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WO2025054599A1 - Traitement et prévention de l'atrophie cérébrale - Google Patents

Traitement et prévention de l'atrophie cérébrale Download PDF

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WO2025054599A1
WO2025054599A1 PCT/US2024/045834 US2024045834W WO2025054599A1 WO 2025054599 A1 WO2025054599 A1 WO 2025054599A1 US 2024045834 W US2024045834 W US 2024045834W WO 2025054599 A1 WO2025054599 A1 WO 2025054599A1
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Prior art keywords
diphenyl
tetrahydro
dimethyl
furanmethanamine
crystal
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Christopher U. Missling
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Anavex Life Sciences Corp
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Anavex Life Sciences Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine

Definitions

  • the present disclosure relates to methods of treating or preventing brain atrophy related to or associated with neurological disorders.
  • Brain atrophy or cerebral atrophy refers to loss of brain cells (neurons), connections between brain cells, and/or loss of brain volume, and when accelerated over the normal brain atrophy of aging is associated with many different diseases that can affect the brain.
  • Brain atrophy can manifest in a generalized form across the entire brain or can be more localized to a portion of the brain.
  • various brain functions including executive functions can be impacted.
  • Symptoms of brain atrophy may include seizures, dementia, memory loss and aphasias.
  • Brain atrophy diseases and conditions of the brain that may involve brain atrophy include among others, Alzheimer’s disease, stroke, traumatic brain injury, Pick’s disease, fronto-temporal dementia, cerebral palsy, Huntington’s disease, leukodystrophies, mitochondrial encephalomyopathies, multiple sclerosis, and infectious diseases such as encephalitis, neurosyphilis, and AIDS.
  • Brain atrophy may be detected and monitored by various non- or minimally invasive brain imaging techniques, such as magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • treatments for brain atrophy are limited.
  • Blood thinners, cholesterol- lowering agents such as statins, and certain antihypertensive medications have been used to address brain atrophy.
  • Medications used to treat Alzheimer's disease such as Aricept (donepezil) and Namenda (memantine), have also been used to slow down atrophy. These medications are however not for suitable for everyone and can have limited to no significant effect in reducing or preventing abnormal brain atrophy.
  • Aricept donepezil
  • Namenda memantine
  • One aspect of the present disclosure encompasses a method of treating or preventing brain atrophy in a human subject comprising administering to the subject a therapeutically effective amount of a therapeutic agent modulating both the sigma- 1 receptor and the muscarinic acetylcholine receptor.
  • the therapeutic agent is selected from: tetrahydro-N, N-dimethyl-2,2-diphenyl-3- furanmethanamine (A2-73 Freebase); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N- methylmethanamine (A19-144 Freebase); tetrahydro-N, N-dimethyl-5,5-diphenyl-3- furanmethanamine (A1-41 Freebase); an enantiomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable crystal thereof, a pharmaceutically acceptable co-crystal thereof, and any combination thereof.
  • the pharmaceutically acceptable salt is selected from a hydrochloride salt, a hydrobromide salt, a fumarate salt, a sulfate salt, a dihydrogen phosphate salt, a benzoate salt, a maleate salt, a mesylate salt, an edysilate salt, or an oxalate salt.
  • the pharmaceutically acceptable salt is the hydrochloride salt
  • the agent is selected from the group consisting of tetrahydro- N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (A2-73); 1 -(2,2- diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (A19-144); tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (A1-41 ); an enantiomer thereof, a pharmaceutically acceptable crystal thereof, a pharmaceutically acceptable co-crystal thereof, and any combination thereof.
  • the pharmaceutically acceptable co-crystal is formed between (i) A2-73 Freebase, A2-73, A19-144 Freebase, A19-144, A1 -41 Freebase, A1-41 , an enantiomer therefore, a crystal thereof; and (ii) an acid or an ionic salt.
  • 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 a quaternary ammonium cationicsalt, a salt of a transitional metal, a salt of an alkaline earth metal, or a salt of alkali metal.
  • the ionic salt is selected from lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, iron (II) chloride, iron (III) chloride, titanium chloride, chromium (III) chloride, scandium (III) chloride, manganese (II) chloride, copper (I) chloride, copper (II) chloride, nickel chloride, or aluminum chloride.
  • the therapeutic agent is selected from A2-73 Freebase, a crystal thereof, an enantiomer thereof, a crystal of the enantiomer thereof, a pharmaceutically acceptable salt thereof, an enantiomer of the pharmaceutically acceptable salt thereof, a crystal of the pharmaceutically acceptable salt thereof, or a co-crystal thereof.
  • the therapeutic agent is selected from A2-73, a crystal thereof, an enantiomer thereof, a crystal of the enantiomer thereof, and a co-crystal thereof.
  • the therapeutic agent is selected from A2-73 Freebase in amorphous form, A2-73 Freebase 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 Freebase fumarate salt in amorphous form, A2-73 Freebase hydrogen fumarate salt in crystal Form I, A2-73 Freebase hydrogen fumarate salt in crystal Form II, A2-73 Freebase hydrogen fumarate salt in crystal Form III, A2-73 Freebase hydrogen fumarate salt in crystal Form IV, A2-73 Freebase hydrogen fumarate salt in crystal Form V, A2-73 Freebase Mesylate Form I, A2-73 Freebase Sulfate Form I, A2-73 Freebase Sulfate Form II, A2-73 Freebase Oxalate Form I, A2- 73 Freebase Oxalate Form II, A2-73 Freebase Oxalate Form III, A2-73 Freebase Dihydrogen
  • the therapeutic agent is selected from A2-73 Crystal Form I, A2-73 Form II, A2-73 Form III, and any combination thereof.
  • the therapeutic agent is selected from (-) A2-73 enantiomer, (+) A2-73 enantiomer, a crystal of the (-) A2-73 enantiomer, a crystal of the (+) A2-73 enantiomer, a co-crystal of the (-) A2-73 enantiomer, a co-crystal of the (+) A2-73 enantiomer, and any combination thereof.
  • the therapeutic agent is selected from A2-73 Crystal Form I, A2-73 Crystal Form III, (-) A2-73 enantiomer, a crystal of the (-) A2-73 enantiomer, a co-crystal of the (-) A2-73 enantiomer, and any combination thereof.
  • the therapeutic agent is a co-crystal of (-) A2-73 enantiomer with zinc chloride in a molar ratio from about 1 :1 to about 2:1.
  • a therapeutically effective amount comprises from about 0.5 mg to about 100 mg per day, such as from about 1 mg to about 60 mg per day, or is selected from about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg per day. In one aspect, a therapeutically effective amount is from about 10 mg to about 50 mg per day.
  • the therapeutically effective amount can be administered through a dosage form selected from an oral dosage form, an intravenous dosage form, and a transdermal dosage form.
  • the dosage form is a capsule formulated for oral administration.
  • the administration is daily administration for at least about 30 days or up to about 96 weeks.
  • the administration comprises an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period during which the therapeutically effective amount of the agent is administered to the subject; and thereafter (b) a resting period.
  • the dosing period and the resting period can be of the same duration, or of different durations.
  • the dosing period is at least about 10 days, 11 days, 12 days, 13 days, and 14 days.
  • the resting period is 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.
  • the subject exhibits amyloid plaques or deposits in the brain.
  • the subject suffers from or is suspected of suffering from a neurological disease.
  • the neurological disease may be selected from cognitive impairment, Lewy body dementia, stroke, traumatic brain injury, infections, spinal cord injury, Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett Syndrome, Fragile X Syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith -Magenis syndrome, multiple sclerosis, Fronto-temporal 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.
  • MND motor neuron disease
  • SCA spinocerebellar ataxia
  • SMA spinal muscular atrophy
  • autism spectrum disorder schizophrenia, post-traumatic stress disorder (PTSD), and
  • Another aspect of the present disclosure encompasses a method of preventing brain atrophy in a subject at risk of developing brain atrophy, by administering to the subject a prophylactically effective amount of an agent modulating both sigma-1 receptor and muscarinic acetylcholine receptor.
  • the brain atrophy is manifested by shrinkage or loss of volume in brain tissue in at least one brain region as compared to brain tissue volume in a control sample wherein the brain region is selected from frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, whole brain white matter and whole brain grey matter, and wherein the control sample is obtained from a healthy individual or is a prior sample from the subject.
  • the brain atrophy is associated with or is suspected of being associated with a brain infection, brain inflammation, a neurological disease, or any combination thereof.
  • a neurological disease may be selected from cognitive impairment, Lewy body dementia, stroke, traumatic brain injury, spinal cord injury, infections, Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett Syndrome, Fragile X Syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith -Magen is syndrome, multiple sclerosis, Fronto-temporal 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.
  • MND motor neuron disease
  • SCA spinocerebellar ataxia
  • SMA spinal muscular atrophy
  • autism spectrum disorder schizophrenia, post-traumatic stress disorder (PTSD), and any
  • the present disclosure provides methods of treating and/or preventing brain atrophy related to and/or associated with Rett syndrome (RSS), also referred to as cerebroatrophic hyperammonemia.
  • RSS is a progressive disorder predominant in females and associated with cortical atrophy, stereotyped hand movements mimicking handwashing, severe mental deficiency, and cortical and extrapyramidal dysfunction.
  • the clinical progression of RSS is consistent with an arrested neuronal development that may be due to either impaired cellular differentiation or the lack of proper trophic factors.
  • the subject loses purposeful use of hands and the ability to speak and can experience other early symptoms including problems in crawling or walking and/or diminished eye contact.
  • the loss of functional use of the hands is followed by compulsive hand movements such as wringing and washing.
  • Apraxia the inability to perform motor functions, can interfere with all body movements, including eye gaze and speech.
  • Children with RSS can also show autistic-like behaviors, such as incontinence, screaming fits, inconsolable crying, breath holding, hyperventilation or air swallowing, avoidance of eye contact, lack of social/emotional reciprocity, markedly impaired use of nonverbal behaviors to regulate social interaction, loss of speech, and sensory problems.
  • the present disclosure provides methods of treating and/or preventing brain atrophy related to or associated with dementia.
  • Dementia is a general term for severe thinking problems that interfere with daily tasks. There’s a connection between brain atrophy and dementia.
  • dementia typically starts with shrinkage of brain tissue that may be restricted to certain parts of the brain.
  • frontotemporal dementia the frontal and temporal lobes of the brain shrink.
  • Genetic mutations have been linked to frontotemporal dementia.
  • Creutzfeldt-Jakob disease related dementia which deteriorates unusually fast.
  • Other types of dementia such as Alzheimer’s dementia or dementia with Lewy bodies may progress more slowly.
  • Alzheimer related dementia accounts for 60-80% of all dementia patients.
  • vascular dementia caused by microscopic bleeding and blood vessel blockage in the brain is the second most common cause of dementia. Those who experience brain changes caused by multiple types of dementia have mixed dementia. In sum, dementia may relate to, associate with, and result from brain atrophy. Progression of brain atrophy further deteriorates dementia.
  • the present disclosure provides methods of treating and/or preventing dementia- related brain atrophy, by reversing, reducing, slowing, halting, and/or blocking brain cell loss, neuron cell toxication, and/or brain shrinkage.
  • the present disclosure also provides methods to modulate brain atrophy that is related to, associated with, and/or resulted from Parkinson’s Disease (PD).
  • PD is caused by a loss of nerve cells in part of the brain called the substantia nigra. It is often age-related and characterized by brain cell degeneration. Such degeneration leads to a dopamine reduction in the brain. Since dopamine plays a vital role in regulating the movement of the body, PD is best known for causing slowed movements, tremors, and balance problems.
  • Structural MRI may be used to monitor and/or predict disease progression in PD.
  • the present disclosure provides methods to modulate PD-related brain atrophy, by reversing, reducing, slowing, halting, and/or blocking brain cell loss, neuron cell toxication, and/or brain shrinkage.
  • brain atrophy in a test subject can be determined by determining the whole brain volume of the subject and comparing change in volume relative to a control or reference volume for the subject, or to control values for brain volume obtained from a population of healthy age-matched subjects.
  • the brain atrophy in a test subject can be determined by determining the brain volume in a selected brain region of the subject and comparing to a control or reference volume of the brain region of the subject, or to control values for the brain region obtained from a population of healthy age-matched subjects.
  • Brain volume can be determined by measuring volume of whole brain grey matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, and whole brain white matter.
  • the present disclosure relates to methods of treating brain atrophy after it has been detected in a subject.
  • Such treatment includes, but is not limited to, reducing or reversing brain shrinkage; halting, slowing, ameliorating or reversing brain volume loss or brain cell loss; halting, slowing, or reversing brain cell death.
  • Such treatment may be achieved by administering to the subject one or more therapeutically active agents, such as a Sigma-1 receptor agonist, and/or a dual modulator of Sigma-1 receptor and muscarinic receptor.
  • the present disclosure also encompasses methods of preventing brain atrophy.
  • such prevention comprises blocking, deterring, delaying, slowing, or avoiding the onset of brain atrophy in a subject.
  • the subject is at risk of developing brain atrophy.
  • Such prophylactic method may be achieved by administering to the subject one or more prophylactically active agents, such as a Sigma-1 receptor agonist, and/or a dual modulator of Sigma-1 receptor and muscarinic receptor.
  • the modulation methods of the present disclosure also comprise any suitable and available tools, instrumentation, apparatus, and/or techniques of monitoring or detecting brain features in various parts of the brain.
  • Such brain feature may include measurements of brain mass, size, volume, density, hydration level, neuron counts, and/or neuron connections.
  • Such tools may include structural MRI.
  • Sigma-1 receptor expression or activity is linked to neuroactivity in neurodevelopment/neurodegeneration, and the activation of the Sigma-1 receptor is associated with neuroprotection in human subjects and in different in vitro and in vivo models. Such neuroprotection may be needed in a subject that have been diagnosed with, or is suspected to have, a neurological disorder, such as a neurodegenerative or a neurodevelopmental disorder.
  • a neurological disorder such as a neurodegenerative or a neurodevelopmental disorder.
  • one aspect of the disclosure encompasses restoring brain volume, halting and/or ameliorating neuron loss, and/or reducing or reversing brain atrophy in such subject with a therapeutic agent or a prophylactic agent which is a Sigma-1 receptor agonist, or is a dual modulator of Sigma-1 receptor and muscarinic receptor.
  • Non-limiting examples of the therapeutic agent or the prophylactic agent include but not limited to entacapone, nebicapone, nitecapone, opicapone, tolcapone, tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine (Anavex 2-73 Freebase), tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEXO2-73, AV2-73, A2-73, or blarcamesine), 1 -(2,2- diphenyltetrahydrofuran-3-yl)-N-methylmethanamine (ANAVEX19-144 Freebase), 1- (2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (ANAVEXO19-144 or A19-144), tetrahydro-N, N-dimethyl-5,5-diphenyl-3- fur
  • the Sigma-1 receptor agonist is A2-73, A2-73 Freebase, or an enantiomer, a crystal form, a pharmaceutically acceptable salt, an analog or a metabolite thereof.
  • the A2-73, A2- 73 Freebase or its salt may be in the form of a racemic, a stereoisomer, an enantiomer, a polymorph, or a co-crystal.
  • the enantiomer may be (+) or (-) rotation or expressed as (R) or (S) forms.
  • a pharmaceutically acceptable co-crystal is formed between: (i) A2-73 Freebase, A2-73, A19-144 Freebase, A19-144, A1-41 Freebase, A1-41 , an enantiomer therefore, a polymorph thereof; and (ii) an acid or an ionic salt.
  • the acid comprises 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, or a combination thereof.
  • the ionic salt comprises a quaternary ammonium cationic salt, a salt of a transitional metal, a salt of an alkaline earth metal, or a salt of alkali metal.
  • the ionic salt comprises lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, iron (II) chloride, iron (III) chloride, titanium chloride, chromium (III) chloride, scandium (III) chloride, manganese (II) chloride, copper (I) chloride, copper (II) chloride, nickel chloride, or aluminum chloride.
  • the therapeutic agent or the prophylactic agent comprises tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (A2-73 Freebase), a polymorph thereof, an enantiomer thereof, a polymorph of the enantiomer thereof, a pharmaceutically acceptable salt thereof, an enantiomer of the pharmaceutically acceptable salt thereof, a polymorph of the pharmaceutically acceptable salt thereof, or a co-crystal thereof.
  • A2-73 Freebase tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine
  • the agent comprises tetrahydro-N,N- dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (A2-73), a polymorph thereof, an enantiomer thereof, a polymorph of the enantiomer thereof, or a cocrystal thereof.
  • the agent comprises of A2-73 Freebase in amorphous form, A2-73 Freebase 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.
  • the A2-73 Freebase in crystal Form I is disclosed and characterized in W02019200345A1 , which is incorporated by reference in its entirety. Specifically, the A2-73 Freebase in crystal Form I is characterized substantially by XRPD pattern shown in FIG. 16 and particle shapes depicted in FIG. 15. In one aspect, A2-73 crystal is the Form I, Form II, and/or Form III crystals as disclosed and characterized in WO2017013498A2, the disclosure of which is herein incorporated by reference in its entirety. Specifically, the A2-73 crystal Form I is characterized substantially by XRPD pattern shown in FIG. 1 and particle shapes depicted in FIGs. 2 and 3. The A2-73 crystal Form II is characterized substantially by XRPD pattern shown in FIG.
  • the pharmaceutically acceptable salt comprises a hydrochloride salt, a hydrobromide salt, a fumarate salt, a sulfate salt, a dihydrogen phosphate salt, a benzoate salt, a mesylate salt, an edysilate salt, or an oxalate salt.
  • the co-crystal comprises a A2-73 pharmaceutically acceptable salt with an organic acid comprising tartaric acid, citric acid, maleic acid, or a combination thereof.
  • the A2-73 is A2-73 amorphous form, A2- 73 Freebase crystal Form I, A2-73 crystal Form I, A2-73 crystal Form II, A2-73 crystal Form III, (+)A2-73 enantiomer, (-)A2-73 enantiomer.
  • the active is A2-73 freebase fumarate salt and/or its crystals, such as A2-73 Freebase fumarate salt in amorphous form, A2-73 Freebase hydrogen fumarate salt crystal Form I, A2-73 Freebase hydrogen fumarate salt crystal Form II, A2-73 Freebase hydrogen fumarate salt crystal Form III, A2-73 Freebase hydrogen fumarate salt crystal Form IV, A2-73 Freebase hydrogen fumarate salt crystal Form V, all of which are disclosed and characterized in W02019200345A1 , such as XRPD patterns shown in FIG. 29, FIG. 30, FIG. 32 FIG. 33, and FIG. 34, respectively.
  • the A2-73 is other salt crystals, such as A2-73 Freebase Mesylate Form I, A2-73 Freebase Sulfate Form I, A2-73 Freebase Sulfate Form II, A2-73 Freebase Oxalate Form I, A2-73 Freebase Oxalate Form II, A2-73 Freebase Oxalate Form III, A2-73 Freebase Dihydrogen phosphate Form I, A2-73 Freebase Edisylate Form I, A2-73 Freebase Benzoate Form I, all of which are disclosed and characterized in W02019200345A1 , such as XRPD patterns shown in FIGs. 18-23 and 25-27, respectively.
  • the active is A2-73 Freebase hydrobromide crystal Form A, A2-73 Freebase hydrobromide crystal Form B, A2-73 maleate crystal Form S5, or A2-73 maleate crystal Form S6. They are disclosed and characterized in WO2021 158586A1 , the disclosure of which is herein incorporated by reference in its entirety.
  • the active is co-crystal Form CSII of A2-73 co-crystal with tartaric acid, co-crystal Form CSIII of A2-73 co-crystal with citric acid, or cocrystal Form CSIV of A2-73 co-crystal with malic acid. They are disclosed and characterized in WO2023208133A1 , which is incorporated by reference in its entirety.
  • the active is co-crystal of A2-73 with zinc chloride disclosed in U.S. Patent No. 12,018,005B1 , which is incorporated by reference in its entirety.
  • the therapeutically effective amount or the prophylactically effective amount of A2-73 may range from 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.
  • the therapeutically effective amount may range from 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.
  • the therapeutically effective amount may be 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.
  • the therapeutically effective amount or the prophylactically effective amount 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.
  • the therapeutic agent is A2-73 crystal Form I, A2-73 crystal Form II or A2-73 crystal Form III, and their therapeutically effective amounts or the prophylactically effective amounts 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.
  • the therapeutically effective amount or the prophylactically effective amount may range 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.
  • the therapeutically effective amount may range 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.
  • the therapeutically effective amount may be 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, about 158 mg, about 160 mg, about 165 mg, about 168 mg, about 170 mg, about 172 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg,
  • the therapeutically effective amount or the prophylactically effective amount 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, 185 mg, 190 mg, 195 mg, or 200 mg.
  • the therapeutically effective amount or the prophylactically effective amount may range 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.
  • the therapeutically effective amount or the prophylactically effective amount may range 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.
  • the therapeutically effective amount or the prophylactically effective amount may be 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, about 158 mg, about 160 mg, about 165 mg, about 168 mg, about 170 mg, about 172 mg, about 175 mg, about 180 mg, about 185 mg, about
  • the therapeutically effective amount or the prophylactically effective amount 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, 185 mg, 190 mg, 195 mg, or 200 mg.
  • the therapeutic agent or the prophylactic agent is A2-73 and A2-73 Freebase
  • the effective therapeutic amount comprises the combined amount of 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.
  • the therapeutic agent is A2-73 and A1 -41 , and the therapeutic effective amount comprises the combined amount 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.
  • the therapeutic agent or the prophylactic agent is administered daily, every other day, or three times per week, or once per week. In other aspect, the agent is administered once day, twice daily or three times daily.
  • the therapeutically effective amount may range from about 0.5 mg/day to about 100 mg/day, from about 1 to about 60 mg/day, from about 20 to about 50 mg/day, from about 20 to about 30 mg/day, or from about 15 to about 25 mg/day.
  • the therapeutically effective amount of A2-73 may range from 0.5 mg/day to 100 mg/day, from 1 to 60 mg/day, from 20 to 50 mg/day, from 20 to 30 mg/day, or from 15 to 25 mg/day.
  • administering the therapeutic effective amount or the prophylactically effective amount may provide blood levels of about 10 ng/ml to about 12 ng/ml of A2-73.
  • administering the therapeutic effective amount of A2-73 can provide blood levels of 10 ng/ml to 12 ng/ml of A2-73.
  • administering the therapeutic effective amount or the prophylactically effective amount of A2-73 can provide blood levels 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 of A2-73.
  • administering the therapeutic effective amount 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.
  • the therapeutic agent or the prophylactic agent such as A2-73, A19-144, A1-41 , or their freebases, salts, or enantiomers, may be administered to the subject daily or every other day for a treatment period, or following an intermittent dosing regimen.
  • A2-73 may be administered every 2, 3, 4, 5, 6, 7, 14, or every 30 days. Frequency of administration can be one time, two times, or three times on the dosing days.
  • the therapeutic agent, such as A2-73 may be administered over a period ranging from about 1 day to about 1 year, from about 1 day to about 1 week, from about 3 days to about 1 month, from about 2 weeks to about 6 months, or from about 2 months to about 4 months.
  • the therapeutic agent may be administered over a period of about 1 day, about 7 days, about 30 days, about 60 days, about 120 days, or about 180 days or more.
  • the therapeutic agent A2 -73 is administered over a period of about 12 weeks, over a period of about 24 weeks, over a period of about 36 weeks, over a period of about 48 weeks, over a period of about 57 weeks, over a period of about 96 weeks, or about 148 weeks, or about 208 weeks, indefinitely, or until resolution of the condition being treated.
  • the dosage regimens may comprise administering to the subject as a pharmaceutical composition or dosage form comprising the therapeutically effective amount of the agent.
  • such administration follows an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period during which a therapeutically effective amount of said pharmaceutical composition is administered to said patient and, thereafter, (b) a resting period.
  • the dosing period and the resting period are of the same duration or are of different durations.
  • the dosing period and the resting period in the range of a lower limit (more than) 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 an upper limit (shorter than) 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.
  • the dosing period of between about 1 day and 12 days and a resting period between about 1 day and 12 days.
  • a dosing period is 12 days and the resting period is 12 days.
  • Such regimen is usefully employed wherein the therapeutically effective amount of said therapeutic agent or its pharmaceutical composition is about 1 mg to about 100 mg and particularly about 30 mg to about 50 mg, and particu larly for oral dosage forms. Also contemplated are A2-73 dosages of about 3 mg to about 5 mg with intravenous administration.
  • Other methods of administering the therapeutic agent or the prophylactic agent such as A2-73 Freebase, A19-144, A19-144 Freebased, A1-41 or A1-41 Freebase, can be found in, e.g., U.S. Patent No. 9750746, U.S. Patent Publication No. 20170360798, U.S. Patent Publication No. 20190022052, U.S. Patent Publication No. 20180360796, U.S. Patent Publication No. 20180169059, U.S.
  • Patent Publication No. 20180177756 U.S. Patent Publication No. 20180169060, and U.S. Patent Publication No. 20190117615.
  • the disclosures of each of the above patents and applications are expressly incorporated herein in their entirety.
  • compositions for delivery of the therapeutic agents, such as a Sigma-1 receptor agonist, or a dual modulator of Sigma-1 receptor and muscarinic receptor.
  • a pharmaceutical formulation comprises a therapeutic agent and a pharmaceutically acceptable excipient or carrier.
  • a dosage form also called “unit dose”. It refers to the end-product encompassing the pharmaceutical composition and being packaged in a form suitable to be marketed and used. Depending on the method/route of administration, dosage form may be in the form of a liquid, a solid, or a semisolid.
  • dosage forms suitable for the delivery of the therapeutic agent such as in the forms of pills, tablets, capsules, drinks, injections, among many others.
  • One aspect of the present disclosure encompasses a pharmaceutical composition or a dosage form comprising a therapeutic amount of the therapeutic agent.
  • the therapeutic agent can be a freebase form, or a pharmaceutically acceptable salt thereof.
  • Pharmaceutically acceptable salts of the compound comprising organic and inorganic salt such as acetate, aspartate, benzoate, bitartrate, citrate, formate, gluconate, glucuronate, glutamate, fumarate, hydrochloride, hydrobromide, hydroiodide, hypophosphite, isobutyrate, isocitrate, lactate, malate, maleate, meconate, methylbromide, methanesulfonate, monohydrate, mucate, nitrate, oxalate, phenylpropionate, phosphate, phthalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tannate, tartrate, terephthalate, valerate
  • the pharmaceutical composition may comprise from about 1 mg to about 50 g, from about 0.1 to about 5 g, from about 0.5 g to about 3 g, from about 1 mg to about 55 mg, from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, from about 180 mg to about 220 mg, from about 0.1 g to about 5 g, or from about 0.5 g to about 3 g of A2-73.
  • Compositions or formulations comprising A2- 73 can be found in, e.g., U.S. Patent No. 9750746, U.S. Patent Publication No.
  • a composition or formulation may comprise A2-73 in an amount of 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.
  • a formulation may comprise A2 -73 in an amount from 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.
  • a formulation may comprise A2-73 in the amount 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.
  • a formulation may comprise A2-73 in the amount 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.
  • a composition may comprise A19-144 in the 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.
  • a composition may comprise A19-144 in an amount 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.
  • a formulation may comprise A19-144 in an amount of about 0.5 mg, about 1 .0 mg, about 3 mg, about 5 mg, about 10 mg, about
  • a formulation may comprise A19-144 in an amount 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, 190 mg, 195 mg, or 200 mg.
  • a formulation may comprise 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.
  • a formulation may comprise A1 -41 in an amount 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.
  • a formulation may comprise A1-41 in an amount 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, about 158 mg, about 160 mg, about 165 mg, about 168 mg, about 170 mg, about 172 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg
  • a formulation may comprise A1-41 in an amount 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, 190 mg, 195 mg, or 200 mg.
  • the therapeutic agent or the prophylactic agent is A2- 73 crystal Form I, A2-73 crystal Form II or A2-73 crystal Form III, and their therapeutically effective amounts 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.
  • the therapeutically effective amount or the prophylactically effective amount of A2-73 can 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.
  • the therapeutically effective amount or the prophylactically effective amount of A2-73 can range from about 0.5 mg/day to about 100 mg/day, from about 1 to about 60 mg/day, from about 20 to about 50 mg/day, from about 20 to about 30 mg/day, or from about 15 to about 25 mg/day. In another aspect, the therapeutically effective amount of A2-73 can range from 0.5 mg/day to 100 mg/day, from 1 to 60 mg/day, from 20 to 50 mg/day, from 20 to 30 mg/day, or from 15 to 25 mg/day. Administering the therapeutic effective amount or the prophylactically effective amount of A2-73 can provide blood levels of about 10 ng/ml to about 12 ng/ml of A2-73.
  • administering the therapeutic effective amount of A2-73 can provide blood levels of 10 ng/ml to 12 ng/ml of A2-73. In another aspect, administering the therapeutic effective amount of A2-73 can provide blood levels 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 of A2-73.
  • administering the therapeutic effective amount or the prophylactically effective amount 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.
  • the therapeutic agent or the prophylactic agent can be formulated and administered to a subject by several different means.
  • a composition can generally be administered parenterally, intraperitoneally, intravascularly, transdermally, subcutaneously, or intrapulmonarily in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable adjuvants, carriers, excipients, and vehicles as desired.
  • parenteral includes subcutaneous, intravenous, intramuscular, intrathecal, or intrasternal injection, or infusion techniques.
  • the therapeutic agent can be formulated to be suitable for administration to a particular type of subjects, such as an elderly or a pediatric subject, a subject with difficulty in swallowing, a subject prone to seizure, or a subject prone to vomiting or nauseating.
  • an elderly is a human being of 65 years of age or older.
  • a pediatric comprises an infant (ages 0-2 yr), a child (ages 2-12), or an adolescent (ages 13-18).
  • the formulation may comprise an excipient desirable by a pediatric subject, such as flavored oral suspensions, flavored caplets, or flavored capsules.
  • a pharmaceutical formulation comprises one or more pharmaceutically acceptable excipients or carriers.
  • excipients or carriers include chemical enhancers, humectants, pressure sensitive adhesives, antioxidants, solubilizers, thickening agents, plasticizers, adjuvants, carriers, excipients, vehicles, coatings, and any combinations thereof.
  • One or more excipients can be selected for oral, transdermal, parenteral, intraperitoneal, intravascular, subcutaneous, by inhalation spray, rectal, or intrapulmonary administration.
  • the therapeutic agent may in general be formulated for improving patient compliance, preventing a subject from removing the drug-delivery device.
  • the therapeutic agent could be formulated for improved patient compliance and preventing removal of a drug-delivery device by providing formulations for extended delivery.
  • Extended delivery can range for periods ranging from more than one day, to months. This may be especially relevant for patients with compromised cognitive and/or motor-control abilities. Extended delivery for periods can range from about 1 day to about 1 year, from about 1 day to about 1 week, from about 3 days to about 1 month, from about 2 weeks to about 6 months, orfrom about 2 months to about 4 months.
  • Extended-release formulations could be used for substantially continuous delivery of drug at a preselected rate.
  • the drug can be delivered at a rate of from about 0.5 mg to about 100 mg/day, from about 40 to about 60 gm/day, or from about 10 to about 30 gm/day.
  • Appropriate amounts of crystalline A2-73 can be readily determined by the ordinarily skilled artisan based upon, for example, the intended duration of administration of the drug by the extended-release formulation, the delivery mechanism, the formulation, and the relative potency of the drug among other factors.
  • Non-limiting examples of binders suitable for the formulations of various aspects include starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethyl cellulose, polyacrylamides, polyvinyloxoazolidone, polyvinyl alcohols, C12-C18 fatty acid alcohols, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof.
  • the polypeptide may be any arrangement of amino acids ranging from about 100 to about 300,000 Daltons.
  • the binder can be introduced into the mixture to be granulated in a solid form, including but not limited to a crystal, a particle, a powder, or any other finely divided solid form known in the art.
  • the binder can be dissolved or suspended in a solvent and sprayed onto the mixture in a granulation device as a binder fluid during granulation.
  • Non-limiting examples of diluents 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, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, saccharides such as sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, and sorbitol, polyhydric alcohols; starches; pre-manufactured direct compression diluents; and mixtures of any of the foregoing.
  • Disintegrants can be effervescent or non -effervescent.
  • non -effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth.
  • Suitable effervescent disintegrants include but are not limited to sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid. iv. Preservatives
  • Non-limiting examples of preservatives include, but are not limited to, ascorbic acid and its salts, ascorbic palmitate, ascorbic stearate, anoxomer, N- acetylcysteine, benzyl isothiocyanate, m-aminobenzoicacid, o-aminobenzoicacid, p- aminobenzoic acid (PABA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, canthaxantin, alpha-carotene, beta-carotene, beta-caraotene, beta-apo-carotenoic acid, carnosol, carvacrol, catechins, cetyl gallate, chlorogenic acid, citric acid and its salts, clove extract, coffee bean extract, p-coumaric acid, 3,4-dihydroxybenzoic acid, N,N’-diphenyl-p-phenylenediamine
  • Suitable flavor-modifying agents include flavorants, taste-masking agents, sweeteners, and the like.
  • Flavorants include, but are not limited to, synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof.
  • Other non-limiting examples of flavors include cinnamon oils, oil of Wintergreen, peppermint oils, clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oils such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.
  • Taste-masking agents include but are not limited to cellulose hydroxypropyl ethers (HPC) such as Klucel®, Nisswo HPC and PrimaFlo HP22; low-substituted hydroxypropyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843; methylcellulose polymers such as Methocel® and Metolose®; Ethylcelluloses (EC) and mixtures thereof such as E461 , Ethocel®, Aqualon®-EC, Surelease; Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such as Natrosol®; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aualon®-CMC; polyvinyl alcohol and poly
  • 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 the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); ch loro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, sylitol, hydrogenated starch hydrolysates and the synthetic sweetener 3, 6-dihydro-6-methyl-1 ,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof.
  • Lubricants and glidants include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin
  • the lubricant compositions may be utilized to lubricate ingredients that form a pharmaceutical composition.
  • the lubricant facilitates removal of solid dosage forms during the manufacturing process.
  • Non-limiting examples of lubricants and glidants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil.
  • the pharmaceutical composition will generally comprise from about 0.01 % to about 10% by weight of a lubricant.
  • the pharmaceutical composition will comprise from about 0.1 % to about 5% by weight of a lubricant. In a further aspect, the pharmaceutical composition will comprise from about 0.5% to about 2% by weight of a lubricant. vii. Dispersants
  • Dispersants may include but are not limited to starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high hydrophilic-lipophilic balance (HLB) emulsifier surfactants. v/77. Colorants
  • Suitable color additives include butare not limited to food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors or dyes, along with their corresponding lakes, and certain natural and derived colorants, may be suitable for use in various aspects of the disclosure. ix. pH modifiers
  • Non-limiting examples of pH modifiers include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate and sodium bicarbonate.
  • Chelating agents include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate and sodium bicarbonate.
  • a chelating agent may be included as an excipient to immobilize oxidative groups, including but not limited to metal ions, to inhibit the oxidative degradation of the morphinan by these oxidative groups.
  • oxidative groups including but not limited to metal ions
  • Non-limiting examples of chelating agents include lysine, methionine, glycine, gluconate, polysaccharides, glutamate, aspartate, and disodium ethylenediaminetetraacetate (Na2EDTA).
  • Na2EDTA disodium ethylenediaminetetraacetate
  • An antimicrobial agent may be included as an excipient to minimize the degradation of the compound according to this disclosure by microbial agents, including but not limited to bacteria and fungi.
  • microbial agents including but not limited to bacteria and fungi.
  • Non-limiting examples of antimicrobials include parabens, chlorobutanol, phenol, calcium propionate, sodium nitrate, sodium nitrite, Na2EDTA, and sulfites including but not limited to sulfur dioxide, sodium bisulfite, and potassium hydrogen sulfite.
  • Release-controlling polymers may be included in the various aspects of the solid dosage pharmaceutical compositions incorporating compounds according to this disclosure.
  • the release-controlling polymers may be used as a tablet coating.
  • a releasecontrolling polymer may be mixed with the granules and other excipients prior to the formation of a tablet by a known process including but not limited to compression in a tablet mold.
  • Suitable release-controlling polymers include but are not limited to hydrophilic polymers and hydrophobic polymers.
  • Suitable hydrophilic release-controlling polymers include, but are not limited to, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, nitrocellulose, crosslinked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pu Hu Ian , sorbitol, xylitol, polysaccharides, ammonia alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, alginate sodium carmellose, calcium carmellose, carrageenan, fucoidan, furcellaran, arabic gum, carrageens gum, ghafti gum, guar gum, karaya gum, locust bean gum, okra gum, tragacanth gum,
  • a solid dosage comprising a compound according to this disclosure may comprise a coating, wherein such a coating may control release of the compound, function as a moisture barrier, or buffer or modify pH.
  • a “control releasing coat” or “controlled release coat” as used herein is defined to mean a functional coat which can for example comprise at least one pH independent polymer, pH dependent polymer (for example enteric or reverse enteric type polymers), soluble polymer, insoluble polymer, lipids, lipidic materials, or combinations thereof.
  • the coating when applied onto a dosage form, may slow (for example when applied to a normal release matrix dosage form), further slow (for example when applied to a controlled release matrix dosage form) or modify the rate of release of a compound according to this disclosure when applied to an uncoated dosage form.
  • the control releasing coat can be designed such that when the control releasing coat is applied to a dosage form, the dosage form in conjunction with the control releasing coat can exhibit the release of the compound according to this disclosure, such as a “modified-release”, “control led-release”, “sustained-release”, “extended-release”, “delayed-release”, “prolonged-release,” or combinations thereof.
  • the “control releasing coat” may optionally comprise additional materials that may alter the functionality of the control releasing coat.
  • moisture barrier is one which impedes or retards the absorption of moisture.
  • Compounds according to this disclosure may be hygroscopic and, as such, may be susceptible to decomposition overtime under highly humid conditions.
  • the proportion of the components of the moisture barrier and the amount of the moisture barrier optionally applied onto the control-releasing coating or onto the core are typically such that the moisture barrier does not fall within the USP definition and requirement for an enteric coat.
  • the moisture barrier may comprise an enteric and/or acrylic polymer, suitably an acrylic polymer, optionally a plasticizer, and a permeation enhancer.
  • the permeation enhancer is a hydrophilicsubstance, which allows water to enter without physical disruption of the coating.
  • the moisture barrier may additionally comprise other conventional inert excipients, which may improve processing of an extended-release formulation.
  • Coating and matrix materials which may be used in accordance with the invention are those known in the art for use in control led-release formulations, such as synthetic polymers of the polyvinyl type, e.g., polyvinylchloride, polyvinylacetate and copolymers thereof, polyvinylalcohol, and polyvinylpyrrolidone; synthetic polymers of the polyethylene type, e.g., polyethylene and polystyrene; acrylic acid polymers; biopolymers or modified biopolymers, such as cellulosic 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), for example aluminum monostearate, cetylalcohol, hydrogenated beef tallow, hydrogenated castor oil, 12- hydroxystearl alcohol, gly
  • the pH-buffering properties of a coating may be strengthened by introducing into the coating substances chosen from a group of compounds usually used in antacid formulations, for example magnesium oxide, hydroxide or carbonate, aluminum or calcium hydroxide, carbonate or silicate; composite aluminum/magnesium compounds, for example Al2O3-6MgO CO2-12H2O, (Mg6Al2(OH)i6CO3'4H2O), MgO Al2O3-2SiO2.nH2O, aluminum bicarbonate coprecipitate or similar compounds; or other pharmaceutically acceptable pH- buffering compounds, for example the sodium, potassium, calcium, magnesium and aluminum salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic acids; or suitable organic bases, including basic amino acids; and salts or combinations thereof.
  • a group of compounds usually used in antacid formulations for example magnesium oxide, hydroxide or carbonate, aluminum or calcium hydroxide, carbonate or silicate
  • composite aluminum/magnesium compounds for example Al2O
  • a pH-dependent coating serves to release the drug in desired areas of the gastrointestinal (Gl) tract, e.g., the stomach or small intestine.
  • Gl gastrointestinal
  • the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the Gl tract.
  • the coating is often called an “enteric coating”.
  • a pH-dependent coating may include, but is not limited to, acrylic acid polymers and copolymers, for example polymers formed from acrylic acid, methacrylic acid, methyl acrylate, amino methylacrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate (e.g., EudragitTM); cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate (CAP), cellulose acetate trimel litate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate and carboxymethylcellulose sodium; shellac (purified lac); vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate (PVAP), vinylacetate croton ic
  • One aspect of the present disclosure encompasses a dosage form (also called “unit dose”) of a Sigma-1 receptor agonist, or a dual modulator of Sigma-1 receptor and muscarinic receptor. It refers to the end-product encompassing the pharmaceutical composition and being packaged in a form suitable to be marketed and used. Depending on the method/route of administration, dosage form may be in the form of a liquid, a solid, or a semisolid.
  • dosage forms suitable for delivery of the therapeutic agent such as in the forms of pills, tablets, capsules, drinks, injections, among many others.
  • the present disclosure provides dosage forms suitable for delivery of the therapeutic agent to the designated patient groups, such as elder patients, pediatric patients, or in the forms suitable to be administered by the health care providers, and/or caregivers.
  • the dosage form may comprise from about 1 mg to about 50 g, from about 1 mg to about 500 mg, from about 1 mg to about 100 mg, from about 1 mg to about 500 mg, from about 50 to about 400 mg, from about 75 to about 150 mg, from about 150 to about 200 mg, from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, or from about 180 mg to about 220 mg of A2-73.
  • the dosage form can comprise 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.
  • dosage forms can comprise from about 1 mg to about 500 mg, or about 1 mg to about 100 mg of A2-73.
  • Dosage forms include those formulated for extended or slow release, and those formulated for immediate release.
  • an immediate release dosage form may include a crystalline form of A2-73 Freebase, A2-73, a A2-73 Freebase salt as disclosed herein.
  • a fast-dissolve oral dosage form may include for example A2-73 crystal Form I.
  • a dosage form may comprise a crystalline Form I of A2-73 Freebase, or crystalline Form I of A2-73 Freebase fumarate salt formulated for inhalation drug delivery, either as a dry powder or aerosol spray.
  • Dosage forms also include those formulated for topical administration.
  • a dosage form can be formulated as one or more of a gel, ointment, emulsion, microemulsion, solution, suspension, paste, gel, foam, spray, lotion, or cream.
  • a topical administration dosage form is a transdermal patch.
  • the transdermal patch can contain from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, or from about 180 mg to about 220 mg of A2-73 Freebase in crystalline form.
  • Dosage forms can alternatively be formulated for oral administration.
  • Dosage forms formulated for oral administration can be tablets to swallow, chew, or dissolve in water or under the tongue, capsules and chewable capsules, powders, granules, teas, drops, or liquid medications or syrups.
  • the dosage form is an enteric coated oral formulation.
  • the dosage form is an enteric coated oral formulation
  • the formulation can comprise from about 0.1 mg to about 60 mg A2-73 Freebase, preferably from about 1 mg to about 50 mg A2-73 Freebase.
  • An enteric coated oral formulation can also contain A2-73 Freebase salt in crystalline forms.
  • the A2-73 Freebase salt can be a fumarate salt, a sulfate salt, a mesylate salt, a dihydrogen phosphate salt, an edisylate salt, a benzoate salt, a hydrochloride salt, and an oxalate salt.
  • the A2-73 salt is a fumarate salt.
  • the enteric coated oral formulation can comprise from about 0.1 to about 100 mg of A2 -73 fumarate salt, preferably from about 1 mg to about 55 mg of A2-73 fumarate salt.
  • an intramuscular dosage form may comprise A2-73 in the free base form, dissolved in an oil matrix for intramuscular injection, or alternatively prepared as a suspension of the free base for intramuscular injection.
  • a dosage form formulated for subcutaneous or intramuscular injection may comprise A2-73 in a salt or free base form as disclosed herein, prepared as microspheres using methods known in the art.
  • A2-73 in free base or salt form may be coated, for example using Atomic Layer Deposition (ALD) techniques, with a thin layer coating such as a coating of zinc oxide and used in a formulation for subcutaneous or intramuscular injection.
  • A2-73 free base may be dissolved in a biodegradable polymer matrix, and then implanted subcutaneously (or used in a transdermal patch as detailed further below).
  • kits to practice the methods disclosed herein may comprise one or more therapeutic agents, pharmaceutically acceptable carriers, solvents, buffers, and the like.
  • the kits may also include instructions for practicing the methods. Instructions included in the kits may be affixed to packaging material or may be included as a package insert. While the instructions are typically written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this disclosure. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. As used herein, the term “instructions” may include the address of an internet site that provides the instructions.
  • the term “comprising” means “including, but not necessarily limited to”; it specifically indicates open-ended inclusion or membership in a so-described combination, group, series and the like.
  • the terms “comprising” and “including” as used herein are inclusive and/or open-ended and do not exclude additional, unrecited elements or method processes.
  • the term “consisting essentially of” is more limiting than “comprising” but not as restrictive as “consisting of.” Specifically, the term “consisting essentially of” limits membership to the specified materials or steps and those that do not materially affect the essential characteristics of the claimed invention.
  • the term “substantially” means to a great or significant extent, but not completely.
  • the term “about” or “approximately” as applied to one or more values of interest refers to a value that is similar to a stated reference value, or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as the limitations of the measurement system.
  • the term “about” refers to any values, including both integers and fractional components that are within a variation of up to ⁇ 10% of the value modified by the term “about.”
  • “about” can mean within 3 or more standard deviations, per the practice in the art.
  • the term “about” can mean within an order of magnitude, in some embodiments within 5-fold, and in some embodiments within 2-fold, of a value.
  • the symbol means “about” or “approximately.”
  • ranges disclosed herein include both end points as discrete values as well as 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 end points are modified by the term “about,” the range specified is expanded by a variation of up to ⁇ 10% of any value within the range or within 3 or more standard deviations, including the end points.
  • active ingredient or “active pharmaceutical ingredient” refer to a pharmaceutical agent, active ingredient, compound, or substance, compositions, or mixtures thereof, that provide a pharmacological, often beneficial, effect.
  • control As used herein, the terms “control,” or “reference” are used herein interchangeably.
  • a “reference” or “control” level may be a predetermined value or range, which is employed as a baseline or benchmark against which to assess a measured result.
  • Control also refers to control experiments or control cells.
  • dose denotes any form of an active ingredient formulation or composition, including cells, that contains an amount sufficient to initiate or produce a therapeutic effect with at least one or more administrations.
  • formulation and “composition” are used interchangeably herein.
  • prophylaxis refers to preventing or reducing the progression of a disorder, either to a statistically significant degree or to a degree detectable by a person of ordinary skill in the art.
  • the term “gene” means a segment of DNA that contains all the information for the regulated biosynthesis of an RNA product, including promoters, exons, introns, and other untranslated regions that control expression.
  • disorder means a segment of DNA that contains all the information for the regulated biosynthesis of an RNA product, including promoters, exons, introns, and other untranslated regions that control expression.
  • disorder means a segment of DNA that contains all the information for the regulated biosynthesis of an RNA product, including promoters, exons, introns, and other untranslated regions that control expression.
  • the terms “disorder”, “disease”, “condition”, and “dysfunction” are used interchangeably and encompass but are not limited to abnormal state that adversely affects the structure or function of all or part of an organism.
  • a disease may be caused by external factors such as pathogens or by internal dysfunctions.
  • internal dysfunctions of the immune system may produce a variety of different diseases, including various forms of immunodeficiency, hyper
  • disease In humans, disease is often referred to any injuries, disabilities, disorders, syndromes, infections, deviant behaviors, or atypical variations of structure and function condition that causes pain, dysfunction, distress, social problems, or death to the person affected. Diseases can affect people not only physically but also mentally, as contracting and living with a disease can alter the affected person's perspective on life. A disease often manifests or is associated with specific signs and symptoms. Intervention or treatment is often desired to eliminate, reduce, and/or reverse the course of a disease, and/or to relieve or ameliorate physical and/or psychological symptoms therein.
  • polymorph As used herein, the terms “polymorph”, “polymorphic form”, “crystal”, and “crystalline” are used interchangeably and refer to an ordered solid form, wherein atoms, ions, and/or molecules are arranged and patterned in specific ways, which give rise to a specific and unique three-dimensional format.
  • One molecule may exist in multiple crystalline forms, which may possess different physiochemical or biological properties.
  • Different polymorphic forms of the same active pharmaceutical ingredient (API) can lead to changes in API’s solubility, dissolution rate, pharmacokinetics and ultimately its bioavailability and efficacy in therapeutic uses.
  • API active pharmaceutical ingredient
  • co-crystal and “cocrystal” are used interchangeably and refer to solids that are crystalline, single-phase materials composed of two or more different molecular or ionic compounds generally in a specific stoichiometric ratio.
  • a co-crystal consists of two or more components that form a unique crystalline structure and has unique properties.
  • a cocrystal may comprise an organic compound with an acid orwith an ionic salt. Widely encountered cocrystals include hydrates, solvates and clathrates. Co-crystals are often stable and possess their own physiochemical and/or biological properties different from the individual components made up the co-crystals.
  • enantiomer As used herein, the terms “enantiomer”, “optical isomer”, or “optical antipode” are used interchangeably and refer to one of the two stereoisomers that are non-superposable onto their own mirror image, due to the chirality of the carbon atom. No amount of re-orientation of a molecule as a whole or conformational change converts one chemical into its enantiomer. Chemical structures with chirality rotate plane-polarized light. Therefore, an enantiomer can be expressed as (-) or (+) form, indicating the direction of the optical rotation.
  • the R/S system is based on the geometry of the molecule; the (+)- and (-)- system is based on its optical rotation properties; and the D/L system is based on the molecule's relationship to enantiomers of glyceraldehyde.
  • dextrorotatory it rotates the plane of polarized light clockwise and can also be denoted as (+).
  • levorotatory rotates the plane of polarized light counterclockwise and can also be denoted as (-).
  • a mixture of equal amounts of each enantiomer does not rotate light.
  • the two enantiomers of the same molecule may have different physiochemical or biological properties, imparting difference in solubility, dissolution rate, pharmacokinetics and ultimately bioavailability. Additionally, one enantiomer may have different crystal structures, i.e. polymorphs. And one enantiomer may form co-crystal with other compounds or molecules.
  • Stereoisomers include both enantiomers and diastereomers. Diastereomers, like enantiomers, share the same molecularformula and are also non -superposable onto each other; however, they are not mirror images of each other.
  • polypeptide means any polypeptide comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres.
  • Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins.
  • Polypeptides may contain amino acids other than the 20 gene-encoded amino acids.
  • Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well-known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.
  • the terms “inhibit,” “inhibition,” and “inhibiting” refer to reducing or suppressing a given biological process, condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the terms “treatment” and “treating” refer to prophylaxis of, preventing, suppressing, repressing, reversing, alleviating, ameliorating, or inhibiting the progress of biological process including a disorder or disease, or eliminating a disease.
  • a treatment may be either performed in an acute or chronic way.
  • the term “treatment” also refers to reducing the seventy of a disease or symptoms associated with such disease prior to affliction with the disease.
  • “Repressing” or “ameliorating” a disease, disorder, or the symptoms thereof involves administering a cell, composition, or compound described herein to a subject after clinical appearance of such disease, disorder, or its symptoms.
  • “Prophylaxis of” or “preventing” a disease, disorder, or the symptoms thereof involves administering a cell, composition, or compound described herein to a subject prior to onset of the disease, disorder, or the symptoms thereof.
  • “Suppressing” a disease or disorder involves administering a cell, composition, or compound described herein to a subject after induction of the disease or disorder thereof but before its clinical appearance or symptoms thereof have manifest.
  • treatment also refers to a clinical intervention made in response to a disease, disorder, or physiological condition manifested by a patient or to which a patient may be susceptible.
  • the aim of treatment includes the alleviation or prevention of symptoms, slowing or stopping the progression or worsening of a disease, disorder, or condition and/or the remission of the disease, disorder, or condition (e.g., a depressive disorder).
  • administering an agent, such as a therapeutic entity to treat a depressive disorder to an animal or cell, is intended to refer to dispensing, delivering, or applying the substance to the intended target.
  • administering is intended to refer to contacting or dispensing, delivering or applying the therapeutic agent to a subject by any suitable route for delivery of the therapeutic agent to the desired location in the animal, including delivery by either the parenteral or oral route, intramuscular injection, subcutaneous/intradermal injection, intravenous injection, intrathecal administration, buccal administration, transdermal delivery, topical administration, and administration by the intranasal or respiratory tract route.
  • administration includes self-administration and administration to a subject by another.
  • prevention refers to prophylaxis or reducing the probability of developing a disease, disorder or condition in a subject, who does not have, but is at risk of or is deemed susceptible to developing the disease, disorder or condition.
  • the term “subject” refers to an animal.
  • the subject is a mammal, and may be a primate (e.g., humans, male orfemale; infant, adolescent, or adult), non-human primates, rats, mice, rabbits, pigs, cows, sheep, goats, horses, dogs, cats, fish, birds, and the like.
  • the subject is a human.
  • a subject may be a laboratory animal (e.g., cynomolgus monkey, rats, mice, guinea pigs and the like).
  • a human subject expressly encompasses any age, size, gender, and race, including an infant, children, teen, adult, or senior (over 65 years of age).
  • Example 1 Study Design for Brain Atrophy Related to Alzheimer Patients [0118] ANAVEX®2-73 (used interchangeably with “A2-73” or“blarcamesine” herein) 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 Alzheimerdisease (mild cognitive impairment/mild dementia) from July 2018 to June 2021 (last patient visit for primary outcome in June 2022).
  • Percent change in volume in whole brain, whole brain grey matter, frontal lobe, insular cortex, limbic lobe, parietal lobe and temporal lobe regions was reduced significantly in treatment group compared with placebo group (p ⁇ 0.005), with hippocampus and whole brain white matter volume demonstrating a trend of reduction of atrophy without reaching statistical significance.
  • CDR-SB Clinical Dementia Rating Scale Sum of Boxes
  • ANAVEX®2-73 was generally safe and well tolerated. The incidence of treatment emergent adverse events (TEAEs) was similar in the active and placebo arms with dizziness being the most common TEAE. TEAEs over 7.5% threshold were predominantly mild or moderate. No clinically significant changes in vital signs, laboratory values and ECG parameters in active and placebo arms were observed. Safety findings in the study were consistent with the known safety profile of ANAVEX®2-73. In addition to safety and efficacy demonstrated on the primary and key secondary endpoints, a pre-specified analysis of patients without the SIGMAR1 gene mutation provides further confidence of the robustness of the SIGMAR1 activation in the treatment of neurodegenerative diseases. Approximately 80% of the total worldwide population lack a SIGMAR1 gene mutation. ANAVEX®2-73 was more efficacious in this pre-specified population. This effect was consistent with the observations from prior clinical trials of ANAVEX®2 -73.
  • a 68-year-old man is diagnosed with Parkinson disease with dementia.
  • MRI exam reveals cortical and subcortical atrophy.
  • He is treated with oral ANAVEX®2-73 at a dose of 30 mg once daily for 48 weeks, atrophy progression is slowed down in cortical and subcortical areas.
  • a 72-year-old man is diagnosed with dementia of idiopathic origin.
  • MRI exam reveals brain shrinkage in the frontal and temporal lobes.
  • He is treated with oral ANAVEX®2-73 at a dose of 35 mg once daily for 48 weeks, brain shrinkage is controlled and confined, no further shrinkage is observed.
  • ANAVEX®2-73 is effective in preventing the onset of brain atrophy.

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Abstract

La présente divulgation concerne des méthodes et des kits de traitement ou de prévention de l'atrophie cérébrale chez un sujet. Les procédés impliquent l'administration d'un agoniste du récepteur Sigma-1 et/ou d'un modulateur double du récepteur Sigma-1 et du récepteur muscarinique. L'atrophie cérébrale peut être associée ou associée à des troubles neurologiques.
PCT/US2024/045834 2023-09-08 2024-09-09 Traitement et prévention de l'atrophie cérébrale Pending WO2025054599A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140296211A1 (en) * 2013-03-28 2014-10-02 Anavex Life Sciences Corp. Anavex2-73 and certain anticholinesterase inhibitors composition and method for neuroprotection
WO2021158586A1 (fr) * 2020-02-04 2021-08-12 Teva Pharmaceuticals International Gmbh Formes à l'état solide de sels de blarcamésine
WO2023097029A1 (fr) * 2021-11-23 2023-06-01 Anavex Life Sciences Corp. Sélection thérapeutique et traitement de troubles neurodégénératifs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140296211A1 (en) * 2013-03-28 2014-10-02 Anavex Life Sciences Corp. Anavex2-73 and certain anticholinesterase inhibitors composition and method for neuroprotection
WO2021158586A1 (fr) * 2020-02-04 2021-08-12 Teva Pharmaceuticals International Gmbh Formes à l'état solide de sels de blarcamésine
WO2023097029A1 (fr) * 2021-11-23 2023-06-01 Anavex Life Sciences Corp. Sélection thérapeutique et traitement de troubles neurodégénératifs

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