, tocapone, tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine (Anavex 2-73 free base), tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX® 2-73, AV2-73, A2-73, or blarcamesine), 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethylamine (ANAVEX 19-144 free base), and 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethylamine hydrochloride (ANAVEX® 2-73, AV2-73, A2-73, or blarcamesine). ANAVEX® 19-144 or A19-144), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethylamine (ANAVEX 1-41 free base), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethylamine hydrochloride (ANAVEX® 1-41 or A1-41), 1-(3-4(((1R,3S,5S)-adamantane-1-yl)(phenyl)methyl)propyl)-4-methylpiperazine (ANAVEX™ 1066 or “AV1066”), (1-(2,8-dimethyl-l-thia-3,8-diazaspiro(4,5)dec-3-yl)-3-(lH-indol-3-yl)prop-l-one) (ANAVEX3-71, also known as AF710B), PRE-084, donepezil, fluvoxamine, amitriptyline, L-687,384, and combinations thereof. Such marketed therapeutic agents also cover their enantiomers, stereoisomers, crystalline forms, salt forms, cocrystal forms, and can be administered to subjects in need in therapeutically effective amounts. In one aspect, σ-1 receptor agonists are A2-73, A2-73 free base, or their enantiomers, crystalline forms, pharmaceutically acceptable salts, analogs, or metabolites. A2-73, the free base of A2-73, or salts thereof may be in the form of racemic mixtures, stereoisomers, enantiomers, polymorphs, or eutectic forms. In one aspect, enantiomers may be (+) or (-) optically active or represented as (R) or (S). In one aspect, pharmaceutically acceptable eutectics are formed between (i) and (ii): (i) the free base of A2-73, A2-73, the free base of A19-144, A19-144, the free base of A1-41, A1-41, its enantiomers, its polymorphs; and (ii) an acid or ionic salt. In another aspect, acids include 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. Ionic salts include quaternary ammonium cation salts, transition metal salts, alkaline earth metal salts, or alkali metal salts.In one respect, ionic salts include lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, ferric chloride (II), ferric chloride (III), titanium chloride, chromium chloride (III), scandium chloride (III), manganese chloride (II), copper chloride (I), copper chloride (II), nickel chloride, or aluminum chloride.

[0044] In one aspect, the therapeutic or prophylactic agent includes tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine (A2-73 free base), its polymorphs, its enantiomers, polymorphs of its enantiomers, its pharmaceutically acceptable salts, enantiomers of its pharmaceutically acceptable salts, polymorphs of its pharmaceutically acceptable salts, or cocrystals thereof. In another aspect, the agent includes tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (A2-73), its polymorphs, its enantiomers, polymorphs of its enantiomers, or cocrystals thereof. In another aspect, the reagents include 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 enantiomers, and (-)A2-73 enantiomers. A2-73 free base in crystalline form I has been disclosed and characterized in WO2019200345A1 (which is incorporated herein by reference in its entirety). Specifically, A2-73 free base in crystalline form I is characterized essentially by the XRPD pattern shown in FIG16 and the particle shape depicted in FIG15. In one aspect, A2-73 crystals are type I, type II, and / or type III crystals as disclosed and characterized in WO2017013498A2, the disclosure of which is incorporated herein by reference in its entirety. Specifically, A2-73 crystal form I is basically composed of Figure 1 The XRPD pattern shown and Figure 2The particle shape is characterized as depicted in Figure 3. Crystal form II of A2-73 is characterized essentially by the XRPD pattern shown in Figure 4, the particle shape depicted in Figure 7, and the FTIR spectrum shown in Figure 5. Crystal form III of A2-73 is characterized essentially by the XRPD pattern shown in Figure 8, the particle shape depicted in Figure 11, and the FTIR spectrum shown in Figure 9. Analogs of A2-73 may include A1-41. Metabolites of A2-73 may include A19-144. In one aspect, pharmaceutically acceptable salts include hydrochloride, hydrobromide, fumarate, sulfate, dihydrogen phosphate, benzoate, methanesulfonate, ethanedisulfonate, or oxalate. In another aspect, eutectic comprises a pharmaceutically acceptable salt of A2-73 with an organic acid including tartaric acid, citric acid, maleic acid, or combinations thereof. In another respect, A2-73 is A2-73 amorphous form, A2-73 free base crystal form I, A2-73 crystal form I, A2-73 crystal form II, A2-73 crystal form III, (+)A2-73 enantiomer, and (-)A2-73 enantiomer. In one aspect, the active material is A2-73 free base fumarate and / or its crystals, such as A2-73 free base fumarate in amorphous form, 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, and A2-73 free base hydrogen fumarate crystal form V, all of which are disclosed and characterized in WO2019200345A1, as shown in the XRPD patterns in Figures 29, 30, 32, 33, and 34, respectively. In another aspect, A2-73 is other salt crystals, such as A2-73 free base methanesulfonate type I, A2-73 free base sulfate type I, A2-73 free base sulfate type II, A2-73 free base oxalate type I, A2-73 free base oxalate type II, A2-73 free base oxalate type III, A2-73 free base dihydrogen phosphate type I, A2-73 free base ethanedisulfonate type I, and A2-73 free base benzoate type I, all of which are disclosed and characterized in WO2019200345A1, as shown in the XRPD patterns in Figures 18-23 and 25-27, respectively. In yet another aspect, the active material 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. They are disclosed and characterized in WO2021158586A1 (the disclosure of which is incorporated herein by reference in its entirety). In another aspect, the active substance is a eutectic type CSII with tartaric acid A2-73 eutectic, a eutectic type CSIII with citric acid A2-73 eutectic, or a eutectic type CSIV with malic acid A2-73 eutectic.They are disclosed and characterized in WO2023208133A1 (which is incorporated herein by reference in its entirety). In another aspect, the active material is a eutectic of zinc chloride with A2-73 disclosed in U.S. Patent No. 12,018,005B1 (which is incorporated herein by reference in its entirety).

[0045] When the therapeutic or prophylactic agent is A2-73 or its free base, or its salts, enantiomers, polymorphs, or eutectics, the therapeutic or prophylactic effective dose of A2-73 may be in the following ranges: about 0.5 mg to about 100 mg, about 1 mg to about 80 mg, about 10 mg to about 70 mg, about 15 mg to about 55 mg, about 30 mg to about 50 mg, or about 3 mg to about 5 mg. When the therapeutic agent is A2-73, the therapeutic effective dose may be in the following ranges: 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. When the drug is A2-73, the therapeutically effective dose may be 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 aspect, when the agent 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 another aspect, the therapeutic agent is A2-73 crystal form I, A2-73 crystal form II, or A2-73 crystal form III, and their therapeutic or prophylactic effective dose may be in the range of about 0.5 mg to about 100 mg, about 1 mg to about 60 mg, about 30 mg to about 50 mg, or about 3 mg to about 5 mg.

[0046] When the therapeutic or prophylactic agent is 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethylamine hydrochloride (A19-144), or 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethylamine (A19-144 free base), or their salts, enantiomers, polymorphs, or cocrystals, the therapeutic or prophylactic effective dose may be in the following ranges: about 0.5 mg to about 200 mg, about 1 mg to about 180 mg, about 10 mg to about 170 mg, about 15 mg to about 155 mg, about 30 mg to about 150 mg, about 40 mg to about 130 mg, about 50 mg to about 110 mg, about 60 mg to about 100 mg, about 70 mg to about 90 mg, about 80 mg to about 85 mg, or about 3 mg to about 5 mg. When the drug is A 19-144, the effective therapeutic dose may be in the following ranges: 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. In one respect, when the drug is A19-144, the therapeutically effective dose can be 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, 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, etc. 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 respect, when the therapeutic agent is A19-144, the effective therapeutic or preventative 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, 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, etc. mg, 185 mg, 190 mg, 195 mg, or 200 mg.

[0047] When the therapeutic or prophylactic agent is tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethylamine hydrochloride (A1-41), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethylamine (A1-41 free base), or its salts, enantiomers, polymorphs, or eutectics, the therapeutic or prophylactic effective dose may be in the following ranges: about 0.5 mg to about 200 mg, about 1 mg to about 180 mg, about 10 mg to about 170 mg, about 15 mg to about 155 mg, about 30 mg to about 150 mg, about 40 mg to about 130 mg, about 50 mg to about 110 mg, about 60 mg to about 100 mg, about 70 mg to about 90 mg, about 80 mg to about 85 mg, or about 3 mg to about 5 mg. When the therapeutic agent is A1-41, the effective therapeutic or preventive dose may be in the following ranges: 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. In one respect, when the therapeutic agent is A1-41, the effective therapeutic or preventative dose may be 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, 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, etc. 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 aspect, when the therapeutic or prophylactic agent is A1-41, the effective therapeutic or prophylactic 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, 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, etc. mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.

[0048] In one aspect, the therapeutic or prophylactic agent is A2-73 and A2-73 free base, and the effective therapeutic dose includes the following combined doses: about 0.5 mg to about 100 mg, about 1 mg to about 80 mg, about 10 mg to about 70 mg, about 15 mg to about 55 mg, about 30 mg to about 50 mg, or about 3 mg to about 5 mg. In another respect, the therapeutic agents are A2-73 and A19-144, and the therapeutically effective doses include the following combinations: about 0.5 mg, about 1.0 mg, about 3 mg, about 5 mg, about 10 mg, 15 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 32 mg, about 35 mg, about 38 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 58 mg, about 60 mg, about 65 mg, about 68 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In another aspect, the therapeutic agents are A2-73 and A1-41, and the therapeutically effective doses include the following combinations: 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] In one aspect, the therapeutic or prophylactic agent may be administered daily, every other day, three times a week, or once a week. In another aspect, the agent may be administered once daily, twice daily, or three times daily. In yet another aspect, the therapeutically effective dose may be in the range of: about 0.5 mg / day to about 100 mg / day, about 1 to about 60 mg / day, about 20 to about 50 mg / day, about 20 to about 30 mg / day, or about 15 to about 25 mg / day. In yet another aspect, the therapeutically effective dose of A2-73 may be in the range of: 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. In one aspect, administration of a therapeutically or prophylactically effective dose may provide a blood level of about 10 ng / ml to about 12 ng / ml of A2-73. In one respect, administration of a therapeutically effective dose of A2-73 can provide blood levels of A2-73 ranging from 10 ng / ml to 12 ng / ml. Furthermore, administration of a therapeutically or prophylactically effective dose of A2-73 can provide blood levels 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 another respect, administration of a therapeutically 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.

[0050] Therapeutic or prophylactic agents, such as A2-73, A19-144, A1-41, or their free bases, salts, or enantiomers, may be administered to the subject daily or every other day during treatment, or according to an intermittent dosing regimen. For example, A2-73 may be administered every 2, 3, 4, 5, 6, 7, 14, or every 30 days. Administration may be once, twice, or three times on the day of administration. Therapeutic agents such as A2-73 may be administered over periods of approximately 1 day to approximately 1 year, approximately 1 day to approximately 1 week, approximately 3 days to approximately 1 month, approximately 2 weeks to approximately 6 months, or approximately 2 months to approximately 4 months. Therapeutic agents may be administered over periods of approximately 1 day, approximately 7 days, approximately 30 days, approximately 60 days, approximately 120 days, or approximately 180 days or longer. In some aspects, the therapeutic agent A2-73 may be administered indefinitely, or until the treated condition is relieved, over periods of approximately 12 weeks, approximately 24 weeks, approximately 36 weeks, approximately 48 weeks, approximately 57 weeks, approximately 96 weeks, approximately 148 weeks, or approximately 208 weeks. Furthermore, the dosing regimen may include administration to the subject in the form of a pharmaceutical composition or dosage form containing a therapeutically effective amount of the agent. In one aspect, such administration is carried out according to an intermittent dosing regimen of at least two cycles, each cycle comprising: (a) a dosing period during which a therapeutically effective amount of the pharmaceutical composition is administered to the patient, and thereafter, (b) a rest period. In some embodiments, the dosing period and the rest period may have the same duration or different durations. Note that the dosing and withdrawal periods fall within the range of (exceeding) the lower limit of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days to (below) the upper limit of about 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, and 14 days. It is also noted that the dosing period is between about 1 day and 12 days, and the withdrawal period is between about 1 day and 12 days. In one aspect, the dosing period is 12 days and the withdrawal period is 12 days. Such a regimen is effectively applied when the therapeutically effective amount of the said therapeutic agent or its pharmaceutical composition is about 1 mg to about 100 mg, and especially about 30 mg to about 50 mg, and especially when used in oral dosage forms. Intravenous administration of A2-73 doses of about 3 mg to about 5 mg is also considered.

[0051] Other methods of applying 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 in, for example, U.S. Patent Nos. 9,750,746, 2017,036,0798, 2019,002,2052, 2018, 2018,036,0796, 2018,016,9059, 2018,017,7756, 2018,016,9060, and 2019,011,761,500. The disclosure of each of the foregoing patents and applications is expressly incorporated herein by reference in its entirety.

[0052] V. Pharmaceutical Composition

[0053] One aspect of this disclosure covers pharmaceutical compositions, also known as pharmaceutical formulations, for the delivery of therapeutic agents, such as σ-1 receptor agonists or dual modulators of σ-1 receptors and muscarinic receptors. Pharmaceutical formulations include therapeutic agents and pharmaceutically acceptable excipients or carriers. Another aspect of this disclosure covers dosage forms (also known as “unit doses”). This refers to a final product containing a pharmaceutical composition and packaged in a form suitable for sale and use. Depending on the method / route of administration, dosage forms can be liquid, solid, or semi-solid. This disclosure provides dosage forms suitable for the delivery of therapeutic agents, such as, in particular, pills, tablets, capsules, oral solutions, and injections.

[0054] One aspect of this disclosure covers pharmaceutical compositions or dosage forms comprising therapeutic amounts of a therapeutic agent. The therapeutic agent may be in the form of a free base or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of the compound include organic and inorganic salts such as acetates, aspartates, benzoates, tartrates, citrates, formates, gluconates, glucurons, glutamates, fumarates, hydrochlorides, hydrobromides, hydroiodates, hypophosphites, isobutyrates, isocitrates, lactates, malates, maleates, meconium salts, methyl bromide, methanesulfonates, monohydrates, mucilages, nitrates, oxalates, phenylpropionates, phosphates, phthalates, propionates, pyruvates, salicylates, stearates, succinates, sulfates, tannates, tartrates, terephthalates, valerates, etc.

[0055] When the therapeutic or prophylactic agent is A2-73, A2-73 free base or a salt thereof, the pharmaceutical composition may contain about 1 mg to about 50 g, about 0.1 to about 5 g, about 0.5 g to about 3 g, about 1 mg to about 55 mg, about 40 mg to about 60 mg, about 80 mg to about 120 mg, about 180 mg to about 220 mg, about 0.1 g to about 5 g, or about 0.5 g to about 3 g of A2-73. Compositions or formulations containing A2-73 can be found in, for example, U.S. Patent No. 9,750,746, U.S. Patent Publication No. 2017,036,0798, U.S. Patent Publication No. 2019,002,2052, U.S. Patent Publication No. 2018,036,0796, U.S. Patent Publication No. 2018,016,9059, U.S. Patent Publication No. 2018,017,7756, U.S. Patent Publication No. 2018,016,9060, and U.S. Patent Publication No. 2019,011,7615, the disclosure of each of these patents being incorporated herein by reference in its entirety.

[0056] When 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 from about 0.5 mg to about 100 mg, from about 1 mg to about 80 mg, from about 10 mg to about 70 mg, from about 15 mg to about 55 mg, from about 30 mg to about 50 mg, or from about 3 mg to about 5 mg. When the therapeutic agent is A2-73, the formulation may contain A2-73 in amounts from 0.5 mg to 100 mg, from 1 mg to 80 mg, from 10 mg to 70 mg, from 15 mg to 55 mg, from 30 mg to 50 mg, or from 3 mg to 5 mg. When the therapeutic agent is A2-73, the formulation may contain A2-73 in amounts of about 0.5 mg, about 1.0 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 32 mg, about 35 mg, about 38 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 58 mg, about 60 mg, about 65 mg, about 68 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In one respect, when 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.

[0057] When the therapeutic or prophylactic agent is A19-144, A19-144 free base or a salt thereof, the composition may contain A19-144 in an amount ranging from about 0.5 mg to about 200 mg, about 1 mg to about 180 mg, about 10 mg to about 170 mg, about 15 mg to about 155 mg, about 30 mg to about 150 mg, about 40 mg to about 130 mg, about 50 mg to about 110 mg, about 60 mg to about 100 mg, about 70 mg to about 90 mg, about 80 mg to about 85 mg, or about 3 mg to about 5 mg. When 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. In one aspect, when the therapeutic agent is A19-144, the formulation may be in the form 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, 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, etc. The amounts of 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 contain A19-144.In one respect, when the therapeutic agent is A19-144, the formulation may be available 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, 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, etc. Amounts of 1 mg, 190 mg, 195 mg, or 200 mg contain A19-144.

[0058] When the therapeutic or prophylactic agent is A1-41, A1-41 free base or a salt thereof, the formulation may contain A1-41 in an amount ranging from about 0.5 mg to about 200 mg, about 1 mg to about 180 mg, about 10 mg to about 170 mg, about 15 mg to about 155 mg, about 30 mg to about 150 mg, about 40 mg to about 130 mg, about 50 mg to about 110 mg, about 60 mg to about 100 mg, about 70 mg to about 90 mg, about 80 mg to about 85 mg, or about 3 mg to about 5 mg. When 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. In one aspect, when the therapeutic agent is A1-41, the formulation may be in the form of about 0.5 mg, about 1.0 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 32 mg, about 35 mg, about 38 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 58 mg, about 60 mg, about 65 mg, about 68 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 115 mg, about 120 mg, about 122 mg, about 125 mg, about 130 mg, about 132 mg, about 135 mg, about 138 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, etc. The amounts of 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 contain A1-41.In one respect, when the therapeutic or prophylactic agent is A1-41, the formulation may be in the following dosages: 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, 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. Amounts of 185 mg, 190 mg, 195 mg, or 200 mg contain A1-41.

[0059] In another aspect, the therapeutic or prophylactic agent is A2-73 crystal form I, A2-73 crystal form II, or A2-73 crystal form III, and their therapeutically effective doses may range from 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 range from about 0.5 mg to about 100 mg, about 1 mg to about 60 mg, about 30 mg to about 50 mg, or about 3 mg to about 5 mg. In yet another aspect, the therapeutic or prophylactic effective dose of A2-73 may range from about 0.5 mg / day to about 100 mg / day, about 1 mg to about 60 mg / day, about 20 mg to about 50 mg / day, about 20 mg to about 30 mg / day, or about 15 mg to about 25 mg / day. In another aspect, the therapeutically effective dose of A2-73 can 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. Administration of a therapeutically or prophylactically effective dose of A2-73 can provide a blood level of about 10 ng / ml to about 12 ng / ml. In one aspect, administration of a therapeutically effective dose of A2-73 can provide a blood level of 10 ng / ml to 12 ng / ml. In another aspect, administration of a therapeutically effective dose of A2-73 can provide a blood level of about 10 ng / ml, about 10.2 ng / ml, about 10.5 ng / ml, about 10.8 ng / ml, about 11 ng / ml, about 11.2 ng / ml, about 11.5 ng / ml, or about 12 ng / ml. In another respect, administration of a therapeutically effective or prophylacticly effective dose of A2-73 can provide blood levels 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 of A2-73.

[0060] Therapeutic or prophylactic agents can be formulated and administered to subjects in several different ways. For example, compositions can typically be administered parenterally, intraperitoneally, intravascularly, transdermally, subcutaneously, or intrapulmonaryly in dose-unit formulations, which, as needed, contain conventional, non-toxic, pharmaceutically acceptable adjuvants, carriers, excipients, and solvents.

[0061] As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intrathecal, or intrasternal injection or infusion techniques. Formulations of pharmaceutical compositions are discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975) and Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY (1980).

[0062] In another aspect, therapeutic agents can be formulated for administration to specific types of subjects, such as elderly or pediatric subjects, subjects with dysphagia, subjects prone to seizures, or subjects prone to vomiting or nausea. As used herein, the elderly are those 65 years of age or older. The elderly can also be used for those 79 years of age or older. Pediatrics includes infants (0-2 years), children (2-12 years), or adolescents (13-18 years). For example, to facilitate administration of therapeutic agents to pediatric subjects, the formulation may contain excipients desired by the pediatric subject, such as flavored oral suspensions, flavored capsule tablets, or flavored capsules. Such flavors could be strawberry, apple, bubblegum, grape, or orange. And such formulations meet all the necessary criteria for pediatric use.

[0063] Pharmaceutical formulations may contain one or more pharmaceutically acceptable excipients or carriers. Non-limiting examples of excipients or carriers include chemical enhancers, humectants, pressure-sensitive binders, antioxidants, solubilizers, thickeners, plasticizers, adjuvants, carriers, excipients, solvents, 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.

[0064] In another aspect, therapeutic agents can often be formulated to improve patient adherence and prevent subjects from removing medication delivery devices. For example, therapeutic agents can be formulated to improve patient adherence and prevent removal of medication delivery devices by providing a formulation for delayed delivery. Delayed delivery can range from more than one day to several months. This is particularly relevant for patients with impaired cognitive and / or motor control abilities. Delayed delivery periods can range 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.

[0065] Delayed-release formulations can be used to deliver a drug substantially continuously at a pre-selected rate. For example, for crystallized 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 gm / day, or about 10 to about 30 gm / day. Those skilled in the art can readily determine the appropriate amount of crystallized A2-73 based, in particular, the expected duration of drug administration via a delayed-release formulation, the delivery mechanism, and the relative potency of the formulation and the drug.

[0066] i. Adhesive

[0067] Non-limiting examples of binders suitable for formulations in multiple aspects include starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethyl cellulose, ethylcellulose, polyacrylamide, polyvinyloxoazolidone, polyvinyl alcohol, and C. 12 -C 18 Fatty acid alcohols, polyethylene glycols, polyols, sugars, oligosaccharides, polypeptides, oligopeptides, and combinations thereof. Polypeptides can be any arrangement of amino acids in the range of about 100 to about 300,000 Daltons.

[0068] The binder may be introduced into the mixture to be granulated in solid form, including but not limited to crystals, particles, powders, or any other subdivision of solid form known in the art. Alternatively, the binder may be dissolved or suspended in a solvent and sprayed as a binder fluid onto the mixture in the granulation apparatus during granulation.

[0069] ii. Diluent

[0070] Non-limiting examples of diluents (also referred to as "fillers" or "thinners") include carbohydrates, inorganic compounds, and biocompatible polymers such as polyvinylpyrrolidone (PVP). Other non-limiting examples of diluents include dibasic calcium sulfate, tribasic calcium sulfate, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, calcium hydrogen phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc (powder), modified starch, sugars such as sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol and sorbitol, polyols; starch; pre-prepared direct compression diluents; and any mixtures of the foregoing substances.

[0071] iii. Disintegrants

[0072] Disintegrants can be effervescent or non-effervescent. Non-limiting examples of non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized starch and its modified forms, sweeteners, clays such as bentonite, microcrystalline cellulose, alginate, sodium starch glycolate, gums such as agar, guar gum, locust bean gum, karaya gum, pectin, and tragacanth gum. Suitable effervescent disintegrants include, but are not limited to, sodium bicarbonate in combination with citric acid and sodium bicarbonate in combination with tartaric acid.

[0073] iv. Preservatives

[0074] Non-limiting examples of preservatives include, but are not limited to: ascorbic acid and its salts, ascorbyl palmitate, ascorbyl stearate, anoxomer, N-acetylcysteine, benzyl isothiocyanate, m-aminobenzoic acid, anthranilic acid, p-aminobenzoic acid (PABA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, canthaxantin, α-carotene, β-carotene, and β-carotene (carotene). otene), β-apocarotene acid, carawayol, 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-phenylene diamine (DPPD), dilauryl thiodipropionate, distearate thiodipropionate, 2,6-di-tert-butylphenol, dodecyl gallate, edetate, ellagic acid, isoascorbic acid, sodium isoascorbate, aescin, esculin, 6 -Ethoxy-1,2-dihydro-2,2,4-trimethylquinoline, ethyl gallate, ethyl maltol, EDTA, eucalyptus extract, eugenol, ferulic acid, flavonoids (e.g., catechins, epicatechin, epicatechin gallate, epigallocatechin (EGC), epigallocatechin gallate (EGCG), polyphenol epigallocatechin-3-gallate), flavonoids (e.g., apigenin, zeaxanthin, luteolin), flavonols (e.g., datiska flavonoids, myricetin). Flavonoids, daemfero, flavanones, ash styrax, fumaric acid, gallic acid, gentian extract, gluconic acid, glycine, guaiac gum, hesperidin, α-hydroxybenzylphosphonic acid, hydroxycinnamic acid, hydroxyglutaric acid, hydroquinone, N-hydroxysuccinic acid, hydroxytyrosol, hydroxyurea, rice husk extract, lactic acid and its salts, lecithin, lecithin citrate; R-α-lipoic acid, lutein, lycopene, malic acid, maltol, 5-methoxytryptamine, methyl gallate, monoglyceride citrate; monoisopropyl citrate.Phellinus linteus, β-naphthylflavonoids, nordihydroguaiac acid (NDGA), octyl gallate, oxalic acid, citrate palmitate, phenothiazine, phosphatidylcholine, phosphoric acid, phosphates / esters, phytic acid, phytylubichromel, capsicum extract, propyl gallate, polyphosphates / esters, quercetin, trans-resveratrol, rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin, sinapic acid, succinic acid, stearyl citrate, eugenol, tartaric acid, thymol, tocopherols (i.e., α-, β-, γ-, and δ-tocopherols), tocotrienols (i.e., α-, β-, γ-, and δ-tocotrienols), tyrosol, vanillic acid, 2,6-di-tert-butyl-4-hydroxymethylphenol (i.e., Ionox) 100), 2,4-(tri-3',5'-bis-tert-butyl-4'-hydroxybenzyl)-trimethylbenzene (i.e., Ionox 330), 2,4,5-trihydroxyphenylbutanone, ubiquinone, tert-butylhydroquinone (TBHQ), thiodipropionic acid, trihydroxyphenylbutanone, tryptophan, tyramine, uric acid, vitamin K and its derivatives, vitamin Q10, wheat germ oil, zeaxanthin or combinations thereof.

[0075] v. Flavoring agent

[0076] Suitable flavoring agents include flavoring agents, masking agents, and sweeteners. Flavoring agents include, but are not limited to, synthetic flavor oils and flavoring aromatic substances and / or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof. Other non-limiting examples of flavoring agents include cinnamon oil, wintergreen oil, peppermint oil, clover oil, hay oil, fennel oil, eucalyptus oil, vanilla oil, citrus oils such as lemon oil, orange oil, grape oil, and grapefruit oil, and fruit essential oils (including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot).

[0077] Flavor masking agents include, but are not limited to, hydroxypropyl cellulose ethers (HPC), such as Klucel®, Nisswo HPC, and PrimaFloHP22; low-substituted hydroxypropyl ethers (L-HPC); hydroxypropyl methyl cellulose ethers (HPMC), such as Seppifilm-LC, Pharmacoat®, Metalose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843; methylcellulose polymers, such as Methocel® and Metalose®; ethyl cellulose (EC) and mixtures thereof, such as E461, Ethocel®, Aqualon®-EC, and Surelease; polyvinyl alcohol (PVA), such as Opadry AMB; hydroxyethyl cellulose, such as Natrosol®; carboxymethyl cellulose and its salts (CMC), such as Aualon®-CMC; and polyvinyl alcohol and polyethylene glycol copolymers, such as Kollicoat. IR®; monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic polymers, and mixtures of acrylic polymers with cellulose ethers, such as Eudragit® EPO, Eudragit® RD100, and Eudragit® E100; cellulose acetate phthalate; sepifilm, such as mixtures of HPMC and stearic acid, cyclodextrin, and mixtures of these materials. In other respects, additional masking agents considered are those described in U.S. Patents 4,851,226, 5,075,114, and 5,876,759, each of which is hereby incorporated by reference in its entirety.

[0078] Non-limiting examples of sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts, such as sodium salts; dipeptide sweeteners, such as aspartame; dihydrochalcone compounds, glycyrrhizin; stevia (stevia rebaudiana) (stevioside); chlorinated derivatives of sucrose, such as sucralose; sugar alcohols, such as sorbitol, mannitol, sylitol, hydrogenated starch hydrolysate, and synthetic sweeteners 3,6-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide, particularly its potassium salt (acesulfame potassium) and sodium and calcium salts.

[0079] vi. Lubricants and flow aids

[0080] The lubricant composition can be used to lubricate the components forming the pharmaceutical composition. As a flow aid, the lubricant facilitates the removal of solid dosage forms during the manufacturing process. Non-limiting examples of lubricants and flow aids include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, sterotex, polyoxyethylene monostearate, talc (powder), polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. The pharmaceutical composition will generally contain about 0.01% by weight to about 10% by weight of the lubricant. In some aspects, the pharmaceutical composition will contain about 0.1% by weight to about 5% by weight of the lubricant. In another aspect, the pharmaceutical composition will contain about 0.5% by weight to about 2% by weight of the lubricant.

[0081] vii. Dispersant

[0082] Dispersants may include, but are not limited to, starch, alginic acid, polyvinylpyrrolidone, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicates, and microcrystalline cellulose as highly hydrophilic-lipophilic balanced (HLB) emulsifiers and surfactants.

[0083] viii. Coloring agent

[0084] According to aspects of this disclosure, the inclusion of colorants may be desirable. Suitable coloring additives include, but are not limited to, food, pharmaceutical and cosmetic pigments (FD&C), pharmaceutical and cosmetic pigments (D&C), or topical pharmaceutical and cosmetic pigments (Ext. D&C). These pigments or dyes and their corresponding lakes, and certain natural and derived colorants may be applicable to various aspects of this disclosure.

[0085] ix. pH adjuster

[0086] Non-limiting examples of pH adjusters include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate, and sodium bicarbonate.

[0087] x. Chelating agents

[0088] Chelating agents can be incorporated as excipients to immobilize oxidizing groups (including but not limited to metal ions) to inhibit the oxidative degradation of morphine by these groups. Non-limiting examples of chelating agents include lysine, methionine, glycine, gluconate, polysaccharides, glutamic acid, aspartate, and disodium ethylenediaminetetraacetate (Na2EDTA).

[0089] xi. Antimicrobial agents

[0090] Antimicrobial agents may be incorporated as excipients to minimize degradation of the compounds according to this disclosure by microbial agents (including, but not limited to, bacteria and fungi). 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.

[0091] xii. Controlled-release polymers

[0092] Controlled-release polymers can be incorporated into various aspects of solid-dose pharmaceutical compositions incorporating compounds according to this disclosure. In one aspect, the controlled-release polymer can be used as a tablet coating. In other aspects, including but not limited to bilayer tablets, the controlled-release polymer can be mixed with granules and other excipients prior to tablet formation by known methods (including but not limited to compression in a tablet mold). Suitable controlled-release polymers include, but are not limited to, hydrophilic and hydrophobic polymers.

[0093] Suitable hydrophilic controlled-release polymers include, but are not limited to: cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, 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, and sodium carboxymethyl cellulose alginate. Carmellose, calcium carboxymethyl cellulose, carrageenan, fucoidan, red algae gum, gum arabic, carrageenan, solanum, guar gum, black privet gum, locust bean gum, okra gum, tragacanth gum, stearin gum, xanthan gum, hypnea, kelp polysaccharide, acrylic polymers, acrylate polymers, carboxyvinyl polymers, copolymers of maleic anhydride and styrene, copolymers of maleic anhydride and ethylene, copolymers of maleic anhydride and propylene or copolymers of maleic anhydride and isobutylene), crosslinked polyvinyl alcohol and polyN-vinyl-2-pyrrolidone, diesters of polydextrin, 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.

[0094] xiii. Coating

[0095] Solid dosage forms containing compounds according to this disclosure may include coatings, wherein such coatings can control the release of the compound, act as a moisture barrier or buffer, or adjust pH. As used herein, "controlled-release coating" or "controlled-release coating" is defined as a functional coating that may, for example, contain at least one pH-independent polymer, a pH-dependent polymer (e.g., enteric or anti-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 slow down (e.g., when applied to a normal-release matrix dosage form), further slow down (e.g., when applied to a controlled-release matrix dosage form), or alter the release rate of the compound according to this disclosure 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 dosage form bound to the controlled-release coating can exhibit the release of the compound according to this disclosure, such as "altered release," "controlled release," "sustained release," "delayed release," "extended release," or a combination thereof. "Controlled-release coatings" may optionally contain additional materials that can alter the functionality of the controlled-release coating.

[0096] As used herein, the term "moisture barrier" refers to a substance that impedes or delays the absorption of moisture. Compounds according to this disclosure may be hygroscopic and therefore may readily decompose over time under highly humid conditions. The proportions of the moisture barrier components and the amount of moisture barrier optionally applied to the controlled-release coating or core generally ensure that the moisture barrier does not fall under the definition and requirements of the USP for enteric coatings. Suitably, the moisture barrier may comprise an enteric polymer and / or an acrylic polymer, preferably an acrylic polymer, optionally a plasticizer, and a penetration enhancer. The penetration enhancer is a hydrophilic substance that allows water to penetrate without physically damaging the coating. The moisture barrier may additionally comprise other conventional inert excipients that can improve the processing of the delayed-release formulation.

[0097] The coating and matrix materials that can be used according to the present invention are those materials known in the art for use in controlled-release formulations, such as polyvinyl-based synthetic polymers, such as polyvinyl chloride, polyvinyl acetate and its copolymers, polyvinyl alcohol and polyvinylpyrrolidone; polyethylene-based synthetic polymers, such as polyethylene and polystyrene; acrylic polymers; biopolymers or modified biopolymers, such as 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), such as aluminum monostearate, cetyl alcohol, hydrogenated tallow, hydrogenated castor oil, 12-hydroxystearyl alcohol, glyceryl monopalmitate or glyceryl dipalmitate; glyceryl monostearate, glyceryl distearate or glyceryl tristearate; myristyl alcohol, stearic acid, stearyl alcohol and polyethylene glycol; waxes; sugars and sugar alcohols.

[0098] The pH buffering properties of the coating can be enhanced by introducing substances selected from the group of compounds commonly used in antacid formulations into the coating, such as magnesium oxides, hydroxides, or carbonates; aluminum or calcium hydroxides, carbonates, or silicates; and complex aluminum / magnesium compounds, such as Al₂O₃·6MgO·CO₂·12H₂O, (Mg₆Al₂(OH)₂) 16 CO3·4H2O), MgO·Al2O3·2SiO2·nH2O, aluminum bicarbonate coprecipitates or similar compounds; or other pharmaceutically acceptable pH-buffered compounds, such as sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, carbonic acid, citric acid or other suitable weak acids, inorganic acids or organic acids; or suitable organic bases, including basic amino acids; and their salts or combinations thereof.

[0099] pH-dependent coatings are used for the release of drugs in desired areas of the gastrointestinal (GI) tract, such as the stomach or small intestine. When pH-independent coatings are desired, the coating is designed to achieve optimal release regardless of pH changes in the surrounding fluids (e.g., the GI tract). When a coating is formulated to release a compound according to this disclosure in the intestine (particularly the upper small intestine), it is often referred to as an "enteric coating". pH-dependent coatings may include, but are not limited to, acrylic polymers and copolymers, such as polymers formed from acrylic acid, methacrylic acid, methyl acrylate, aminomethacrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate (e.g., Eudragit™); cellulose polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate (CAP), cellulose trimellitate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate and sodium carboxymethyl cellulose; shellac (purified lac); vinyl polymers and copolymers, such as polyvinylpyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate (PVAP), vinyl acetate-crotonic acid copolymer and ethylene-vinyl acetate copolymer; zein; and salts and combinations thereof.

[0100] VI. Dosage Form

[0101] One aspect of this disclosure covers dosage forms (also referred to as "unit doses") of σ-1 receptor agonists or dual modulators of σ-1 receptors and muscarinic receptors. It refers to a final product comprising a pharmaceutical composition and packaged in a form suitable for sale and use. Depending on the method / route of administration, the dosage form may be liquid, solid, or semi-solid. This disclosure provides dosage forms suitable for the delivery of therapeutic agents, particularly in the form of pills, tablets, capsules, oral solutions, or injections. This disclosure provides dosage forms suitable for the delivery of therapeutic agents to designated patient populations such as elderly patients, pediatric patients, or dosage forms suitable for administration by healthcare providers and / or caregivers.

[0102] Another aspect of this disclosure covers dosage forms of σ-1 receptor agonists or dual modulators of σ-1 receptors and muscarinic receptors in therapeutically or prophylactically effective amounts. Specifically, when such agonists are A2-73 or A2-73 free base, the dosage form may contain about 1 mg to about 50 g, about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 1 mg to about 500 mg, about 50 to about 400 mg, about 75 to about 150 mg, about 150 to about 200 mg, 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. For example, dosage forms may contain 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, or 300 or more mg of A2-73. In some aspects, dosage forms may contain about 1 mg to about 500 mg, or about 1 mg to about 100 mg of A2-73.

[0103] Dosage forms include those formulated for delayed or slow release and those formulated for immediate release. For example, immediate-release dosage forms may include crystalline forms of the A2-73 free base, A2-73, or A2-73 free base salts as disclosed herein. For example, rapidly dissolving oral dosage forms may include, for example, A2-73 crystal form I. Alternatively, dosage forms may include A2-73 free base crystal form I or A2-73 free base fumarate crystal form I, formulated for inhaled drug delivery as a dry powder or aerosol spray.

[0104] Dosage forms also include those formulated for topical application. For example, dosage forms can be formulated as one or more of gels, ointments, emulsions, microemulsions, solutions, suspensions, pastes, foams, sprays, lotions, or creams. In one aspect, a topical dosage form is a transdermal patch. When a dosage form is formulated as a transdermal patch, the 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 crystalline A2-73 free base.

[0105] Dosage forms can also be alternatively formulated for oral administration. Dosage forms formulated for oral administration can be tablets, capsules and chewable capsules, powders, granules, tea, drops or liquid medicines, or syrups that are swallowed, chewed, dissolved in water or under the tongue. In some respects, the dosage form is an enteric-coated oral preparation.

[0106] When 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.

[0107] Enteric-coated oral formulations may also contain a free A2-73 alkali salt in crystalline form. The free A2-73 alkali salt may be fumarate, sulfate, methanesulfonate, dihydrogen phosphate, ethanedisulfonate, benzoate, hydrochloride, or oxalate. In one aspect, the A2-73 salt is fumarate. When the A2-73 salt is 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.

[0108] Dosage forms also encompass those formulated for subcutaneous and / or intramuscular injection. For example, intramuscular dosage forms may include A2-73 in the form of a free base, dissolved in an oil matrix for intramuscular injection, or alternatively, prepared as a suspension of the free base for intramuscular injection. Dosage forms formulated for subcutaneous or intramuscular injection may include A2-73 in the form of a salt or free base as disclosed herein, prepared into microspheres using methods known in the art. Alternatively, A2-73 in the form of a free base or salt may be coated, for example, using atomic layer deposition (ALD) technology with a thin-layer coating such as zinc oxide coating and used in formulations for subcutaneous or intramuscular injection. Alternatively, the A2-73 free base may be dissolved in a biodegradable polymer matrix and then implanted subcutaneously (or used in transdermal patches, as further detailed below).

[0109] VII. Reagent test kit

[0110] In one aspect, this disclosure provides kits for practicing the methods disclosed herein. The kit may contain one or more therapeutic agents, pharmaceutically acceptable carriers, solvents, buffers, etc. The kit may also include instructions for practicing these methods. The instructions included in the kit may be affixed to packaging material or may be included as a packaging insert. While instructions are generally written or printed material, they are not limited thereto. This disclosure contemplates any medium capable of storing and communicating such instructions to the end user. Such media include, but are not limited to, electronic storage media (e.g., disks, magnetic tapes, cassette tapes, chips), optical media (e.g., CD-ROMs), etc. As used herein, the term "instructions" may include the address of a website providing the instructions.

[0111] definition

[0112] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. The following references provide general definitions for many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition, 1994); The Cambridge Dictionary of Science and Technology (Walker, ed., 1988); The Glossary of Genetics, 5th edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, unless otherwise stated, the following terms have the meanings assigned to them.

[0113] In describing elements of this disclosure or preferred aspects thereof, the articles “a / an,” “the,” and “described” are intended to indicate the presence of one or more elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and to indicate that additional elements may exist besides those listed.

[0114] As used in this article, the term "or" can be combined or separate.

[0115] The term “comprising” means “including, but not necessarily limited to”; it specifically indicates open-ended inclusion or membership in combinations, groups, series, etc., as described herein. As used herein, the terms “comprising” and “including” are inclusive and / or open-ended and do not exclude additional unlisted elements or process techniques. The term “consistent with…” is more restrictive than “comprising” but less restrictive than “consisting with…”. Specifically, the term “consistent with…” limits membership to the specified substances or steps and those that do not substantially affect the essential features of the claimed invention.

[0116] As used herein, terms such as “include / including,” “contain / containing,” and “have” mean “include.” Whether explicitly stated or not, this disclosure also considers other embodiments that “include the embodiments or elements presented herein,” “consist of the embodiments or elements presented herein,” and “consist primarily of the embodiments or elements presented herein.”

[0117] As used in this article, the term "substantially" means to a great extent or significantly, but not entirely.

[0118] As used herein, the term "about" or "approximately," when applied to one or more values ​​of interest, refers to a value similar to the reference value, or a value within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, the range of error depending in part on how the value is measured or determined, such as limitations of the measurement system. In one aspect, the term "about" refers to any value, including both the integer and decimal parts of a value modified by the term "about" within a maximum variation of ±10%. Alternatively, according to convention in the art, "about" may mean within a standard deviation greater than 3. Alternatively, as in the context of biological systems or processes, the term "about" may mean within an order of magnitude of the value, in some embodiments within five times the value, and in some embodiments within two times the value. Symbols as used herein "It means "about" or "approximately".

[0119] All ranges disclosed herein include both endpoints (as discrete values) and all integers and fractions specified within the range. For example, a range of 0.1–2.0 includes 0.1, 0.2, 0.3, 0.4, ... 2.0. If the endpoints are modified by the term “about,” the specified range extends to any variation (including the endpoints) within a range of up to ±10% or more of the standard deviation.

[0120] As used herein, the terms “active ingredient” or “pharmaceutical active ingredient” refer to a pharmaceutical preparation, active ingredient, compound, or substance, composition, or mixture thereof that provides a pharmacologically, generally beneficial, effect.

[0121] As used herein, the terms “control” or “reference” are used interchangeably. A “reference” or “control” level can be a predetermined value or range used as a baseline or benchmark against which the measured results are evaluated. “Control” also refers to a control experiment or control cells.

[0122] As used herein, the term “dosage” means any form of active ingredient formulation or composition, including cells, containing an amount sufficient to initiate or produce a therapeutic effect upon at least one or more administrations. The terms “formulation” and “composition” are used interchangeably herein.

[0123] As used herein, the term “prevention” means preventing or reducing the progression of a barrier to a statistically significant degree, or to a degree that is detectable by a person skilled in the art.

[0124] As used in this article, the term "gene" refers to a segment of DNA that contains all the information for the regulated biosynthesis of RNA products, including promoters, exons, introns, and other untranslated regions that control expression.

[0125] As used herein, the terms “disorder,” “disease,” “symptom,” and “functional impairment” are used interchangeably and encompass, but are not limited to, abnormal states 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 functional disorders. For example, internal dysfunction of the immune system can produce a variety of different diseases, including various forms of immunodeficiency, hypersensitivity, allergies, and autoimmune disorders. In humans, disease often refers to any injury, disability, disorder, syndrome, infection, abnormal behavior, or atypical variation in structural and functional states that causes pain, functional impairment, suffering, social problems, or death in the affected person. Diseases can affect people not only physically but also psychologically, as having and living with a disease can alter an affected person’s perspective on life. Diseases often manifest specific signs and symptoms or are associated with them. Interventions or treatments are often intended to eliminate, reduce, and / or reverse the course of disease, and / or alleviate or improve the physical and / or psychological symptoms present therein.

[0126] As used herein, the terms “polymorph,” “polymorphic form,” “crystal,” and “crystallization” are used interchangeably and refer to an ordered solid form in which atoms, ions, and / or molecules are arranged in a specific manner and form a pattern, resulting in a particular and unique three-dimensional format. A molecule can exist in multiple crystalline forms, which can have different physicochemical or biological properties. Different polymorphic forms of the same active pharmaceutical ingredient (API) can lead to variations in the API’s solubility, dissolution rate, pharmacokinetics, and ultimately, bioavailability and potency in therapeutic applications. Developing polymorphic forms and determining which polymorphic form is the most stable and / or most advantageous is crucial in drug design and manufacturing.

[0127] As used herein, the term "co-crystal" is used interchangeably and refers to a solid, a crystalline, single-phase material composed of two or more distinct molecular or ionic compounds typically in a specific stoichiometric ratio. Essentially, a eutectic consists of two or more components forming a unique crystalline structure and possessing unique properties. Eutectic can contain organic compounds with acids or ionic salts. Common eutectic types include hydrates, solvates, and cage-like structures. Eutectic is often stable and possesses physicochemical and / or biological properties distinct from the individual components that make up the eutectic.

[0128] As used herein, the terms “enantiomer,” “optical isomer,” or “optically active enantiomer” are used interchangeably and refer to one of two stereoisomers that cannot be superimposed on their own mirror image due to the chirality of the carbon atom. No amount of overall molecular reorientation or conformational change can convert a chemical into its enantiomer. Chiral chemical structures cause plane-polarized light to rotate. Therefore, enantiomers can be represented as (-) or (+), indicating the direction of optical rotation. Three common nomenclature rules exist for specifying one of the two enantiomers (absolute configuration) of a given chiral molecule: the R / S system is based on the molecule's geometry; the (+)- and (-)- systems are based on their optical rotation; and the D / L system is based on the molecule's enantiomerity relationship with glyceraldehyde. When a molecule is represented as dextrorotatory, it rotates the plane of polarization clockwise and can also be represented as (+). When it is represented as levorotatory, it rotates the plane of polarization counterclockwise and can also be represented as (-). A mixture of equal amounts of each enantiomer is called a "racemic mixture" or "racemate," which does not cause light rotation. Two enantiomers of the same molecule can have different physicochemical or biological properties, resulting in differences in solubility, dissolution rate, pharmacokinetics, and final bioavailability. Furthermore, an enantiomer can have different crystal structures, i.e., polymorphs. And an enantiomer can form cocrystals with other compounds or molecules. Stereoisomers include both enantiomers and diastereomers. Diastereomers, like enantiomers, have the same molecular formula and are also non-overlapping; however, they are not mirror images of each other.

[0129] As used herein, the term "peptide" refers to any polypeptide containing two or more amino acids linked together by peptide bonds or modified peptide bonds, i.e., isosteric peptides. Polypeptides can be short-chain (often referred to as peptides, glycopeptides, or oligomers) or long-chain (often referred to as proteins). Polypeptides can contain amino acids other than the 20 amino acids encoded by genes. Polypeptides include amino acid sequences modified through natural processes such as post-translational processing or through chemical modification techniques well known in the art. Such modifications are well described in basic textbooks and more detailed monographs, as well as in a large body of research literature.

[0130] As used herein, the term "inhibit / inhibition / inhibiting" means to reduce or prevent a given biological process, condition, symptom, disorder, or disease, or to significantly reduce the baseline activity of a biological activity or process.

[0131] As used herein, the term "treatment" means the prevention, aversion, halting, inhibition, reversal, mitigation, improvement, or suppression of the progression of a biological process (including a disorder or disease), or the elimination of a disease. Treatment can be administered in an acute or chronic manner. The term "treatment" also refers to reducing the severity of a disease or symptoms associated with such a disease before the onset of the disease. "Inhibition" or "prevention" of a disease, disorder, or its symptoms involves administering the cell, composition, or compound described herein to a subject after the clinical manifestation of such a disease, disorder, or its symptoms. "Prophylaxis of" or "preventing" of a disease, disorder, or its symptoms involves administering the cell, composition, or compound described herein to a subject before the onset of the disease, disorder, or its symptoms. "Aversion" of a disease or disorder involves administering the cell, composition, or compound described herein to a subject after the onset of the disease or disorder, but before the clinical manifestation or symptoms of the disease or disorder have appeared.

[0132] As used herein, the terms “treatment,” “therapy,” and “treatment regimen” refer to clinical interventions directed at a patient’s disease, disorder, or physical condition that the patient may be susceptible to. The goals of treatment include relieving or preventing symptoms, slowing or stopping the progression or worsening of a disease, disorder, or condition, and / or alleviating a disease, disorder, or condition (e.g., depression).

[0133] The terms “effective amount” and “therapeutic effective amount” refer to amounts sufficient to produce beneficial or desired biological and / or clinical outcomes.

[0134] As used herein, the term "administration" of a pharmaceutical agent, such as a therapeutic entity for treating depression administered to an animal or cell, is intended to refer to the dispensing, delivery, or application of a substance to an intended target. With respect to a therapeutic agent, the term "administration" is intended to mean contacting, dispensing, delivering, or applying a therapeutic agent to a subject by any suitable route of delivery to the desired location in the animal, including delivery via parenteral or oral routes, intramuscular injection, subcutaneous / intradermal injection, intravenous injection, intrathecal administration, buccal administration, transdermal delivery, local administration, and administration via the nasal or respiratory tract. The term "administration" includes self-administration and administration by another person to a subject.

[0135] As used in this article, “prevention” means preventing or reducing the likelihood of developing a disease, disorder, or condition in a subject who does not have such a disease, disorder, or condition but is at risk or is considered susceptible to it.

[0136] As used herein, the term "subject" refers to an animal. Generally, a subject is a mammal and can be a primate (e.g., a human, male or female; an infant, adolescent, or adult), a non-human primate, a rat, a mouse, a rabbit, a pig, a cow, a sheep, a goat, a horse, a dog, a cat, a fish, a bird, etc. In one respect, a subject is a human. Subjects can be laboratory animals (e.g., cynomolgus monkeys, rats, mice, guinea pigs, etc.). Human subjects explicitly encompass any age, size, sex, and race, including infants, children, adolescents, adults, or the elderly (over 65 years of age).

[0137] It should be understood that the various models of treatment or prevention of medical conditions described herein are intended to mean “substantial,” which includes both complete and incomplete treatment or prevention, in which detectable, biologically or medically relevant results are achieved.

[0138] Since various changes can be made to the cells and methods described above without departing from the scope of the invention, all content contained in the foregoing description and the embodiments given below should be interpreted as exemplary rather than restrictive.

[0139] Example

[0140] The above disclosure is provided solely for publication prior to the filing date of this application. Nothing herein should be construed as an admission that the present invention is not entitled to rely on prior inventions preceding such disclosure.

[0141] The following embodiments are incorporated to illustrate the present disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques discovered by the inventors that work well in the practice of the present disclosure. However, given the present disclosure, those skilled in the art will understand that many changes can be made to the present disclosure without departing from its spirit and scope and still obtaining similar or analogous results; therefore, all presented should be interpreted as exemplary and not in a limiting sense.

[0142] Example 1: Study Design for Brain Atrophy in Alzheimer's Disease Patients

[0143] ANAVEX®2-73 (which is used interchangeably with “A2-73” or “blarcamesine” in this text) 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). The trial enrolled 508 participants with early symptomatic Alzheimer’s disease (mild cognitive impairment / mild dementia) from July 2018 to June 2021 (the last patient visit for the primary outcome was in June 2022). The trial results confirmed positive outcomes for cognitive and functional endpoints with blarcamesine at doses ranging from 10 mg to 50 mg daily (A2-73 was administered to patients at daily doses of approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, or approximately 50 mg).

[0144] Example 2: Changes in midbrain atrophy in Alzheimer's disease patients

[0145] Changes in brain atrophy levels were monitored using structural MRI by comparing MRI scans taken at the start of the trial with those taken at the end of week 48. The comparisons showed that blarcamesine slowed and sometimes reversed brain atrophy in key regions of the entire brain. This effect was absent in the placebo group. A significant reduction in atrophy was observed in patients treated with blarcamesine compared to placebo (see Table 1 and...). Figure 1 Compared with the placebo group, the percentage change in volume of the whole brain, whole brain gray matter, frontal lobe, insular cortex, limbic lobe, parietal lobe and temporal lobe regions was significantly reduced in the treatment group (p < 0.005). The hippocampus and whole brain white matter volumes showed a trend of atrophy and reduction, but did not reach statistical significance.

[0146] Table 1: Summary of Changes in Brain Atrophy

[0147]

[0148]

[0149] Example 3. Discussion of the treatment of brain atrophy associated with Alzheimer's disease

[0150] The above clinical results show that, in the intention-to-treat (ITT) population analysis, 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 improvements visible in patients with Alzheimer's disease. Compared to placebo patients, patients treated with ANAVEX® 2-73 were 84% more likely to have improved cognition, with a change in ADAS-Cog score of -0.50 points or better from baseline to the end of treatment, odds ratio 1.84 (p = 0.015). On average, patients treated with ANAVEX® 2-73 who showed cognitive improvement had an ADAS-Cog cognitive score improvement of -4.03 points. Compared to placebo, ANAVEX® 2-73 treatment was 167% more likely to improve function, with a clinically meaningful improvement of +3.5 points or better ADCS-ADL score, odds ratio 2.67 (p = 0.0255). These data reflect robust improvements compared to the placebo group. The data also confirm clinically meaningful results in cognition and function compared to baseline. Furthermore, measured by ADAS-Cog, at the end of treatment, ANAVEX® 2-73 treatment resulted in a statistically significant 45% reduction in cognitive decline compared to placebo. These data represent treatment differences of -1.85 points in mean score change (p=0.033).

[0151] Compared with placebo, ANAVEX® 2-73 treatment also met the secondary endpoint of reducing clinical decline in cognition and function, as assessed by the Clinical Dementia Rating Scale Total Score (CDR-SB), with a treatment difference of -0.42 points in mean score change (p=0.040), representing a 27% reduction in the ITT population.

[0152] ANAVEX® 2-73 was generally safe and well-tolerated. The incidence of treatment-oriented adverse events (TEAEs) was similar in the active substance and placebo groups, with dizziness being the most common TEAE. TEAEs exceeding the 7.5% threshold were primarily mild or moderate. No clinically significant changes in vital signs, laboratory values, or ECG parameters were observed in either the active substance or placebo groups. The safety findings of this study are consistent with the known safety profile of ANAVEX® 2-73. In addition to the confirmed safety and efficacy at the primary and key secondary endpoints, the pre-specified analysis in 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 is consistent with observations from previous clinical trials of ANAVEX® 2-73.

[0153] In addition to the results and observations described above, the changes in brain atrophy in the treatment group were consistent with the treatment effect. Results showed a statistically significant reduction in brain atrophy in the treatment group compared to the placebo group. The reduction included decreased atrophic volume in the whole brain, whole brain gray matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, and temporal lobe regions. This is the first reported reduction or reversal of brain atrophy through pharmacological therapy. Therefore, ANAVEX® 2-73 is effective in reducing and reversing brain atrophy.

[0154] Example 4: Treatment of brain atrophy associated with Rett syndrome

[0155] An 8-year-old girl was diagnosed with Rett syndrome. Her neuropathological examination revealed widespread brain atrophy involving the cerebrum and cerebellum. The examination also showed decreased neuronal cell size and increased cell density throughout the brain. After the girl was given oral capsules of ANAVEX® 2-73 at a dose of 20 mg once daily for 16 weeks, a reduction and reversal of brain atrophy was detected.

[0156] Example 5: Treatment of brain atrophy associated with Parkinson's disease

[0157] A 68-year-old man was diagnosed with Parkinson's disease with dementia. MRI revealed cortical and subcortical atrophy. He was treated with oral ANAVEX® 2-73 at a dose of 30 mg once daily for 48 weeks, and the progression of atrophy in the cortical and subcortical regions slowed.

[0158] Example 6: Treatment of brain atrophy associated with dementia

[0159] A 72-year-old male was diagnosed with idiopathic dementia. MRI revealed brain shrinkage in the frontal and temporal lobes. He was treated with oral ANAVEX® 2-73 at a dose of 35 mg once daily for 48 weeks, during which brain atrophy was controlled and limited, and no further shrinkage was observed.

[0160] Example 7: Prevention of Brain Atrophy

[0161] Two 67-year-old men experienced similar forgetfulness over a two-month period: it began with forgetting where their car keys were, then progressed to forgetting how to drive home. MRI scans revealed no observable brain shrinkage in either man. One man received oral ANAVEX® 2-73 at a daily dose of 20 mg for eight weeks. His memory improved; he no longer forgot his home address or car keys, and his MRI showed no brain shrinkage. The other man did not take ANAVEX® 2-73 or any other medication. His forgetfulness worsened to the point where he could no longer drive. His MRI revealed significant brain shrinkage. In conclusion, ANAVEX® 2-73 effectively prevents the onset of brain atrophy.

Claims

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

2. The method according to claim 1, wherein the therapeutic agent is selected from: Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine; 1-(2,2-Diphenyltetrahydrofuran-3-yl)-N-methylmethylamine; Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanylamine; Its enantiomers; its pharmaceutically acceptable salts; its pharmaceutically acceptable crystals; its pharmaceutically acceptable eutectics; 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, methanesulfonate, ethanedisulfonate, or oxalate.

4. The method according to claim 2 or claim 3, wherein the therapeutic agent is selected from: Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride; 1-(2,2-Diphenyltetrahydrofuran-3-yl)-N-methylmethylamine hydrochloride; Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethylamine hydrochloride; Its enantiomers, its pharmaceutically acceptable crystals, its pharmaceutically acceptable eutectics, and any combination thereof.

5. The method according to any one of claims 2-4, wherein the pharmaceutically acceptable eutectic is formed between (i) and (ii): (i) Selected from the following compounds: Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine; 1-(2,2-Diphenyltetrahydrofuran-3-yl)-N-methylmethylamine; Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanylamine; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride; 1-(2,2-Diphenyltetrahydrofuran-3-yl)-N-methylmethylamine hydrochloride; Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethylamine hydrochloride; Its enantiomers, or their crystals; and (ii) Acids or ionic salts.

6. The method according to claim 5, wherein the acid is selected from fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphoric acid, dihydrogen phosphoric acid, 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 claim 6, wherein the ionic salt is selected from quaternary ammonium cation salts, transition metal salts, alkaline earth metal salts, or alkali metal salts.

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

9. The method according to any one of claims 1-8, wherein the therapeutic agent is selected from tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine, its crystals, its enantiomers, crystals of its enantiomers, its pharmaceutically acceptable salts, enantiomers of its pharmaceutically acceptable salts, crystals of its pharmaceutically acceptable salts, and their cocrystals.

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

11. The method according to any one of claims 1-10, wherein the therapeutic agent is selected from: Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine exists in an amorphous form; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form I (A2-73 crystal form I); Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form II (A2-73 crystal form II); Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form III (A2-73 crystal form III); (+)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in amorphous form; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in amorphous form; (+)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in crystalline form; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in crystalline form; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrogen fumarate exists in an amorphous form; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrogen fumarate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrogen fumarate in crystal form II; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrogen salt in crystal form III; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrogen fumarate in crystal form IV; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrogen salt in crystal form V; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine methanesulfonate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine sulfate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine sulfate in crystal form II; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine oxalate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine oxalate in crystal form II; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine dihydrogen phosphate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine ethanedisulfonate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine benzoate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrobromide in crystal form A; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrobromide in crystal form B; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine maleate in crystalline form S5; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine maleate in crystalline form S6; The eutectic form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride and tartaric acid, CSII; The eutectic form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine hydrochloride and citric acid, CSIII; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine hydrochloride and malic acid eutectic CSIV; Cocrystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride and zinc chloride; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride and zinc chloride eutectic; (+)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine hydrochloride eutectic with zinc chloride; and Any combination thereof.

12. The method according to any one of claims 1-11, wherein the therapeutic agent is selected from: Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form II; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form III; The eutectic of any of them; and Any combination thereof.

13. The method according to any one of claims 1-11, wherein the therapeutic agent is selected from: (+)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in amorphous form; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in amorphous form; (+)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in crystalline form; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in crystalline form; Its eutectic; and Any combination thereof.

14. The method according to any one of claims 1-11, wherein the therapeutic agent is selected from... Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form I (A2-73 crystal form I); Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form III (A2-73 crystal form III); (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in amorphous form; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in crystalline form; Its eutectic; and Any combination thereof.

15. The method according to any one of claims 1-11, wherein the therapeutic agent is a eutectic of (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine 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 1-15, wherein the therapeutically effective amount comprises about 0.5 mg to about 100 mg daily.

17. The method according to any one of claims 1-16, wherein the therapeutically effective amount is about 1 mg to about 60 mg daily, or selected from about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg daily.

18. The method according to any one of claims 1-17, wherein the therapeutically effective dose is about 10 mg to about 50 mg daily.

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

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

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

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

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

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

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

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

27. The method according to any one of claims 23-25, wherein the rest period is shorter than about 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 1-27, wherein the subject exhibits amyloid plaques or deposits in the brain.

29. The method according to any one of claims 1-28, wherein the subject has or is suspected of having a neurological disease.

30. The method of claim 29, wherein the neurological disease 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, prions, Rett syndrome, Fragile X syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder unclassified (PDD-NOS), childhood disintegrative disorder, Smith-Magnus 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, the method being carried out by administering to the subjects a preventatively effective amount of a drug that modulates both σ-1 receptors and muscarinic acetylcholine receptors.

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

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

34. The method of claim 33, wherein the neurological disease 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, prions, Rett syndrome, fragile X syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder unclassified (PDD-NOS), childhood disintegrative disorder, Smith-Magnus 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 31-34, wherein the risk of brain atrophy is associated with one or more symptoms selected from the following in the subject: amnesia, speech difficulties, writing difficulties, language loss, inability to understand words, memory impairment, cognitive impairment, hallucinations, mood and personality changes, irrational judgment, seizures, loss of consciousness, spasms, clenched teeth, or any combination thereof.

36. The method according to any one of claims 31-35, wherein the risk of brain atrophy is associated with one or more disorders selected from the group consisting of: 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, prions, Rett syndrome, Fragile X syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder unclassified (PDD-NOS), childhood disintegrative disorder, Smith-Magnanis 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 method according to any one of claims 31-36, wherein the reagent is selected from: Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine; 1-(2,2-Diphenyltetrahydrofuran-3-yl)-N-methylmethylamine; Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanylamine; Its enantiomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable crystals, its pharmaceutically acceptable eutectics, and any combination thereof.

38. The method of claim 37, wherein the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, fumarate, sulfate, dihydrogen phosphate, benzoate, maleate, methanesulfonate, ethanedisulfonate, and oxalate.

39. The method according to claims 37-38, wherein the pharmaceutically acceptable salt is a hydrochloride salt, and the therapeutic agent is selected from the group consisting of: Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride; 1-(2,2-Diphenyltetrahydrofuran-3-yl)-N-methylmethylamine hydrochloride; Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethylamine hydrochloride; Its enantiomers, its pharmaceutically acceptable crystals, its pharmaceutically acceptable eutectics, and any combination thereof.

40. The method according to any one of claims 37-39, wherein the pharmaceutically acceptable eutectic is formed between (i) and (ii): (i) Selected from the following compounds: Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine; 1-(2,2-Diphenyltetrahydrofuran-3-yl)-N-methylmethylamine; Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanylamine; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride; 1-(2,2-Diphenyltetrahydrofuran-3-yl)-N-methylmethylamine hydrochloride; Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethylamine hydrochloride; Its enantiomers, or their crystals; and (ii) Acids or ionic salts.

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

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

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

44. The method according to any one of claims 31-43, wherein the reagent is selected from tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine, its crystals, its enantiomers, crystals of its enantiomers, its pharmaceutically acceptable salts, enantiomers of its pharmaceutically acceptable salts, crystals of its pharmaceutically acceptable salts, and their cocrystals.

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

46. ​​The method according to any one of claims 31-45, wherein the reagent is selected from: Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine exists in an amorphous form; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form I (A2-73 crystal form I); Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form II (A2-73 crystal form II); Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form III (A2-73 crystal form III); (+)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in amorphous form; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in amorphous form; (+)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in crystalline form; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in crystalline form; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrogen fumarate exists in an amorphous form; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrogen fumarate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrogen fumarate in crystal form II; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrogen salt in crystal form III; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrogen fumarate in crystal form IV; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrogen salt in crystal form V; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine methanesulfonate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine sulfate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine sulfate in crystal form II; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine oxalate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine oxalate in crystal form II; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine dihydrogen phosphate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine ethanedisulfonate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine benzoate in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrobromide in crystal form A; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrobromide in crystal form B; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine maleate in crystalline form S5; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine maleate in crystalline form S6; The eutectic form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride and tartaric acid, CSII; The eutectic form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine hydrochloride and citric acid, CSIII; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine hydrochloride and malic acid eutectic CSIV; Cocrystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride and zinc chloride; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride and zinc chloride eutectic; (+)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanylamine hydrochloride eutectic with zinc chloride; and Any combination thereof.

47. The method according to any one of claims 31-46, wherein the reagent is selected from... Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form II; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form III; Its eutectic; and Any combination thereof.

48. The method according to any one of claims 31-46, wherein the reagent is selected from: (+)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in amorphous form; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in amorphous form; (+)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in crystalline form; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in crystalline form; Its eutectic; and Any combination thereof.

49. The method according to any one of claims 31-46, wherein the reagent is selected from: Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form I; Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in crystal form III; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride in amorphous form; (-)Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is in crystalline form; Its eutectic; and Any combination thereof.

50. The method according to any one of claims 31-49, wherein the reagent is a eutectic of (-)tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine 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 31-50, wherein the effective preventive dose comprises about 0.5 mg to about 100 mg daily.

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

53. The method according to any one of claims 31-52, wherein the effective preventive dose is about 10 mg to about 50 mg daily.

54. The method according to any one of claims 31-53, wherein the preventive effective amount is administered by a dosage form selected from: oral dosage form, intravenous dosage form, and transdermal dosage form.

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

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

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

58. The method according to any one of claims 31-57, wherein the administration comprises an intermittent dosing regimen of at least two cycles, each cycle comprising: (a) During the administration period, during which the subject is given a preventatively effective dose of the drug; and thereafter (b) the rest period.

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

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

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

62. The method according to claims 58-60, wherein the rest period is shorter than about 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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