Treating cognitive disorders using trapidil

Abstract

To provide a pharmaceutical agent for treating or preventing cognitive impairment associated with Lewy body dementia in a subject.SOLUTION: Provided is a pharmaceutical agent which is trapidil (N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine), deuterated trapidil, a pharmaceutically acceptable salt of trapidil, or a pharmaceutically acceptable salt of deuterated trapidil.SELECTED DRAWING: Figure 7

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 942,645, filed on December 2, 2019, the entire disclosure of which is incorporated herein by reference.

Summary of the Invention

[0002] In certain embodiments herein, methods, pharmaceutical combinations, dosage forms, and kits for the treatment of cognitive impairment or mental illness are disclosed. In some embodiments, the mental illness includes clinical depression, anxiety disorder, apathy, anhedonia, or psychosis. In some embodiments, the treatment includes the use of a therapeutically effective amount of trapidil, a derivative thereof, a metabolite, a prodrug, an analog, or a pharmaceutically acceptable salt. In some embodiments, a combination of administrations for the treatment of the cognitive impairment or mental illness described herein is provided, the combination of administrations including trapidil, as well as a dopamine agonist or a dopamine precursor (e.g., levodopa).

[0003] In some embodiments herein, provided is a method for treating or preventing a cognitive impairment or mental illness of a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts. In some embodiments, the aforementioned subject is diagnosed with Parkinson's disease. In some embodiments, the aforementioned cognitive impairment or mental illness is not caused by Parkinson's disease. In some embodiments, the aforementioned cognitive impairment or mental illness is at least partially caused by Parkinson's disease. In some embodiments, the aforementioned cognitive impairment or mental illness is not caused by schizophrenia. In some embodiments, the aforementioned cognitive impairment or mental illness is at least partially caused by schizophrenia. In some embodiments, the method described herein further comprises administering an additional therapeutic agent to the subject. In some embodiments, the aforementioned additional therapeutic agent is a Parkinson's disease therapy. In some embodiments, the aforementioned cognitive impairment is at least partially caused by a therapeutic agent. In some embodiments, administration of trapidil treats or prevents a cognitive impairment at least partially caused by an additional therapeutic agent. In some embodiments, the aforementioned additional therapeutic agent comprises (a) an antidepressant, (b) an antipsychotic, (c) an anxiolytic, (d) a dopamine precursor, (e) a dopamine agonist, or (f) any combination of (a) to (e). In some embodiments, the aforementioned additional therapeutic agent is a dopamine precursor. In some embodiments, the aforementioned dopamine precursor is levodopa. In some embodiments, the aforementioned additional therapeutic agent is a dopamine agonist. In some embodiments, the aforementioned dopamine agonist is rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, and / or apomorphine. In some embodiments, the aforementioned cognitive impairment is a neurodegenerative disorder.In some embodiments, the aforementioned cognitive impairment is related to an antagonist of N-methyl-D-aspartic acid receptor (NMDA-R). In some embodiments, the aforementioned cognitive impairment is caused by abnormal dopaminergic signaling caused by neurodegeneration. In some embodiments, the mental illness is anxiety, depression, apathy, anhedonia, psychosis, or a combination thereof. In some embodiments, the aforementioned cognitive impairment is a cognitive dysfunction. In some embodiments, the aforementioned cognitive dysfunction is mild cognitive impairment and / or dementia. In some embodiments, the aforementioned cognitive dysfunction is caused by schizophrenia or attention deficit / hyperactivity disorder. In some embodiments, the aforementioned dementia is Alzheimer's disease, senile dementia, Parkinson's disease dementia, Lewy body dementia, semantic dementia, subcortical dementia, aphasia, logopenic progressive aphasia, primary progressive aphasia, progressive non-fluent aphasia, pseudodementia, apraxia, agnosia, behavioral / personality changes, impaired judgment, amnesia, frontotemporal dementia, frontotemporal dementia Parkinsonism linked to chromosome 17, cognitive vulnerability, cognitive deviation, corticobasal degeneration, corticobasal syndrome, Lewy body disease, or drug / substance-induced cognitive decline. In some embodiments, the aforementioned cognitive dysfunction includes deficits in any of five cognitive domains, namely, attention, working memory, executive function, visuospatial function, and memory. In some embodiments, the aforementioned cognitive dysfunction is a deficit in executive function, difficulty in attention, slowed thinking, difficulty in word finding, difficulty in information learning or memory, or any combination thereof. In some embodiments, the aforementioned subject suffers from Parkinson's disease. In some embodiments, trapidil is N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine. In some embodiments, its derivatives include AR12455, AR12456, AR12460, AR12463, AR12464, AR12465, or AR12565.In some embodiments, the metabolite includes desethyl-trapidil, 5-piperidin-4'-oril-7-[N-pentyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, 5-piperidin-4'-oril-7-[N-pent-4-oril-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, a hydroxy derivative or a ketopentyl derivative, piperidinol or piperidinone, TP1, or TP2. In some embodiments, the pharmaceutically acceptable salt includes a salt having hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid. In some embodiments, rapidil, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt is administered orally. In some embodiments, rapidil, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt is administered intravenously or subcutaneously. In some embodiments, rapidil, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt and an additional therapeutic agent are administered simultaneously or sequentially. In some embodiments, rapidil, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt is administered before or after the administration of the additional therapeutic agent. In some embodiments, the aforementioned additional therapeutic agent is administered intravenously or subcutaneously. In some embodiments, the aforementioned additional therapeutic agent includes (a) an antidepressant, (b) an antipsychotic, (c) an antianxiety agent, (d) a dopamine precursor, (e) a dopamine agonist, or (f) any combination of (a) to (e). In some embodiments, the aforementioned additional therapeutic agent is a dopamine precursor. In some embodiments, the aforementioned dopamine precursor is levodopa. In some embodiments, the aforementioned additional therapeutic agent is a dopamine agonist. In some embodiments, the aforementioned dopamine agonist is rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, and / or apomorphine.In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered to a subject three times a day.

[0004] In this specification, in some embodiments, there is provided a pharmaceutical combination for use in a treatment method for treating a cognitive impairment or related mental disorder of a subject in need thereof, and the aforementioned pharmaceutical combination comprises a therapeutic combination of tropidyl, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts, and a further therapeutic agent. In some embodiments, the aforementioned subject is diagnosed with Parkinson's disease. In some embodiments, the aforementioned cognitive impairment or mental disorder is not caused by Parkinson's disease. In some embodiments, the aforementioned cognitive impairment or mental disorder is at least partially caused by Parkinson's disease. In some embodiments, the aforementioned cognitive impairment or mental disorder is not caused by schizophrenia. In some embodiments, the aforementioned cognitive impairment or mental disorder is at least partially caused by schizophrenia. In some embodiments, the aforementioned cognitive impairment is at least partially caused by a further therapeutic agent. In some embodiments, administration of tropidyl treats or prevents a cognitive impairment at least partially caused by a further therapeutic agent. In some embodiments, the aforementioned further therapeutic agent comprises (a) an antidepressant, (b) an antipsychotic, (c) an antianxiety agent, (d) a dopamine precursor, (e) a dopamine agonist, or (f) any combination of (a) to (e). In some embodiments, the aforementioned further therapeutic agent is a dopamine precursor. In some embodiments, the aforementioned dopamine precursor is levodopa. In some embodiments, the aforementioned further therapeutic agent is a dopamine agonist. In some embodiments, the aforementioned further therapeutic agent is a dopamine agonist. In some embodiments, the aforementioned dopamine agonist is rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, and / or apomorphine. In some embodiments, the aforementioned cognitive impairment is a neurodegenerative disorder.In some embodiments, the aforementioned cognitive impairment is related to an antagonist of N-methyl-D-aspartic acid receptor (NMDA-R). In some embodiments, the aforementioned cognitive impairment is caused by abnormal dopaminergic signaling caused by neurodegeneration. In some embodiments, the aforementioned mental illness includes anxiety, depression, apathy, anhedonia, or psychosis, or any combination thereof. In some embodiments, the aforementioned cognitive impairment includes cognitive dysfunction. In some embodiments, the aforementioned cognitive dysfunction includes mild cognitive impairment and / or dementia. In some embodiments, the aforementioned cognitive dysfunction is caused by schizophrenia or attention deficit / hyperactivity disorder. In some embodiments, the aforementioned dementia includes senile dementia, Parkinson's disease dementia, Lewy body dementia, semantic dementia, subcortical dementia, aphasia, logopenic progressive aphasia, primary progressive aphasia, progressive non-fluent aphasia, pseudodementia, apraxia, agnosia, behavioral / personality changes, decreased judgment, amnesia, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, cognitive vulnerability, cognitive deviation, corticobasal degeneration, corticobasal syndrome, Lewy body disease, or drug / substance-induced cognitive decline. In some embodiments, the aforementioned cognitive dysfunction includes a defect in any of the five cognitive domains, namely, attention, working memory, executive function, visuospatial function, and memory. In some embodiments, the aforementioned cognitive dysfunction is a defect in executive function, difficulty in attention, dulling of thinking, difficulty in word finding, difficulty in information learning or memory, or any combination thereof. In some embodiments, trapidil is N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine. In some embodiments, its derivatives include AR12455, AR12456, AR12460, AR12463, AR12464, AR12465, or AR12565.In some embodiments, the metabolite includes desethyl-trapidil, 5-piperidin-4'-oril-7-[N-pentyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, 5-piperidin-4'-oril-7-[N-pent-4-oril-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, a hydroxy derivative or a ketopentyl derivative, piperidinol or piperidinone, TP1, or TP2. In some embodiments, the pharmaceutically acceptable salts of rapidil include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid. In some embodiments, rapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered orally. In some embodiments, rapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered intravenously or subcutaneously. In some embodiments, rapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts and an additional therapeutic agent are administered simultaneously or sequentially. In some embodiments, rapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered before or after the administration of an additional therapeutic agent. In some embodiments, the aforementioned pharmaceutical combinations further include at least one pharmaceutically acceptable excipient, carrier, or diluent. In some embodiments, the aforementioned pharmaceutical combinations are fixed-dose combinations and further include at least one pharmaceutically acceptable excipient, carrier, or diluent. In some embodiments, rapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered to the subject three times a day.

[0005] In some embodiments herein, a combination for administration for use in the treatment of a cognitive impairment or mental illness of a subject in need thereof is provided, and the aforementioned combination for administration includes administering to the subject a therapeutically effective combination of tropidyl, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts, and a further therapeutic agent. In some embodiments, the aforementioned subject has been diagnosed with Parkinson's disease. In some embodiments, the aforementioned cognitive impairment or mental illness is not caused by Parkinson's disease. In some embodiments, the aforementioned cognitive impairment or mental illness is at least partially caused by Parkinson's disease. In some embodiments, the aforementioned cognitive impairment or mental illness is not caused by schizophrenia. In some embodiments, the aforementioned cognitive impairment or mental illness is at least partially caused by schizophrenia. In some embodiments, the aforementioned further therapeutic agent is a Parkinson's disease therapy. In some embodiments, the aforementioned cognitive impairment is at least partially caused by the further therapeutic agent. In some embodiments, administration of tropidyl treats or prevents a cognitive impairment at least partially caused by the further therapeutic agent. In some embodiments, the aforementioned further therapeutic agent includes (a) an antidepressant, (b) an antipsychotic, (c) an anxiolytic, (d) a dopamine precursor, (e) a dopamine agonist, or (f) any combination of (a) to (e). In some embodiments, the aforementioned further therapeutic agent is a dopamine precursor. In some embodiments, the aforementioned dopamine precursor is levodopa. In some embodiments, the aforementioned further therapeutic agent is a dopamine agonist. In some embodiments, the aforementioned dopamine agonist is rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, and / or apomorphine. In some embodiments, the aforementioned cognitive impairment is a neurodegenerative disorder.In some embodiments, the aforementioned cognitive impairment is related to an antagonist of N-methyl-D-aspartic acid receptor (NMDA-R). In some embodiments, the aforementioned cognitive impairment is abnormal dopaminergic signaling caused by neurodegeneration. In some embodiments, the aforementioned mental disorders include anxiety disorder, depression, apathy, anhedonia, or psychosis, or any combination thereof. In some embodiments, the aforementioned cognitive impairment includes cognitive dysfunction. In some embodiments, the aforementioned cognitive dysfunction includes mild cognitive impairment and / or dementia. In some embodiments, the aforementioned cognitive dysfunction is caused by schizophrenia or attention deficit / hyperactivity disorder (ADHD). In some embodiments, the aforementioned dementia includes Alzheimer's disease, senile dementia, Parkinson's disease dementia, Lewy body dementia, semantic dementia, subcortical dementia, aphasia, logopenic progressive aphasia, primary progressive aphasia, progressive non-fluent aphasia, pseudo-dementia, apraxia, agnosia, behavioral / personality changes, impaired judgment, amnesia, frontotemporal dementia, frontotemporal dementia Parkinsonism linked to chromosome 17, cognitive vulnerability, cognitive deviation, corticobasal degeneration, corticobasal syndrome, Lewy body disease, or drug / substance-induced cognitive decline. In some embodiments, the aforementioned cognitive dysfunction includes deficits in any of the five cognitive domains, namely attention, working memory, executive function, visuospatial function, and memory. In some embodiments, the aforementioned cognitive dysfunction is a deficit in executive function, difficulty in attention, dulling of thinking, difficulty in word finding, difficulty in information learning or memory, or any combination thereof. In some embodiments, trapidil is N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine. In some embodiments, its derivatives include AR12455, AR12456, AR12460, AR12463, AR12464, AR12465, or AR12565.In some embodiments, the metabolite includes desethyl-trapidil, 5-piperidin-4'-oril-7-[N-pentyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, 5-piperidin-4'-oril-7-[N-pent-4-oril-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, a hydroxy derivative or a ketopentyl derivative, piperidinol or piperidinone, TP1, or TP2. In some embodiments, the pharmaceutically acceptable salt thereof includes salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid. In some embodiments, rapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered orally. In some embodiments, rapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered intravenously or subcutaneously. In some embodiments, rapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts and an additional therapeutic agent are administered in separate dosage forms, or in an integrated dosage form. In some embodiments, rapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered before or after the administration of an additional therapeutic agent. In some embodiments, the aforementioned combination of administrations further includes at least one pharmaceutically acceptable excipient, carrier, or diluent. In some embodiments, the aforementioned combination of administrations is a fixed combination of administrations and further includes at least one pharmaceutically acceptable excipient, carrier, or diluent. In some embodiments, the aforementioned combination of administrations is administered to the subject three times a day.

[0006] Incorporation by reference All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The novel features of aspects of the present invention are particularly set forth in the appended claims. To better understand the features and advantages of the present invention, reference should be made to the following detailed description of exemplary embodiments in which the principles of the present invention are utilized and the accompanying drawings.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9A

Figure 9B

Mode for Carrying Out the Invention

[0008] Often, cognitive impairment (e.g., cognitive dysfunction, cognitive deficit, cognitive disease) affects a subject's ability to make decisions, learn new things, concentrate, or remember. Cognitive impairment ranges from mild to severe enough to affect daily activities and may result in the loss of the ability to function independently. The cognitive impairment described herein is exacerbated by existing diseases, including neurological disorders such as Parkinson's disease and schizophrenia. In many individuals with cognitive impairment, mental illnesses such as anxiety, clinical depression, apathy, and anhedonia may also develop. The combination of cognitive impairment and mental illness can introduce confounding factors into the patient's outcome.

[0009] Cognitive impairment and mental illness affect millions of people in the United States. It is estimated that 16 million Americans are living with cognitive impairment, and most of these patients are 65 years of age or older. The number of individuals living with this cognitive impairment is expected to increase with the growing aging population. This impending increase will place a significant burden on the healthcare system. Nearly 80% of patients with existing diseases such as Parkinson's disease develop some form of cognitive impairment. Approximately 1 in 5 adults in the United States are living with a mental illness (51.5 million Americans in 2019).

[0010] Cognitive impairment can also be drug-induced. For example, many Parkinson's disease patients given high levels of levodopa (the gold standard of care for treating the motor symptoms of Parkinson's disease) may have an increased risk of developing cognitive impairment. Administration of levodopa creates continuous dopaminergic stimulation of the striatal dopamine receptors. Initially, the cognitive impairment in Parkinson's disease patients responds well to dopaminergic stimulation by levodopa (e.g., is alleviated or prevented). However, over-activation of the dopamine receptors caused by increasing the dose of levodopa may cause the cognitive impairment in Parkinson's disease patients to worsen over time. In addition, excessive dopaminergic stimulation may have side effects along a "U-shaped" curve, with too little or too much dopamine causing cognitive impairment in Parkinson's disease patients. To address the loss of response to levodopa in Parkinson's disease patients, the dose is increased over the patient's lifetime, which may, in some cases, span many years. In early-onset Parkinson's disease patients, the development of cognitive impairment or mental illness resulting from the treatment plan may sometimes be unavoidable.

[0011] Therefore, there is a need for effective treatment strategies for treating cognitive impairment and / or mental illness. This need is particularly acute for patients suffering from diseases in which cognitive deficits are part of the symptoms, or existing diseases that increase the likelihood of developing cognitive impairment or mental illness (e.g., schizophrenia, Parkinson's disease), and which, in the first place, are worsened (or in some cases caused) by the gold standard of care.

[0012] Trapimil is a vasodilator and antiplatelet drug used for the treatment of ischemic coronary heart, liver, and kidney diseases. Trapimil is a reported enhancer of protein kinase A regulatory subunits 2 (PRKAR2A and PRKAR2B). The reported mechanism of action of Trapimil is not shared with known therapeutic agents used to treat cognitive impairments or mental illnesses such as cognitive enhancers (acetylcholinesterase inhibitors), antipsychotics, antidepressants, and anxiolytics.

[0013] Surprisingly, the inventors of the present disclosure have determined by single-cell deconvolution computational analysis that in a Parkinson's disease animal model, Trapimil is not a known dopamine 1 receptor agonist, but modulates neurons expressing the dopamine 1 receptor. As shown in Example 1, Trapimil induces a large change in gene expression in neurons expressing the dopamine 1 receptor rather than the dopamine 2 receptor. Such selective changes in gene expression are similar to dopamine 1 agonists. In some embodiments, activating and / or modulating neurons expressing the dopamine 1 receptor by administering a therapeutically effective dose of Trapimil to a subject. In some embodiments, preventing abnormal dopamine signaling by activating and / or modulating neurons expressing the dopamine 1 receptor (e.g., induced by administering a therapeutically effective amount of Trapimil). In some embodiments, treating or preventing cognitive impairment and / or mental illness in a subject, such as a subject suffering from Parkinson's disease, by activating and / or modulating neurons expressing the dopamine 1 receptor (e.g., induced by administering a therapeutically effective amount of Trapimil). In some embodiments, the cognitive impairment is at least partially caused by levodopa administered to treat the subject's Parkinson's disease, or another dopamine precursor or dopamine agonist.

[0014] The inventors of the present disclosure have discovered that cognitive function can be enhanced in non-human primate studies by administering tropidyl alone or in combination with levodopa. Additionally, it has been observed that animals administered tropidyl show improvements in total reaction time and reaction accuracy. This decrease in reaction time suggests an improvement in motivation and / or processing speed. Without being bound by any particular theory, it is believed that the observed improvement in motivation may correct anhedonic mental disorders. Anhedonia is one of many mental disorders that are highly correlated with cognitive impairment, such as those common among Parkinson's disease patients, and can function as a predictor of potential cognitive decline in these patients.

[0015] The inventors also show herein that the cognitive deficits observed in a mouse model of schizophrenia are improved by the administration of tropidyl. Mice administered tropidyl showed improved percentages in the spontaneous alternation behavior test in a Y-maze, suggesting an improvement in working memory.

[0016] In some embodiments herein, a method of treating or preventing cognitive impairment or mental illness using tropidyl, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts is disclosed. In some embodiments, the aforementioned subject suffers from Parkinson's disease. In some embodiments, the aforementioned cognitive impairment or mental disorder is not caused by or related to Parkinson's disease. In some embodiments, the aforementioned subject suffers from schizophrenia. Also disclosed herein is a pharmaceutical combination or combination of administrations comprising tropidyl, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts and a further therapeutic agent. In some embodiments, the aforementioned further therapeutic agent comprises (a) an antidepressant, (b) an antipsychotic, (c) an antianxiety agent, (d) a dopamine precursor, (e) a dopamine agonist, or (f) any combination of (a) to (e). In some embodiments, the aforementioned further therapeutic agent is a dopamine precursor (e.g., levodopa). In some embodiments, the aforementioned further therapeutic agent is a combination therapy of a dopamine precursor (e.g., levodopa) and adjuvant therapy (e.g., carbidopa). In some embodiments, the aforementioned further therapeutic agent is a dopamine agonist (e.g., rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, or apomorphine). In some embodiments, the aforementioned pharmaceutical combination is therapeutically effective for treating or preventing the subject's cognitive impairment or mental illness. In some embodiments, the aforementioned pharmaceutical combination further comprises at least one pharmaceutically acceptable excipient, carrier, or diluent. In some embodiments, the aforementioned pharmaceutical combination is a fixed combination for administration.

[0017] I. Treatment Method In some embodiments herein, a method for treating or preventing cognitive impairment or mental illness using a therapeutic agent described herein, or a combination of therapeutic agents, is disclosed. In some embodiments, the aforementioned therapeutic agent is tropidyl, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt. In some embodiments, the aforementioned subject suffers from Parkinson's disease or schizophrenia. In some embodiments, the aforementioned subject suffers from drug-induced cognitive impairment such as cognitive dysfunction. In some embodiments, the drug that causes cognitive impairment is a dopamine precursor (e.g., levodopa) or a dopamine agonist. In some embodiments, the aforementioned subject suffers from schizophrenia. In some embodiments, the aforementioned method further comprises administering an additional therapeutic agent. In some embodiments, the aforementioned additional therapeutic agent is a dopamine precursor (e.g., levodopa). In some embodiments, the aforementioned additional therapeutic agent is a combination therapy of a dopamine precursor (e.g., levodopa) and adjuvant therapy (e.g., carbidopa). In some embodiments, the aforementioned additional therapeutic agent is a dopamine agonist (e.g., rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, or apomorphine). In some embodiments, the aforementioned pharmaceutical combination is therapeutically effective for treating or preventing the subject's cognitive impairment or mental illness. In some embodiments, the aforementioned subject is a human. In some embodiments, tropidyl, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt, and an additional therapeutic agent (e.g., levodopa) are administered together (e.g., in a combined dosage form) or individually. In some embodiments, a dose of tropidyl up to 200 milligrams is administered to the subject.

[0018] A. Diseases and Disorders 1. Cognitive Impairment Cognitive impairment includes categories of mental health disorders that primarily affect cognitive abilities such as learning, memory, perception, or problem-solving. In some embodiments, cognitive impairment includes, for example, mild cognitive impairment (e.g., the stage between the expected decline in cognitive function due to normal aging and dementia) and / or cognitive dysfunction such as dementia. Non-limiting examples of dementia include Alzheimer's disease, Parkinson's disease dementia, senile dementia, and Lewy body dementia. In some embodiments, cognitive dysfunction (e.g., mild cognitive impairment) includes deficits in any of the following five cognitive domains: attention, working memory, executive function, visuospatial function, and memory. In some embodiments, deficits in attention affect the ability of the subject to concentrate and focus. In some embodiments, deficits in executive function affect the subject's ability to multitask and solve problems. In some embodiments, deficits in visuospatial ability affect the subject's ability to perceive information three-dimensionally, such as being unable to judge distances or form a mental map of a certain route. In some embodiments, cognitive dysfunction (e.g., mild cognitive impairment) is a deficit in executive function, difficulty in attention, dullness of thinking, difficulty in finding words, and / or difficulty in information learning or memory.

[0019] In some embodiments, the cognitive impairment is associated with or caused by a therapeutic agent for treating a disease or disorder other than a cognitive impairment or mental illness (e.g., Parkinson's disease). In some embodiments, the therapeutic agent that causes or is associated with a cognitive impairment or mental illness is a dopamine precursor or dopamine agonist. In some embodiments, the therapeutic agent that causes or is associated with a cognitive impairment or mental illness is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, bromocriptine, lisuride, apomorphine, levodopa, entacapone, tolcapone, selegiline, and / or rasagiline. In some embodiments, the drug that causes or is associated with a cognitive impairment or mental illness is an N-methyl-D-aspartic acid receptor antagonist.

[0020] In some embodiments, the cognitive impairment includes Parkinson's disease dementia, semantic dementia, subcortical dementia, postoperative cognitive dysfunction, memory loss, aphasia, logopenic progressive aphasia, primary progressive aphasia, progressive non-fluent aphasia, pseudodementia, apraxia, agnosia, behavioral / personality changes, decreased judgment, amnesia, frontotemporal dementia, frontotemporal dementia with Parkinsonism linked to chromosome 17, cognitive vulnerability, cognitive deviation, corticobasal degeneration, corticobasal syndrome, Lewy body disease, or drug / substance-induced cognitive decline. In some embodiments, the cognitive dysfunction is due to schizophrenia or attention deficit / hyperactivity disorder. In some embodiments, the aforementioned cognitive impairment is not caused by Parkinson's disease.

[0021] 2. Mental illness The mental disorders described in this specification include mental disorders that affect the emotions or mental state of a subject (e.g., the way a person thinks, feels, or behaves). In some embodiments, the mental disorders described in this specification include anxiety disorders, depression, apathy, anhedonia, or psychosis, or any combination thereof. In some embodiments, the foregoing mental disorders include mental disorders such as schizophrenia or bipolar disorder. In some embodiments, the foregoing mental disorders are clinically diagnosed. In some embodiments, the foregoing mental disorders are not caused by Parkinson's disease.

[0022] B. Subject The subjects disclosed in this specification are mammals such as, for example, humans, mice, rats, guinea pigs, rabbits, non-human primates, or domestic animals. In some embodiments, the foregoing subject is a human. In some embodiments, the foregoing subject is a patient diagnosed with a disease or disorder disclosed in this specification. In some embodiments, the foregoing subject is not diagnosed with a disease or disorder. In some embodiments, the disease or disorder is a cognitive impairment or mental disorder described in this specification.

[0023] In some embodiments, the foregoing subject has Parkinson's disease. In some embodiments, the foregoing subject does not have Parkinson's disease. In some embodiments, the foregoing subject is diagnosed with Parkinson's disease. The four main motor symptoms of Parkinson's disease are tremors, stiffness, bradykinesia (slow movement), and postural instability (balance problems). Observing two or more of these symptoms in a subject is an appropriate method for diagnosing Parkinson's disease. Appropriate methods also include performing a particular single-photon emission computed tomography (SPECT) scan (e.g., a dopamine transporter scan (DaTscan)).

[0024] In some embodiments, the aforementioned subject suffers from schizophrenia. In some embodiments, the aforementioned subject does not suffer from schizophrenia. In some embodiments, the aforementioned subject has been diagnosed with schizophrenia. A subject may be diagnosed with schizophrenia if they exhibit at least two of delusions, hallucinations, disorganized speech and behavior, catatonic stupor, or abnormal behavior / hyperactive behavior over the course of one month.

[0025] C. Therapeutic Agent 1. Tropidyl Compound In some embodiments herein, therapeutic agents are disclosed that include tropidyl, which are useful for treating the cognitive impairments or disorders of the subjects disclosed herein, or diseases or disorders described herein such as mental illnesses. In some embodiments, the aforementioned subject suffers from Parkinson's disease. In some embodiments, the aforementioned therapeutic agent includes additional therapeutic agents such as dopamine precursors (e.g., levodopa). Also, in some embodiments, a pharmaceutical composition is provided that includes tropidyl and, optionally, an additional therapeutic agent (e.g., levodopa).

[0026] Tropidyl, triazolopyrimidine, belongs to the class of antianginal and vasodilator drugs. As demonstrated in Example 1, tropidyl has been shown to modulate gene expression in neurons expressing dopamine 1 receptors.

[0027] Tropidyl has the IUPAC name N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine and has the following chemical structure.

[0028]

Chemical Structure

[0029] In some embodiments, trapidil is also known by the names AR12008, Avantrin, Trapymin, Trapymine, Rapidilum, Angichromen, Estelinol, Karnachol, Perucarate, Rocornal, trapidil Towa Pharmaceutical, and Travisco. In further instances, trapidil is referred to herein as SB-0107.

[0030] In some embodiments, trapidil derivatives include, but are not limited to, AR12455, AR12456, AR12460, AR12463, AR12464, AR12465, or AR12565.

[0031] In some embodiments, trapidil derivatives include, but are not limited to, AR12455

[0032]

Chemical Structure

[0033] , AR12456

[0034]

Chemical Structure

[0035] , AR12460

[0036]

Chemical Structure

[0037] , AR12463

[0038]

Chemical Structure

[0039] , AR12464

[0040] [Chemistry]

[0041] , AR12465

[0042] [Chemistry]

[0043] , AR12565

[0044] [Chemistry]

[0045] , or 5 - piperidino - 7 - (N-(n - amyl)-N-(β - hydroxyethyl)-amino)-s - triazolo(1,5 - a)pyrimidine)

[0046] [Chemistry] contains.

[0047] In some embodiments, AR12455 is 5-n-butylamino-7-[N-(n-hexyl)-N-(β-hydroxyethyl)-amino]-s-triazolo-[1,5-a]pyrimidine. In some embodiments, AR12456 is 5-diethylamino-7-[N-(n-hexyl)-N-(β-hydroxyethyl)amino]-s-triazolo-[1,5-a]pyrimidine. In some embodiments, AR12460 is 2-((5-(diethylamino)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)(hexyl)amino)ethane-1-ol. In some embodiments, AR12463 is 5-morpholino-7-[N-amyl-N-(β-hydroxyethyl)aminol-s-triazolo-[1,5-a]pyrimidine. In some embodiments, AR12464 is 5-morpholino7-[N-(n-butyl)-N-(β-hydroxyethyl)amino]-s-triazolo-[1,5-a]pyrimidine. In some embodiments, AR12465 is 5-piperidino-7-[N-hexyl-N-(β-hydroxyethyl)amino]-s-triazolo-[1,5-a]pyrimidine. In some embodiments, AR12565 is 2-((5-(diethylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl)(phenethyl)amino)ethane-1-ol.

[0048] In some embodiments, the trapidil metabolites include, but are not limited to, desethyl-trapidil, 5-piperidin-4'-olyl-7-[N-pentyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, 5-piperidin-4'-olyl-7-[N-pent-4'-olyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, hydroxy derivatives or ketopentyl derivatives, piperidinol or piperidinone, TP-1

[0049] [Chemical formula]

[0050] or TP-2

[0051] [Chemical formula] comprises

[0052] In some embodiments, the pharmaceutically acceptable salts of trapidil include, but are not limited to, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid.

[0053] In some embodiments, trapidil is the trapidil disclosed in U.S. Patent No. 6,015,578, European Patent No. 0301423, or International Publication No. WO1993 / 009781.

[0054] In some embodiments, trapidil is a trapidil derivative disclosed in Heinroth-Hoffmann et al. (1990) “Influence of trapidil and trapidil Derivatives on the Content of Cyclic Nucleotides in Human Intima Cells Cultured from Atherosclerotic Plaques,” Drug Development Research, 19(3), 321-327, Heinroth et al. (1983) “Influence of trapidil derivatives on arachidonic acid- and prostaglandin endoperoxide analogue-induced platelet aggregation and thromboxane A2 formation,” Biomedica biochimica acta, 43(8-9), S389-92, or Krause et al. (1985) Advances in Pharmacological Research and Practice: Proceedings of the 4th Congress of the Hungarian Pharmacological Society, Budapest, pages 139-142.

[0055] In some embodiments, trapidil is a trapidil metabolite disclosed in Thurmann et al. (1997) “Pharmacokinetics of the PDGF-antagonist trapidil in patients with and without renal impairment,” Clinical nephrology, 47(2), 99-105, or Pfeifer et al. (1990) “Biotransformation of the trapidil (rocornal) derivative AR 12463 in the rat,” Die Pharmazie, 45(8), 609-614.

[0056] In some embodiments, trapidil is a trapidil salt disclosed in U.S. Patent No. 6,369,065.

[0057] In some embodiments, also disclosed herein is a method of treating a patient by modulating neurons that express dopamine 1 by administering a therapeutically effective dose of trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof.

[0058] In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered as an oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered as an oral administration. In some embodiments, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered as a parenteral (e.g., intravenous, subcutaneous, intramuscular) administration. In other cases, trapidil, a derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt thereof is administered as a transdermal administration.

[0059] In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered orally. In some embodiments, the oral dosage ranges from about 10 mg per day to about 3000 mg per day. In some embodiments, the range of oral dosage is from about 10 mg per day to about 2900 mg per day, from about 10 mg per day to about 2800 mg per day, from about 10 mg per day to about 2700 mg per day, from about 10 mg per day to about 2600 mg per day, from about 10 mg per day to about 2500 mg per day, from about 10 mg per day to about 2400 mg per day, from about 10 mg per day to about 2300 mg per day, from about 10 mg per day to about 2200 mg per day, from about 10 mg per day to about 2100 mg per day, from about 10 mg per day to about 2000 mg per day, from about 10 mg per day to about 1900 mg per day, from about 10 mg per day to about 1800 mg per day, from about 10 mg per day to about 1700 mg per day, from about 10 mg per day to about 1600 mg per day, from about 10 mg per day to about 1500 mg per day, from about 10 mg per day to about 1400 mg per day, from about 10 mg per day to about 1300 mg per day, from about 10 mg per day to about 1200 mg per day, from about 10 mg per day to about 1100 mg per day, from about 10 mg per day to about 1000 mg per day, from about 10 mg per day to about 950 mg per day, from about 10 mg per day to about 900 mg per day, from about 10 mg per day to about 850 mg per day, from about 10 mg per day to about 800 mg per day, from about 10 mg per day to about 750 mg per day, from about 10 mg per day to about 700 mg per day, from about 10 mg per day to about 650 mg per day, from about 10 mg per day to about 600 mg per day, from about 10 mg per day to about 550 mg per day, from about 10 mg per day to about 500 mg per day, from about 10 mg per day to about 450 mg per day, from about 10 mg per day to about 400 mg per day,From about 10 mg per day to about 350 mg per day, from about 10 mg per day to about 300 mg per day, from about 10 mg per day to about 250 mg per day, from about 10 mg per day to about 200 mg per day, from about 10 mg per day to about 150 mg per day, from about 10 mg per day to about 100 mg per day, from about 50 mg per day to about 3000 mg per day, from about 100 mg per day to about 3000 mg per day, from about 150 mg per day to about 3000 mg per day, from about 200 mg per day to about 3000 mg per day, from about 300 mg per day to about 3000 mg per day, from about 400 mg per day to about 3000 mg per day, from about 500 mg per day to about 3000 mg per day, from about 600 mg per day to about 3000 mg per day, from about 700 mg per day to about 3000 mg per day, from about 800 mg per day to about 3000 mg per day, from about 900 mg per day to about 3000 mg per day, from about 1000 mg per day to about 3000 mg per day, from about 1100 mg per day to about 3000 mg per day, from about 1200 mg per day to about 3000 mg per day, from about 1300 mg per day to about 3000 mg per day, from about 1400 mg per day to about 3000 mg per day, from about 1500 mg per day to about 3000 mg per day, from about 1600 mg per day to about 3000 mg per day, from about 1700 mg per day to about 3000 mg per day, from about 1800 mg per day to about 3000 mg per day, from about 1900 mg per day to about 3000 mg per day, from about 2000 mg per day to about 3000 mg per day, from about 2100 mg per day to about 3000 mg per day, from about 2200 mg per day to about 3000 mg per day, from about 2300 mg per day to about 3000 mg per day, from about 2400 mg per day to about 3000 mg per day, from about 2500 mg per day to about 3000 mg per day, from about 2600 mg per day to about 3000 mg per day, from about 2700 mg per day to about 3000 mg per dayFrom about 2800 mg per day to about 3000 mg per day, from about 2900 mg per day to about 3000 mg per day, from about 50 mg per day to about 2800 mg per day, from about 100 mg per day to about 2800 mg per day, from about 150 mg per day to about 2800 mg per day, from about 200 mg per day to about 2800 mg per day, from about 300 mg per day to about 2800 mg per day, from about 400 mg per day to about 2800 mg per day, from about 500 mg per day to about 2800 mg per day, from about 600 mg per day to about 2800 mg per day, from about 700 mg per day to about 2800 mg per day, from about 800 mg per day to about 2800 mg per day, from about 900 mg per day to about 2800 mg per day, from about 1000 mg per day to about 2800 mg per day, from about 1100 mg per day to about 2800 mg per day, from about 1200 mg per day to about 2800 mg per day, from about 1300 mg per day to about 2800 mg per day, from about 1400 mg per day to about 2800 mg per day, from about 1500 mg per day to about 2800 mg per day, from about 1600 mg per day to about 2800 mg per day, from about 1700 mg per day to about 2800 mg per day, from about 1800 mg per day to about 2800 mg per day, from about 1900 mg per day to about 2800 mg per day, from about 2000 mg per day to about 2800 mg per day, from about 2100 mg per day to about 2800 mg per day, from about 2200 mg per day to about 2800 mg per day, from about 2300 mg per day to about 2800 mg per day, from about 2400 mg per day to about 2800 mg per day, from about 2500 mg per day to about 2800 mg per day, from about 2600 mg per day to about 2800 mg per day, from about 2700 mg per day to about 2800 mg per day, from about 50 mg per day to about 2500 mg per day, from about 100 mg per day to about 2500 mg per day, from about 150 mg per day to about 2500 mg per day, from about 200 mg per day to about 2500 mg per day,From about 300 mg per day to about 2500 mg per day, from about 400 mg per day to about 2500 mg per day, from about 500 mg per day to about 2500 mg per day, from about 600 mg per day to about 2500 mg per day, from about 700 mg per day to about 2500 mg per day, from about 800 mg per day to about 2500 mg per day, from about 900 mg per day to about 2500 mg per day, from about 1000 mg per day to about 2500 mg per day, from about 1100 mg per day to about 2500 mg per day, from about 1200 mg per day to about 2500 mg per day, from about 1300 mg per day to about 2500 mg per day, from about 1400 mg per day to about 2500 mg per day, from about 1500 mg per day to about 2500 mg per day, from about 1600 mg per day to about 2500 mg per day, from about 1700 mg per day to about 2500 mg per day, from about 1800 mg per day to about 2500 mg per day, from about 1900 mg per day to about 2500 mg per day, from about 2000 mg per day to about 2500 mg per day, from about 2100 mg per day to about 2500 mg per day, from about 2200 mg per day to about 2500 mg per day, from about 2300 mg per day to about 2500 mg per day, from about 2400 mg per day to about 2500 mg per day, from about 50 mg per day to about 2200 mg per day, from about 100 mg per day to about 2200 mg per day, from about 150 mg per day to about 2200 mg per day, from about 200 mg per day to about 2200 mg per day, from about 300 mg per day to about 2200 mg per day, from about 400 mg per day to about 2200 mg per day, from about 500 mg per day to about 2200 mg per day, from about 600 mg per day to about 2200 mg per day, from about 700 mg per day to about 2200 mg per day, from about 800 mg per day to about 2200 mg per day, from about 900 mg per day to about 2200 mg per day, from about 1000 mg per day to about 2200 mg per day, from about 1100 mg per day to about 2200 mg per day,From about 1200 mg per day to about 2200 mg per day, from about 1300 mg per day to about 2200 mg per day, from about 1400 mg per day to about 2200 mg per day, from about 1500 mg per day to about 2200 mg per day, from about 1600 mg per day to about 2200 mg per day, from about 1700 mg per day to about 2200 mg per day, from about 1800 mg per day to about 2200 mg per day, from about 1900 mg per day to about 2200 mg per day, from about 2000 mg per day to about 2200 mg per day, from about 2100 mg per day to about 2200 mg per day, from about 50 mg per day to about 2000 mg per day, from about 100 mg per day to about 2000 mg per day, from about 150 mg per day to about 2000 mg per day, from about 200 mg per day to about 2000 mg per day, from about 300 mg per day to about 2000 mg per day, from about 400 mg per day to about 2000 mg per day, from about 500 mg per day to about 2000 mg per day, from about 600 mg per day to about 2000 mg per day, from about 700 mg per day to about 2000 mg per day, from about 800 mg per day to about 2000 mg per day, from about 900 mg per day to about 2000 mg per day, from about 1000 mg per day to about 2000 mg per day, from about 1100 mg per day to about 2000 mg per day, from about 1200 mg per day to about 2000 mg per day, from about 1300 mg per day to about 2000 mg per day, from about 1400 mg per day to about 2000 mg per day, from about 1500 mg per day to about 2000 mg per day, from about 1600 mg per day to about 2000 mg per day, from about 1700 mg per day to about 2000 mg per day, from about 1800 mg per day to about 2000 mg per day, from about 1900 mg per day to about 2000 mg per day, from about 50 mg per day to about 1800 mg per day, from about 100 mg per day to about 1800 mg per day, from about 150 mg per day to about 1800 mg per day, from about 200 mg per day to about 1800 mg per day,From about 300 mg per day to about 1800 mg per day, from about 400 mg per day to about 1800 mg per day, from about 500 mg per day to about 1800 mg per day, from about 600 mg per day to about 1800 mg per day, from about 700 mg per day to about 1800 mg per day, from about 800 mg per day to Up to about 1800 mg, from about 900 mg per day to about 1800 mg per day, from about 1000 mg per day to about 1800 mg per day, from about 1100 mg per day to about 1800 mg per day, from about 1200 mg per day to about 1800 mg per day, from about 1300 mg per day to about 1800 mg per day, from about 1400 mg per day to about 1800 mg per day, from about 1500 mg per day to about 1800 mg per day, from about 1600 mg per day to about 1800 mg per day, from about 1700 mg per day to about 1800 mg per day, from about 50 mg per day to about 1500 mg per day, from about 100 mg per day to about 1500 mg per day, from about 150 mg per day to about 1500 mg per day, from about 200 mg per day to about 1500 mg per day, from about 300 mg per day to about 1500 mg per day, from about 400 mg per day to about 1500 mg per day, from about 500 mg per day to about 1500 mg per day, from about 600 mg per day to about 1500 mg per day, from about 700 mg per day to about 1500 mg per day, from about 800 mg per day to about 1500 mg per day, from about 900 mg per day to about 1500 mg per day, from about 1000 mg per day to about 1500 mg per day, from about 1100 mg per day to about 1500 mg per day, from about 1200 mg per day to about 1500 mg per day, from about 1300 mg per day to about 1500 mg per day, from about 1400 mg per day to about 1500 mg per day, from about 50 mg per day to about 1200 mg per day, from about 100 mg per day to about 1200 mg per day, from about 150 mg per day to about 1200 mg per day, from about 200 mg per day to about 1200 mg per day, from about 300 mg per day to about 1200 mg per day, from about 400 mg per day to about 1200 mg per day, from about 500 mg per day to about 1200 mg per day, from about 600 mg per day to about 1200 mg per day, from about 700 mg per day to about 1200 mg per day, from about 800 mg per day to about 1200 mg per day,From about 900 mg per day to about 1200 mg per day, from about 1000 mg per day to about 1200 mg per day, from about 1100 mg per day to about 1200 mg per day, from about 50 mg per day to about 1000 mg per day, from about 100 mg per day to about 1000 mg per day, from about 150 mg per day to about 1000 mg per day, from about 200 mg per day to about 1000 mg per day, from about 300 mg per day to about 1000 mg per day, from about 400 mg per day to about 1000 mg per day, from about 500 mg per day to about 1000 mg per day, from about 600 mg per day to about 1000 mg per day, from about 700 mg per day to about 1000 mg per day, from about 800 mg per day to about 1000 mg per day, from about 900 mg per day to about 1000 mg per day, from about 50 mg per day to about 800 mg per day, from about 100 mg per day to about 800 mg per day, from about 150 mg per day to about 800 mg per day, from about 200 mg per day to about 800 mg per day, from about 300 mg per day to about 800 mg per day, from about 400 mg per day to about 800 mg per day, from about 500 mg per day to about 800 mg per day, from about 600 mg per day to about 800 mg per day, from about 700 mg per day to about 800 mg per day, from about 50 mg per day to about 600 mg per day, from about 100 mg per day to about 600 mg per day, from about 150 mg per day to about 600 mg per day, from about 200 mg per day to about 600 mg per day, from about 300 mg per day to about 600 mg per day, from about 400 mg per day to about 600 mg per day, from about 500 mg per day to about 600 mg per day, from about 50 mg per day to about 500 mg per day, from about 100 mg per day to about 500 mg per day, from about 150 mg per day to about 500 mg per day, from about 200 mg per day to about 500 mg per day, from about 300 mg per day to about 500 mg per day, from about 400 mg per day to about 500 mg per day,From about 50 mg per day to about 400 mg per day, from about 100 mg per day to about 300 mg per day, from about 100 mg per day to about 200 mg per day, from about 200 mg per day to about 500 mg per day, from about 300 mg per day to about 500 mg per day, or from about 400 mg per day to about 500 mg per day.

[0060] In some embodiments, the oral dosage is about 10 mg per day, about 15 mg per day, about 20 mg per day, about 30 mg per day, about 40 mg per day, about 50 mg per day, about 100 mg per day, about 150 mg per day, about 200 mg per day, about 250 mg per day, about 300 mg per day, about 350 mg per day, about 400 mg per day, about 450 mg per day, about 500 mg per day, about 550 mg per day, about 600 mg per day, about 650 mg per day, about 700 mg per day, about 750 mg per day, about 800 mg per day, about 850 mg per day, about 900 mg per day, about 950 mg per day, about 1000 mg per day, about 1100 mg per day, about 1200 mg per day, about 1300 mg per day, about 1400 mg per day, about 1500 mg per day, about 1600 mg per day, about 1700 mg per day, about 1800 mg per day, about 1900 mg per day, about 2000 mg per day, about 2100 mg per day, about 2200 mg per day, about 2300 mg per day, about 2400 mg per day, about 2500 mg per day, about 2600 mg per day, about 2700 mg per day, about 2800 mg per day, about 2900 mg per day, or about 3000 mg per day.

[0061] In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in a single dose. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in multiple doses per day, for example, 2, 3, 4, 5, 6, or more doses. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered intravenously or subcutaneously. In such cases, the intravenous or subcutaneous dosage ranges from about 1 mg / kg body weight to about 10 mg / kg body weight, from about 2 mg / kg body weight to about 10 mg / kg body weight, or from about 4 mg / kg body weight to about 8 mg / kg body weight.

[0062] 2. Combination Therapy As used herein, in certain embodiments, a method of treating or preventing cognitive impairment in a subject in need thereof is disclosed, the method comprising administering to the subject a therapeutically effective dose of trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts, and an additional therapeutic agent. In some embodiments, the aforementioned additional therapeutic agent is administered concurrently with trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts. In some embodiments, the aforementioned additional therapeutic agent is administered before or after trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts. In some embodiments, the combination of trapidil and the additional therapeutic agent is therapeutically effective in treating or preventing cognitive impairment or mental illness in a subject in need thereof.

[0063] In some embodiments, the administration of trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts potentiates the additional therapeutic agent, such that a sub-clinical dose of the additional therapeutic agent is required to treat cognitive impairment or mental illness. In some embodiments, the aforementioned additional therapeutic agent is levodopa.

[0064] In some embodiments, the aforementioned additional therapeutic agent includes an antidepressant. Non-limiting examples of antidepressants include citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, Selfemra, Prozac Weekly), fluvoxamine (Luvox), paroxetine (Paxil, Paxil CR, Pexeva), sertraline (Zoloft), vortioxetine (formerly known as Brintellix, Trintellix), and vilazodone (Viibryd). In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with an antidepressant.

[0065] In some embodiments, the aforementioned additional therapeutic agent includes an antipsychotic agent. Non-limiting examples of antipsychotic agents include aripiprazole (Abilify), asenapine (Saphris), cariprazine (Vraylar), clozapine (Clozaril), lurasidone (Latuda), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon). In some embodiments, the aforementioned antipsychotic agent includes chlorpromazine, fluphenazine, haloperidol, perphenazine, or any combination thereof. In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with an antipsychotic agent.

[0066] In some embodiments, the aforementioned additional therapeutic agent includes an anxiolytic agent. Non-limiting examples of anxiolytic agents include alprazolam (Xanax), chlordiazepoxide (Librium), clonazepam (Klonopin), diazepam (Valium), and lorazepam (Ativan). In some embodiments, trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with an anxiolytic agent.

[0067] In some embodiments, the additional therapeutic agent described above includes a dopamine precursor or a dopamine agonist. In some embodiments, tropidyl, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with a dopamine precursor. In some embodiments, tropidyl, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with a dopamine agonist.

[0068] In some embodiments, the dopamine precursor includes levodopa. In some embodiments, the dopamine precursor is a combination of levodopa and carbidopa. In some embodiments, the dopamine precursor is a combination of levodopa and benserazide. In some embodiments, tropidyl, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with levodopa and / or carbidopa. In some embodiments, tropidyl, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with levodopa and / or benserazide.

[0069] In some embodiments, the additional therapeutic agent described above is a dopamine agonist including pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, bromocriptine, lisuride, apomorphine, levodopa, entacapone, selegiline, rasagiline, and / or tolcapone. In some embodiments, tropidyl, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered in combination with pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, bromocriptine, lisuride, apomorphine, levodopa, entacapone, selegiline, rasagiline, and / or tolcapone.

[0070] In some embodiments, the aforementioned additional therapeutic agent is administered orally, either alone or in combination with Trapidil. In some embodiments, the aforementioned additional therapeutic agent is administered intravenously or subcutaneously, either alone or in combination with Trapidil.

[0071] In some embodiments, Trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts and the additional therapeutic agent are administered simultaneously. In some embodiments, Trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts and the additional therapeutic agent are administered sequentially. In some embodiments, Trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered before the additional therapeutic agent. In some embodiments, Trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered after the additional therapeutic agent. In some embodiments, Trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts and the additional therapeutic agent are administered in an integrated dosage form. In some embodiments, Trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts and the additional therapeutic agent are administered in separate dosage forms.

[0072] D. Administration Schedule of Therapeutic Agents In some embodiments, the therapeutic agents, combination therapies, or pharmaceutical compositions described herein are administered according to a specific administration schedule. In some embodiments, the pharmaceutical composition is administered once a day, twice a day, three times a day or more. The pharmaceutical composition is administered daily, every day, every other day, five days a week, once a week, every other week, two weeks a month, three weeks a month, once a month, twice a month, three times a month, or more. The pharmaceutical composition is administered for at least one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, eighteen months, two years, three years, or more.

[0073] In some embodiments, trapidil and the additional therapeutic agent are administered simultaneously, sequentially, or at intervals. In some embodiments, trapidil and the additional therapeutic agent are administered simultaneously. In some embodiments, trapidil and the additional therapeutic agent are administered sequentially. In further cases, trapidil and the additional therapeutic agent are administered at intervals (e.g., on the first day, there is a first administration of the first pharmaceutical composition (e.g., trapidil), and then, at least 1 day, 2 days, 3 days, 4 days, 5 days, or more are left between the administrations of at least the second pharmaceutical composition (e.g., the additional therapeutic agent)).

[0074] If the patient's condition improves, at the physician's discretion, the composition is continuously administered, or instead, the dose of the administered composition is temporarily reduced or temporarily interrupted for a specific period (i.e., a "drug holiday"). In some embodiments, the length of the drug holiday varies between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during the drug holiday is between 10% and 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0075] Once the patient's disease (e.g., cognitive impairment or disorder) improves, a maintenance dose is administered as needed. Thereafter, the dose or dosing frequency, or both, may be reduced to a level at which the improved disease, disorder, or illness is maintained, depending on the symptoms.

[0076] In some embodiments, the amount of a given agent corresponding to such an amount varies depending on factors such as a particular compound, the severity of the disease, and the idiosyncrasies (e.g., body weight) of the subject or host in need of treatment, but nonetheless, is determined in a well - used manner by techniques known in the art, depending on the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, and the subject or host being treated. In some embodiments, the desired dosage is conventionally provided as a single dose or as divided doses, administered simultaneously (or over a short period of time) or at appropriate intervals, such as two, three, four or more sub - doses per day.

[0077] Due to the large number of variables regarding individual treatment regimens, the foregoing ranges are merely suggestive and it is not uncommon to deviate significantly from these recommended values. Such dosages are adjusted according to a number of variables including, but not limited to, the activity of the compound being used, the disease or disorder being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or disorder being treated, and the judgment of the physician.

[0078] In some embodiments, the toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell culture or experimental animals, including, but not limited to, determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The ratio of the dose between toxicity and therapeutic effect is the therapeutic index, which is expressed as the ratio between the LD50 and the ED50. Compounds with a high therapeutic index are preferred. Data obtained from cell - culture assays and animal studies are used in formulating the dosage range for human use. The dosage of such compounds preferably lies within a range of circulating concentrations that includes the ED50 with minimal toxicity. The dosage varies within this range depending on the dosage form used and the route of administration utilized.

[0079] II. Compositions and Formulations In this specification, in some embodiments, a pharmaceutical composition (or combination) comprising a therapeutic agent disclosed herein is disclosed. In some embodiments, the pharmaceutical composition comprises tropidyl, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts. In some embodiments, the pharmaceutical composition, or combination, further comprises an additional therapeutic agent. In some embodiments, the aforementioned additional therapeutic agent is a dopamine precursor (e.g., levodopa). In some embodiments, the aforementioned additional therapeutic agent is a combination therapy of a dopamine precursor (e.g., levodopa) and adjuvant therapy (e.g., carbidopa). In some embodiments, the aforementioned additional therapeutic agent is a dopamine agonist (e.g., rotigotine, cabergoline, pergolide, bromocriptine, piribedil, pramipexole, ropinirole, lisuride, quinagolide, or apomorphine). In some embodiments, the pharmaceutical composition or combination is therapeutically effective for treating or preventing cognitive impairment or mental illness in a subject. In some embodiments, the aforementioned pharmaceutical composition or combination further comprises at least one pharmaceutically acceptable excipient, carrier, or diluent. In some embodiments, the aforementioned pharmaceutical combination is a fixed-dose combination. In some embodiments, the dosage of tropidyl in the aforementioned pharmaceutical composition or combination is about 200 milligrams or less.

[0080] A. Pharmaceutical Compositions and Formulations In this specification, in certain embodiments, a pharmaceutical composition or combination comprising a therapeutic agent described herein is disclosed. In some embodiments, the aforementioned therapeutic agent is tropidyl. In some embodiments, the aforementioned pharmaceutical composition further comprises an additional therapeutic agent. In some embodiments, the aforementioned additional therapeutic agent is a dopamine precursor (e.g., levodopa) or a dopamine agonist. In some embodiments, the pharmaceutical composition or combination is formulated by conventional techniques using one or more physiologically acceptable carriers, including excipients and auxiliaries, which facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the chosen route of administration. All well-known techniques, carriers, and excipients are used as appropriate and as understood in the art. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the entire contents of which are incorporated herein by reference.

[0081] A pharmaceutical composition, as used herein, refers to a mixture of a compound described herein, such as tropidyl and additional therapeutic agents for treating Parkinson's disease, and other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients. The aforementioned pharmaceutical composition or combination facilitates the administration of the compound to an organism. When practicing the therapeutic or use methods provided herein, a therapeutically effective amount of the compound described herein is administered as a pharmaceutical composition to a mammal suffering from a disease, disorder, or illness to be treated. Preferably, the aforementioned mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compound used, and other factors. The compound may be used alone or in combination with one or more therapeutic agents as a component of a mixture.

[0082] In certain embodiments, the composition or combination also includes one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid, bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris(hydroxymethyl)aminomethane, and buffers such as citric acid / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0083] In other embodiments, the composition or combination also includes one or more salts in amounts necessary to bring the weight molar osmolarity of the composition within an acceptable range. Such salts include those having cations of sodium, potassium, or ammonium and anions of chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite, and suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0084] The term "pharmaceutical combination", as used herein, means a product resulting from the mixing or combining of more than one active ingredient, including both fixed combinations of active ingredients and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., the compounds described herein and adjuvants, are both administered to a patient simultaneously in a single substance or dosage form. The term "non-fixed combination" means that the active ingredients, e.g., the compounds described herein and adjuvants, are administered to a patient as separate substances simultaneously, concurrently, or sequentially without specific intervening time limitations, and such administration provides the patient's body with effective levels of two compounds. The latter also applies to cocktail therapies, e.g., the administration of three or more active ingredients.

[0085] The pharmaceutical formulations described herein can be administered to a subject by a plurality of administration routes including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast-dissolving formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiple microparticle formulations, and mixed immediate release and controlled release formulations.

[0086] In some embodiments, pharmaceutical compositions containing the compounds described herein are prepared by conventional methods, such as, by way of example only, conventional mixing, dissolving, granulating, sugarcoating, pulverizing, emulsifying, encapsulating, entrapping or compressing means.

[0087] In some embodiments, an "antifoaming agent" reduces foaming during processing that results in coagulation of an aqueous dispersion or air bubbles in a finished film or generally impedes processing. Typical antifoaming agents include silicone emulsions or sorbitan sesquioleate.

[0088] The "antioxidant" includes, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium bisulfite, and tocopherol. In certain embodiments, the antioxidant enhances chemical stability as needed.

[0089] In certain embodiments, the compositions provided herein also include one or more preservatives for inhibiting microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thimerosal, stabilized chlorine dioxide, and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0090] In further embodiments, the formulations described herein benefit from antioxidants, metal chelating agents, thiol-containing compounds, and other common stabilizers. Examples of such stabilizers include, but are not limited to, (a) glycerol from about 0.5% to about 2% w / v, (b) methionine from about 0.1% to about 1% w / v, (c) monothioglycerol from about 0.1% to about 2% w / v, (d) EDTA from about 1 mM to about 10 mM, (e) ascorbic acid from about 0.01% to about 2% w / v, (f) polysorbate 80 from 0.003% to about 0.02% w / v, (g) polysorbate 20 from 0.001% to about 0.05% w / v, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc, or (n) combinations thereof.

[0091] B. Dosage Forms In some embodiments, the compositions or combinations described herein are formulated for administration to a subject via any conventional means, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. In some embodiments, the foregoing compositions are formulated for administration in a combined dosage form. In some embodiments, the foregoing compositions are formulated for administration in separate dosage forms.

[0092] Furthermore, the pharmaceutical compositions described herein comprise trapidil and a further therapeutic agent and are formulated into any suitable dosage form for oral ingestion by the patient to be treated, including, but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, etc., solid oral dosage forms, aerosols, controlled release formulations, fast dissolving formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsatile release formulations, multiple microparticle formulations, and immediate release and controlled release combination formulations.

[0093] Pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, adding suitable auxiliaries if desired, and then treating the mixture of granules to obtain cores for tablets or dragees. Suitable excipients include, for example, fillers such as sugars including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrants such as crosslinked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate may be added.

[0094] The core of the sugar-coated tablet is provided with an appropriate coating. For this purpose, a concentrated sugar solvent is used, which optionally contains gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solvent, and an appropriate organic solvent or solvent mixture. Dyes or pigments are added to the tablet or sugar-coated tablet coating to identify or characterize the dosages of various combinations of active compounds.

[0095] Pharmaceutical preparations for oral use include push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and containing plasticizers such as glycerol or sorbitol. The push-fit capsules may contain active ingredients, mixed optionally with stabilizers, together with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate. In the case of soft capsules, the active compound may be dissolved or suspended in an appropriate liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. All formulations for oral administration must be in dosages appropriate for such administration.

[0096] In some embodiments, the solid dosage forms disclosed herein may be in the form of tablets (including suspension tablets, fast-dissolving tablets, chewable disintegrating tablets, fast-disintegrating tablets, effervescent tablets, or caplets), pills, powders (including aseptically packaged powders, distributable powders, or effervescent powders), capsules (both soft and hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or including "sprinkle capsules"), solid dispersions, solid solutions, biodegradable dosage forms, controlled-release formulations, pulsatile-release dosage forms, multiple microparticle dosage forms, pellets, granules, or aerosols. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to fast-dissolving tablets. Additionally, the pharmaceutical formulations described herein may be administered as a single capsule or as a dosage form of multiple capsules. In some embodiments, the pharmaceutical formulation is administered in 2, or 3, or 4 capsules or tablets.

[0097] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of trapidil and / or additional therapeutic agents with one or more pharmaceutical excipients to form a mixed composition body. When referring to these mixed composition bodies as being homogeneous, it means that the particles of trapidil and / or additional therapeutic agents are uniformly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. The individual unit dosages may further include a film coating that disintegrates upon oral ingestion or upon contact with a diluent. These formulations can be manufactured by conventional pharmacological techniques.

[0098] Conventional pharmacological techniques include, for example, one or a combination of (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion methods. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluid bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tableting, extrusion, etc.

[0099] In some embodiments, the pharmaceutical solid dosage forms described herein include the compounds described herein and one or more additional pharmaceutically acceptable additives such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersants, surfactants, lubricants, coloring agents, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, antioxidants, preservatives, or a combination of one or more thereof. In yet other aspects, film coatings are provided around formulations of trapidil and / or additional therapeutic agents using standard coating procedures such as those described in Remington’s Pharmaceutical Sciences, 20th Edition (2000). In another embodiment, some or all of the particles of trapidil and / or additional therapeutic agents are not microencapsulated and not coated.

[0100] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0101] Suitable fillers for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrose, dextrate, dextran, starch, pregelatinized starch, hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0102] In order to release the compound of trapidil and / or further therapeutic agents from the solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage form is compressed with a binder. The disintegrant aids in disintegrating the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants used in the solid dosage forms described herein include, but are not limited to, natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolates such as Promogel® or Explotab®, celluloses such as wood products, methylcellulose crystals such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol®), cross-linked carboxymethyl cellulose, or cross-linked croscarmellose, cross-linked starches such as cross-linked sodium starch glycolate, cross-linked polymers such as crospovidone which is cross-linked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays (magnesium aluminum silicate) such as Veegum® HV, agar, guar, locust bean, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponges, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate combined with starch, and the like.

[0103] The binder imparts adhesiveness to solid oral dosage form formulations, aids in plug formation for capsule formulations filled with powder, which can be filled into soft shell capsule or hard shell capsule formulations, and for tablet formulations, ensures that the tablets remain intact after compression and aids in ensuring uniform mixing prior to the compression or filling step. Suitable substances for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g., Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrin, amylose, magnesium aluminum silicate, polysaccharic acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), sugars such as lactose, gum arabic, tragacanth, natural or synthetic gums such as ghatti gum, mucilage of isapol husk, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabinogalactan, Veegum®, polyethylene glycol, wax, sodium alginate, and the like.

[0104] Generally, binder levels of 20 to 70% are used in gelatin capsule formulations filled with powder. The level of binder used in tablet formulations varies depending on whether direct compression, wet granulation, roller compression, or other excipients such as fillers that can act as moderate binders themselves are used. Formulators in the art can determine the binder level for a formulation, but it is common for binder use levels in tablet formulations to be up to 70%.

[0105] Lubricants or glidants suitable for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, salts of alkali metals and alkaline earth metals, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol, such as Carbowax®, PEG4000, PEG5000, PEG6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium, or sodium lauryl sulfate, and the like.

[0106] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and baker's dextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like.

[0107] The term "water-insoluble diluent" refers to calcium phosphate, calcium sulfate, starch, modified starch and microcrystalline cellulose, and microfine cellulose (e.g., about 0.45 g / cm 3represents compounds typically used in pharmaceutical formulations, such as those having a density of, for example, Avicel, powdered cellulose), and talc.

[0108] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10 (registered trademark)), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.

[0109] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic (registered trademark) (BASF), and the like.

[0110] Suspensions suitable for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, such as polyethylene glycol having a molecular weight of about 300 to about 6000, about 3350 to about 4000, or about 7000 to about 5400, vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethyl cellulose, methylcellulose, hydroxy - propylmethylcellulose, polysorbate 80, hydroxyethylcellulose, sodium alginate, gums, such as tragacanth gum, acacia gum, guar gum, xanthan gum including xanthan, sugars, cellulose - based, such as sodium carboxymethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, etc., polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, etc.

[0111] Antioxidants suitable for use in the solid dosage forms described herein include, for example, butylhydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0112] It should be recognized that there is significant overlap among the additives used in the solid dosage forms described herein. Thus, the above - listed additives should be regarded merely as exemplary and, without limitation, as types of additives that can be included in the solid dosage forms described herein. The amounts of such additives can be readily determined by one of ordinary skill in the art according to the particular desired properties.

[0113] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Exemplarily, the plasticizer is generally a high-boiling solid or liquid. Suitable plasticizers may be added in an amount from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[0114] Compressed tablets are solid dosage forms prepared by compressing a mixture mass of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth contain one or more flavoring agents. In other embodiments, the compressed tablets contain a film surrounding the final compressed tablet. In some embodiments, the film coating can provide delayed release of trapidil and / or additional therapeutic agents from the formulation. In other embodiments, the film coating aids patient compliance (e.g., Opadry® coating, or sugar coating). Film coatings containing Opadry® typically range from about 1% to about 3% of the tablet weight. In other embodiments, the compressed tablets contain one or more excipients.

[0115] The capsule formulation is prepared, for example, by placing the mixture body of the formulation of trapidil and / or further therapeutic agents described above inside the capsule. In some embodiments, the formulation (non-aqueous suspension and solvent) is placed in soft gelatin capsules. In other embodiments, the formulation is placed in standard gelatin capsules or non-gelatin capsules, such as capsules containing HPMC. In other embodiments, the formulation is placed in sprinkle capsules, where the capsule formulation may be swallowed whole or the capsule formulation may be opened and its contents sprinkled on food before eating. In some embodiments, the therapeutic dose is divided into a plurality of (e.g., two, three, or four) capsules. In some embodiments, the total dose of the formulation is delivered in capsule form.

[0116] In various embodiments, the particles of trapidil and / or further therapeutic agents, and one or more excipients are dry mixed and compressed into a mass such as a tablet, and the mass substantially disintegrates in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, thereby providing a hardness sufficient to release the formulation into gastrointestinal fluids.

[0117] In another aspect, the dosage form may include a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulating material. Exemplary materials include, but are not limited to, pH adjusters, erosion promoters, defoamers, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0118] Materials useful for microencapsulation as described herein include materials compatible with either trapidil or a further therapeutic agent that sufficiently isolate either trapidil or a compound of the further therapeutic agent from other incompatible excipients. Materials compatible with either trapidil or a compound of the further therapeutic agent are materials that delay the release of either trapidil or a compound of the further therapeutic agent in vivo.

[0119] Exemplary microencapsulation materials useful for delaying the release of formulations containing the compounds described herein include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ether (L-HPC), Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, hydroxypropyl methyl cellulose ethers (HPMC) such as Methocel®-A, hydroxypropyl methyl cellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Metolose®, methyl cellulose polymers such as E461, ethyl cellulose (EC) and mixtures thereof, such as Ethocel®, Aqualon®-EC, Surelease®, polyvinyl alcohol (PVA), such as Opadry AMB, hydroxyethyl cellulose, such as Natrosol®, carboxymethyl cellulose and salts of carboxymethyl cellulose (CMC), such as Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol copolymers, such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic polymers, and mixtures of cellulose ethers and acrylic polymers, such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5. Eudragit® NE30D and Eudragit® NE40D, cellulose acetate phthalate, Seprafilm, for example, a mixture of HPMC and stearic acid, cyclodextrin, and mixtures of these materials are included.

[0120] In yet another embodiment, plasticizers such as polyethylene glycol, for example, PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, microencapsulation materials useful for delaying the release of pharmaceutical compositions are from the USP or the National Formulary (NF). In still other embodiments, the microencapsulation material is Klucel. In still other embodiments, the microencapsulation material is Methocel.

[0121] The microencapsulated compound of either Trapidil or a further therapeutic agent may be formulated by methods known to those skilled in the art. Such known methods include, for example, spray drying processes, dissolution processes by rotary disk, hot melt processes, spray cooling methods, fluidized beds, electrostatic deposition, centrifugal extrusion, rotary suspension separation, polymerization at liquid - gas or solid - gas interfaces, extrusion by pressure, or spraying into a solvent extraction tank. In addition to these, various chemical techniques such as complex coacervation, dissolution evaporation, polymer - polymer incompatibility, interfacial polymerization in liquid media, in - situ polymerization, solvent evaporation in liquid media, and desolvation in liquid media may also be used. Further, other methods such as roller compaction, extrusion / spheronization, coacervation, or nanoparticle coating may also be used.

[0122] In other embodiments, the solid dosage formulations of any of the compounds of trapidil and / or further therapeutic agents are plasticized (coated) with one or more layers. Exemplarily, the plasticizer is generally a high-boiling solid or liquid. Suitable plasticizers may be added in an amount from about 0.01 wt% to about 50 wt% (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[0123] In other embodiments, powders comprising formulations having any of the compounds of trapidil and / or further therapeutic agents described herein may be formulated to include one or more pharmaceutical excipients and flavorants. Such powders may be prepared, for example, by mixing the formulation with optional pharmaceutical excipients to form a blended composition body. Further embodiments include suspending agents and / or wetting agents. This blended composition body is uniformly subdivided into unit dose packages or multiple dose package units.

[0124] In yet another embodiment, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse the drug in water for oral administration. Effervescent salts are granules or coarse powders containing the drug in a dry mixture, usually composed of sodium bicarbonate, citric acid, and / or tartaric acid. When the salts of the compositions described herein are added to water, the acid and base react to liberate carbon dioxide gas, thereby causing "effervescence". Examples of effervescent salts include, for example, the following components, namely, sodium bicarbonate, or a mixture of sodium bicarbonate and sodium carbonate, citric acid, and / or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide may be used in place of the combination of sodium bicarbonate, citric acid, and tartaric acid, provided that the components are suitable for pharmaceutical use and result in a pH of about 6.0 or greater.

[0125] In some embodiments, the solid dosage forms described herein may be formulated as enteric-coated delayed-release oral dosage forms, i.e., oral dosage forms of pharmaceutical compositions as described herein that utilize an enteric coating to affect release in the small intestine of the gastrointestinal tract system. Enteric-coated dosage forms may be compressed, molded, or extruded tablets / molds (with or without a coating) containing granules, powders, pellets, beads, or particles (with or without a coating themselves) of the active ingredient and / or other compositional components. Enteric-coated oral dosage forms may also be capsules (with or without a coating) containing pellets, beads, or granules of a solid carrier, or compositions (with or without a coating themselves).

[0126] As used herein, the term "delayed release" refers to delivery such that it is achievable at a generally predictable location in the gastrointestinal tract distal to the location where release would have been achieved if there had been no change in delayed release. In some embodiments, the method for delaying release is a coating. Any coating should be of sufficient thickness so that the entire coating does not dissolve in the digestive fluid at a pH of less than about 5, but does dissolve at a pH of about 5 or greater. To achieve delivery further down the gastrointestinal tract system, it is expected that any anionic polymer exhibiting a pH-dependent solubility profile may be used as an enteric coating in the methods and compositions described herein. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In other embodiments, the polymers and their compatible mixtures, and some of their properties, include, but are not limited to, the following.

[0127] Shellac, also known as refined lac, is a purified product obtained from the resinous secretion of insects. This coating dissolves in a medium with pH > 7.

[0128] Acrylic polymers. The performance of acrylic polymers (mainly solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include copolymers of methacrylic acid and ammonium methacrylate salts. Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available as solubilized in organic solvents, aqueous dispersions, or dry powders. Eudragit series RL, NE, and RS are insoluble but permeable in the gastrointestinal tract and are mainly used for colon targeting. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D, and S are insoluble in the stomach and dissolve in the intestine.

[0129] Cellulose derivatives. Examples of suitable cellulose derivatives are ethyl cellulose, a reaction mixture of a partial acetate ester of cellulose and phthalic anhydride. Its performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH > 6. Aquateric (FMC) is an aqueous, spray-dried CAP pseudo-latex having particles < 1 μm. Other components in Aquateric may include Pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman), methyl cellulose (Pharmacoat, Methocel), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose succinate (HPMCS), and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). Its performance can vary based on the degree and type of substitution. For example, HPMCP grades such as HP-50, HP-55, HP-55S, HP-55F are suitable. Its performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF) which dissolves at pH 5, AS-MG (MF) which dissolves at pH 5.5, and AS-HG (HF) which dissolves at higher pH. These polymers are polyvinyl acetate phthalate (PVAP), provided as granules or as fine powders for aqueous dispersions. PVAP dissolves at pH > 5 and is much less permeable to water vapor and gastric juice.

[0130] In some embodiments, the coating may and usually does contain a plasticizer, which is well-known in the art, and possibly other coating excipients such as colorants, talc, and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glycerol triacetate), acetyltriethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglyceride, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxyl group-containing acrylic polymers usually contain 10 to 25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques such as spray coating or pan coating are used to apply the coating. The thickness of the coating must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired local delivery site in the gastrointestinal tract.

[0131] To solubilize or disperse the coating material and to improve the coating performance and the coated product, colorants, detackifiers, surfactants, defoamers, lubricants (e.g., carnauba wax or PEG) may be added to the coating in addition to the plasticizer.

[0132] In other embodiments, the formulations described herein that include trapidil and / or additional therapeutic agents are delivered using a pulsed dosage form. The pulsed dosage form can provide one or more immediate release pulses at a predetermined time after a controlled delay time or at a specific site. Many other types of controlled release systems known to those of skill in the art are suitable for use with the formulations described herein. Examples of such delivery systems include, for example, polymer-based systems such as polylactic acid, polyglycolic acid, polyanhydrides, and polycaprolactone, porous matrices, sterols such as cholesterol, cholesterol esters, and fatty acids, or non-polymer-based systems that are lipids including monoglycerides, diglycerides, and triglycerides, hydrogel release systems, silastic systems, peptide-based systems, wax coatings, biodegradable dosage forms, compressed tablets using conventional binders, and the like. See, for example, Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990), Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 751-753 (2002), U.S. Patent Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983.

[0133] In some embodiments, there is provided a pharmaceutical formulation comprising particles of trapidil and / or additional therapeutic agents described herein and at least one dispersant or suspending agent for oral administration to a subject. The aforementioned formulation may be a powder and / or granules for suspension, which, when mixed with water, provides a substantially uniform suspension.

[0134] The dosage form of the liquid formulation for oral administration may be an aqueous suspension selected from the group consisting of, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002). Additionally, the liquid dosage form may include additives such as (a) a disintegrant, (b) a dispersant, (c) a wetting agent, (d) at least one preservative, (e) a viscosity enhancer, (f) at least one sweetening agent, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersion may further include a crystal growth inhibitor.

[0135] The aqueous suspensions and dispersions described herein can remain in a homogeneous state for at least 4 hours, as defined in the USP Pharmacist's Pharmacopeia (2005 edition, chapter 905). For determination of the homogeneity of the entire composition, the homogeneity should be determined by a consistent sampling method. In one embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 1 minute. In another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 30 seconds. In yet another embodiment, agitation is not necessary to maintain a homogeneous aqueous dispersion.

[0136] Examples of disintegrants used in aqueous suspensions and dispersions include, but are not limited to, starches such as natural starches like corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolates such as Promogel® or Explotab®, celluloses such as wood products, methylcellulose crystals such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked cellulose such as crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone which is crosslinked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays (aluminum magnesium silicate) such as Veegum® HV, agar, guar, locust bean, karaya, pectin, or gums such as tragacanth, sodium starch glycolate, bentonite, natural sponges, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

[0137] In some embodiments, dispersants suitable for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and carbohydrate-based dispersants such as hydroxypropylcellulose, hydroxypropylcellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose, hydroxypropylmethylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate, microcrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymer (Plasdone®, e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide), and poloxamines (e.g., Poloxamine 908®, also known as Tetronic 908® (BASF Corporation, Parsippany, N.J.), a tetrafunctional block copolymer resulting from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine).In other embodiments, the dispersant is selected from the group consisting of none of the following agents, which includes hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP), hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate, microcrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer having ethylene oxide and formaldehyde, poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide), or poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®).

[0138] Wetting agents optimal for the aqueous suspensions and dispersions described herein are known in the art and include, but are not limited to, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available Tweens (e.g., Tween 20® and Tween 80® (ICI Specialty Chemicals))), and polyethylene glycols (e.g., Carbowax 3350® and Carbowax 1450®, and Carbopol 934® (Union Carbide)), oleic acid, glycerol monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphatidylcholine, and the like.

[0139] Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of paraoxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. The preservative, when used herein, is incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.

[0140] Suitable viscosity enhancers for the aqueous suspensions or dispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Plasdon® S-630, carbomer, polyvinyl alcohol, alginate, gum arabic, chitosan, and combinations thereof. The concentration of the viscosity enhancer depends on the agent selected and the desired viscosity.

[0141] Examples of sweeteners suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, butterscotch, berry, cassis, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cyclamic acid salt, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, kaede, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, thaumatin, sucralose, sorbitol, swiss cream, tagatose, tangelo, thaumatin, tutti frutti, vanilla, walnut, watermelon, Japanese quince, wintergreen, xylitol, or combinations of these flavor components, for example, anise - menthol, cherry - anise, cinnamon - orange, cherry - cinnamon, chocolate - mint, honey - lemon, lemon - lime, lemon - mint, menthol - eucalyptus, orange - cream, vanilla - mint, and mixtures thereof. In one embodiment, the aqueous liquid dispersion may contain a sweetener or flavorant at a concentration ranging from about 0.001% to about 1.0% by volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion may contain a sweetener or flavorant at a concentration ranging from about 0.005% to about 0.5% by volume of the aqueous dispersion.In yet another embodiment, the aqueous liquid dispersion may contain a sweetening or flavoring agent at a concentration ranging from about 0.01% to about 1.0% based on the volume of the aqueous dispersion.

[0142] In addition to the additives listed above, the liquid formulation may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents. Exemplary emulsifying agents include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, sodium docusate, cholesterol, cholesterol esters, taurocholic acid, phosphatidylcholine, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, or mixtures of these substances.

[0143] In some embodiments, the pharmaceutical formulations described herein may be self-emulsifying drug delivery systems (SEDDS). An emulsion is typically a dispersion of one immiscible phase in another phase in the form of droplets. Generally, emulsions are created by active mechanical dispersion. In contrast to emulsions or microemulsion agents, SEDDS spontaneously form an emulsion when added to excessive water without external mechanical dispersion or agitation. The advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. In addition, immediately prior to administration, water or an aqueous phase can be added, thereby ensuring the stability of unstable or hydrophobic active ingredients. Thus, SEDDS provides an effective delivery system for the oral and parenteral delivery of hydrophobic active ingredients. SEDDS can provide an improvement in the bioavailability of hydrophobic active ingredients. Methods for generating self-emulsifying dosage forms are known in the art and include, but are not limited to, for example, U.S. Patent Nos. 5,858,401, 6,667,048, and 6,960,563, which are specifically incorporated herein by reference respectively.

[0144] It should be recognized that there is overlap among the additives listed above for use in the aqueous dispersions or suspensions described herein because certain additives are often classified differently by different physicians in the art or are generally used for any of several different effects. Thus, the additives listed above should be regarded merely as exemplary and, without limitation, as being of the types of additives that can be included in the formulations described herein. The amount of such additives can be readily determined by one of ordinary skill in the art according to the particular properties desired.

[0145] 1. Injectable Formulations Formulations containing a compound of trapidil or a further therapeutic agent suitable for intramuscular, subcutaneous, or intravenous injection may include sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions for reconstitution into a sterile injectable solution or dispersion, and sterile powders. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene-glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (such as olive oil), and organic esters for injection such as ethyl oleate. Suitable fluidity may be maintained, for example, by the use of coatings such as lecithin, by maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Formulations suitable for subcutaneous injection may also include additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms can be brought about by the use of agents that delay absorption such as aluminum monostearate and gelatin.

[0146] For intravenous injection, the compounds described herein may be formulated in an aqueous solution, preferably in a physiologically compatible buffer such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, suitable penetration enhancers are used in the formulation for the permeation barrier. Such penetration enhancers are generally known in the art. In other parenteral injections, suitable formulations may include aqueous or non-aqueous solutions, preferably together with a physiologically compatible buffer or excipient. Such excipients are generally known in the art.

[0147] Parenteral injection may include bolus injection or continuous infusion. Injectable formulations may be provided in unit dosage forms, for example, ampoules or multi-dose containers, with the addition of preservatives. The pharmaceutical compositions described herein are in forms suitable for parenteral injection, such as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending agents, stabilizers, and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In addition, suspensions of the active compound may be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free distilled water, before use.

[0148] 2. Further Formulations In certain embodiments, delivery systems for pharmaceutical compounds, such as liposomes and emulsions, may be utilized. In certain embodiments, the compositions provided herein may also include mucoadhesive polymers selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0149] In some embodiments, the compounds described herein may be administered topically and formulated into various topically administrable compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compounds may contain solubilizing agents, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0150] In some embodiments, the compounds described herein may also be formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing synthetic polymers such as polyvinylpyrrolidone, PEG in addition to conventional suppository bases such as cocoa butter or other glycerides. In the suppository form of the composition, low melting point waxes such as mixtures of fatty acid glycerides, optionally combined with cocoa butter, are first melted.

[0151] III. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and illustrative only and are not restrictive of the claimed subject matter.

[0152] In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless specifically stated otherwise. Further, the use of the term "including" is not limited, like other forms such as "include", "includes", and "included".

[0153] When used herein, ranges and amounts may be expressed as “about” a particular value or range. “About” also includes the exact amount. Thus, “about 5 μL” means both “about 5 μL” and “5 μL”. In general, the term “about” includes amounts that are expected to be within experimental error.

[0154] The headings of the sections used herein are for structural purposes only and are not to be construed as limiting the subject matter described.

[0155] When used herein, the terms “drug,” “pharmaceutical,” “small molecule drug,” “biological agent,” “biopharmaceutical,” and “therapeutic” are used interchangeably to refer to exogenous compounds administered to a patient for therapeutic purposes. These compounds are obtained by a patient, with a prescription from a healthcare provider or without a prescription for a commercial product.

[0156] When used herein, “cognitive disorder” refers to a disease that affects cognitive abilities, which may have an underlying brain pathology. In some embodiments, the cognitive disorder is a single disease, symptom, sign, or diagnosis. In some embodiments, the cognitive disorder is a series of closely related diseases, symptoms, signs, or diagnoses.

[0157] When used herein, “cognitive impairment” refers to a cognitive disorder that causes a decline or defect in cognitive ability. In some embodiments, the cognitive impairment includes a decline or defect in one or more of five cognitive domains, including attention, working memory, executive function, visuospatial function, and memory.

[0158] When used herein, “cognition” refers to mental activities, including, for example, working memory, executive function, visuospatial function, memory, association, concept formation, pattern recognition, language, attention, perception, behavior, problem solving, and mental imagery.

[0159] As used herein, "derivative" refers to a compound derived from or obtained from a compound disclosed herein. In some embodiments, the derivative improves its solubility, absorbability, biological half-life, etc., or reduces the toxicity of the molecule, removes or reduces undesirable side effects of the molecule.

[0160] In some embodiments, derivatives of the compounds described herein include isotopically labeled compounds (e.g., with radioactive isotopes), or compounds by other means including, but not limited to, the use of a chromophore or fluorescent moiety, bioluminescent label, or chemiluminescent label. Apart from the fact that one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature, the compounds described herein include isotopically labeled compounds that are identical to those recited in the various formulas and structures presented herein. Examples of isotopes incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine such as, for example, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36Cl. In some embodiments, the isotopically labeled compounds described herein, such as compounds incorporating radioactive isotopes such as 3H and 14C, are useful in drug and / or substrate tissue distribution assays.

[0161] In some embodiments, derivatives of the compounds described herein are deuterated versions of the compounds. In some embodiments, the deuterated version of the compound includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more deuterium substitutions. In some embodiments, substitution with isotopes such as deuterium provides certain therapeutic advantages resulting from greater metabolic stability, such as an extended half-life in vivo or a reduced required dose of administration.

[0162] In some embodiments, derivatives of the compounds described herein include AR12455, AR12456, AR12460, AR12463, AR12464, AR12465, or AR12565.

[0163] As used herein, a "metabolite" of a compound disclosed herein refers to intermediates and products of that compound formed when the compound is metabolized. In further embodiments, the compounds described herein are metabolized when administered to a desired organism, thereby producing metabolites, which are then used to produce desired actions, including desired therapeutic effects. In some embodiments, metabolites of the compounds disclosed herein are active metabolites. The term "active metabolite" refers to biologically active derivatives of a compound formed when the compound is metabolized. The term "metabolized" as used herein refers to the overall process by which a particular substance is changed by an organism, including, but not limited to, hydrolysis reactions and enzyme-catalyzed reactions. Thus, in some embodiments, an enzyme produces a specific structural change to a compound.

[0164] In some embodiments, sites on organic radicals (e.g., alkyl groups, aromatic rings) of the compounds described herein are sensitive to various metabolic reactions. Incorporation of appropriate substituents on the organic radical reduces, minimizes, or eliminates this metabolic pathway. In a specific embodiment, appropriate substituents for reducing or eliminating the sensitivity of an aromatic ring to a metabolic reaction are, by way of example only, halogen, deuterium, alkyl group, haloalkyl group, or deuterated alkyl group.

[0165] In some embodiments, exemplary metabolites disclosed herein include, but are not limited to, desethyl-trapidil, 5-piperidin-4'-olyl-7-[N-pentyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, 5-piperidin-4'-olyl-7-[N-pent-4'-olyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, hydroxy derivatives or ketopentyl derivatives, piperidinol or piperidinone, TP1 or TP2.

[0166] In some embodiments, metabolites of the compounds disclosed herein are optionally identified either by administration of the compound to a host and analysis of tissue samples from the host or by incubation of the compound with hepatocytes in vitro and analysis of the resulting compound.

[0167] As used herein, a "prodrug" of a compound disclosed herein refers to an agent that is converted in vivo to the compound disclosed herein. Prodrugs are often useful because in some situations they are easier to administer than the parent drug. In some embodiments, the prodrug is bioavailable by oral administration, while the parent drug is not. In some embodiments, the prodrug has improved solubility in a pharmaceutical composition compared to the parent drug. In certain embodiments, the prodrug is chemically converted in vivo upon administration to a biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized to a biologically, pharmaceutically, or therapeutically active form of the compound by one or more steps or processes. To produce a prodrug, a pharmaceutically active compound is modified such that it is regenerated upon in vivo administration. In some embodiments, the prodrug is designed to alter the metabolic stability or transport properties of the drug to mask side effects or toxicity, improve the flavor of the drug, or alter other features or properties of the drug. In some embodiments, the prodrug is designed as a reversible drug derivative for use as a modulator to enhance drug delivery to a site-specific tissue. Knowledge of pharmacokinetic processes and drug metabolism in vivo enables one of ordinary skill in the art to design a prodrug of a compound once the pharmaceutically active compound is known. (See, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pp. 352-401; Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).

[0168] As used herein, "analog" refers to a compound that is structurally and functionally similar to, or mimics the action of, a compound disclosed herein. In some embodiments, the analog mimics the biological action of a compound disclosed herein. In other instances, the analog mimics the physical action of a compound disclosed herein.

[0169] As used herein, "pharmaceutically acceptable salt" refers to a salt of a compound disclosed herein that has no persistent adverse effects on the overall health of the subject being treated, does not inhibit the biological activity or properties of the compound, and is relatively non-toxic. In some embodiments, "pharmaceutically acceptable salts" include salts with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids. Salts with inorganic bases include, for example, alkali metals such as sodium or potassium, alkaline earth metals such as calcium, magnesium or aluminum, and ammonia. Salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine. Salts with inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Salts with basic amino acids include, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid.

[0170] As used herein, "mental disorder" refers to a disorder that affects mood, thinking, behavior, or combinations thereof. In some embodiments, mental disorders include clinical depression, anxiety disorders, anhedonia, or anergia. In some embodiments, the aforementioned mental disorders are psychotic disorders.

[0171] As used herein, "Parkinson's disease" refers to a disease of the brain that affects motor function. Prominent symptoms of Parkinson's disease include (i) tremors in the hands, arms, legs, jaw or head, (ii) stiffness in the limbs and trunk, (iii) slowness of movement, and (iv) impairment of balance and coordination functions.

[0172] It should be understood that references to pharmaceutically acceptable salts include solvated forms. In some embodiments, the solvate contains either a stoichiometric or non-stoichiometric amount of solvent and is formed during the crystallization process using a pharmaceutically acceptable solvent such as water or ethanol. A hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in both solvated and unsolvated forms, as well as in solvated forms.

[0173] The methods and formulations described herein also include the use of N-oxides (where appropriate) of the compounds described herein, or pharmaceutically acceptable salts, as well as active metabolites of these compounds having the same type of activity.

[0174] As used herein, the terms "individual", "subject" and "patient" mean any mammal. In some embodiments, the aforementioned mammal is a human. In some embodiments, the aforementioned mammal is non-human. None of the terms require or are limited to situations characterized by the supervision (e.g., continuous or intermittent) of a healthcare provider (e.g., a physician, registered nurse, clinical nurse, physician assistant, office staff or hospice staff).

[0175] "Binder" provides adhesiveness, and examples thereof include alginic acid and its salts, carboxymethyl cellulose, methyl cellulose (e.g., Methocel (registered trademark)), hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel (registered trademark)), ethyl cellulose (e.g., Ethocel (registered trademark)), and cellulose derivatives such as microcrystalline cellulose (e.g., Avicel (registered trademark)), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharic acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sucrose (e.g., Dipac (registered trademark)), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab (registered trademark)), and sugars such as lactose, natural or synthetic rubbers such as acacia, tragacanth, and ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone (e.g., Polyvidone (registered trademark) CL, Kollidon (registered trademark) CL, Polyplasdone (registered trademark) XL-10), larch arabinogalactan, Veegum (registered trademark), polyethylene glycol, wax, sodium alginate, and the like are included.

[0176] "Carrier" or "carrier material" includes excipients commonly used in pharmaceuticals and should be selected based on compatibility with the compounds disclosed herein, such as trapidil and compounds of additional therapeutic agents, and the release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizing agents, stabilizers, lubricants, wetting agents, diluents, etc. "Pharmaceutically compatible carrier materials" include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose composites, sugars sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, etc. See, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0177] "Dispersant" and / or "viscosity modifier" includes substances that control the diffusion and homogeneity of the drug by means of a liquid medium or a granulation method or a formulation method. In some embodiments, these agents also promote the effectiveness of the coating or corrosion matrix. Exemplary diffusion promoters / dispersants include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and carbohydrate-based dispersants such as hydroxypropylcellulose (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), microcrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide), and poloxamines (e.g., Tetronic 908® (also known as Poloxamine 908®), a tetrafunctional block copolymer resulting from the successive addition of propylene oxide and ethylene oxide to ethylenediamine, BASF Corporation, Parsippany, N.J.)) polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polyethylene glycol (for example, polyethylene glycol may have a molecular weight from about 300 to about 6000, from about 3350 to about 4000, or from about 7000 to about 5400), sodium carboxymethyl cellulose, methyl cellulose, polysorbate 80, sodium alginate, gums such as tragacanth gum, gum arabic, guar gum, xanthan gum including xanthan, sugars, cellulose-based such as sodium carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), alginates, chitosan, and combinations thereof. Plasticizers such as cellulose or triethyl cellulose may also be used as dispersants. Dispersants particularly useful in liposome dispersions and self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol and isopropyl myristate.

[0178] Combinations of one or more corrosion accelerators with one or more diffusion accelerators may also be used in the compositions of the present invention.

[0179] The term "diluent" refers to a chemical compound used to dilute a compound of interest prior to delivery. A diluent may also be used to stabilize a compound because it can provide a more stable environment. (pH control or maintenance is also possible) Salts dissolved in a buffer, including but not limited to phosphate buffered saline, are utilized as diluents in the art. In certain embodiments, the diluent increases the bulk of the composition to facilitate compression or creates sufficient bulk for homogeneous mixing for filling of capsules. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®, calcium hydrogen phosphate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium phosphate, anhydrous lactose, spray-dried lactose, pregelatinized starch, compression sugars such as Di-Pac® (Amstar), mannitol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, powdered sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, mannitol, sodium chloride, inositol, bentonite, and the like.

[0180] The term "disintegrate" includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluids. A "disintegration agent or disintegrant" promotes the decomposition or disintegration of a substance. Examples of disintegrants include starches, such as natural starches like corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolates such as Promogel® or Explotab®; celluloses such as wood products, methylcellulose, such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®; crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, such as methylcellulose, croscarmellose, or crosslinked cellulose; crosslinked starches such as crosslinked sodium starch glycolate; crosslinked polymers such as crospovidone, which is crosslinked polyvinylpyrrolidone; alginates such as alginic acid or salts of alginic acid such as sodium alginate; clays (magnesium aluminum silicate) such as Veegum® HV; agar; guar; locust bean; karaya; pectin; or gums such as tragacanth; sodium starch glycolate; bentonite; natural sponges; surfactants; resins such as cation exchange resins; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate combined with starch, and the like.

[0181] "Drug absorption" or "absorption" typically refers to the process of movement of a drug across a barrier from the site of administration of the drug, e.g., from the gastrointestinal tract to the portal vein or lymphatic system, to the blood vessels or site of action.

[0182] "Enteric coating" is a substance that remains substantially intact in the stomach but dissolves and releases the drug in the small intestine or colon. Generally, enteric coatings prevent release in the low pH environment of the stomach but ionize at a higher pH, typically a pH of 6 - 7, and thus contain a polymeric material that dissolves sufficiently in the small intestine or colon to release the active agent there.

[0183] "Corrosion promoter" includes substances that control the erosion of certain substances in gastrointestinal fluids. Corrosion promoters are generally known to those skilled in the art. Exemplary corrosion promoters include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[0184] "Filling agents" include compounds such as lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrate, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol.

[0185] "Flavoring agents" and / or "sweetening agents" useful in the formulations described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, butterscotch, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cyclamic acid salt, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sorbitol, sucralose, sorbitol, swiss cream, tagatose, tangelo, thaumatin, tutti frutti, vanilla, walnut, watermelon, Japanese quince, wintergreen, xylitol, or combinations of these flavor components, for example, anise - menthol, cherry - anise, cinnamon - orange, cherry - cinnamon, chocolate - mint, honey - lemon, lemon - lime, lemon - mint, menthol - eucalyptus, orange - cream, vanilla - mint, and mixtures thereof are included.

[0186] "Lubricant" and "lubricating agent" are compounds that prevent, reduce, or inhibit the adhesion or friction of substances. Exemplary lubricants include, for example, hydrocarbons such as stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, mineral oil, or hydrogenated vegetable oils such as hydrogenated soybean oil (Sterotex®), higher fatty acids and their alkali metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, glycerol, talc, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG-4000) or methoxypolyethylene glycol, such as Carbowax®, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica, such as Syloid®, Cab-O-Sil®, starch such as corn starch, silicone oil, surfactants, and the like.

[0187] "Measurable serum concentration" or "measurable plasma concentration" typically describes the concentration of a therapeutic agent in serum or plasma measured in mg, μg, or ng per 1 mL, 1 dL, or 1 L of serum absorbed into the bloodstream after administration. When used herein, measurable plasma concentration is typically measured in ng / ml or μg / ml.

[0188] "Pharmacodynamics" refers to the factors that determine the biological response observed relative to the concentration of a drug at the site of action.

[0189] "Pharmacokinetics" refers to the factors that determine the achievement and maintenance of an appropriate concentration of a drug at the site of action.

[0190] A "plasticizer" is a compound used to soften microencapsulation materials or film coatings and make them less brittle. Suitable plasticizers include, for example, polyethylene glycols such as PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, triethyl cellulose, and triacetin. In some embodiments, the plasticizer may also function as a dispersant or wetting agent.

[0191] "Solubilizers" include compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium docusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrin, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycocholate, transcutol, propylene glycol, and dimethyl isosorbide.

[0192] "Stabilizers" include compounds such as any antioxidant, buffer, acid, preservative, etc.

[0193] As used herein, "steady state" refers to the situation where the amount of drug administered is equal to the amount of drug excreted within one dosing interval that results in a plateau or constant plasma drug exposure.

[0194] The "suspending agent" includes polyvinylpyrrolidone, for example, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol, for example, polyethylene glycol having a molecular weight of about 300 to about 6000, about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethyl cellulose, methyl cellulose, hydroxy-propylmethyl cellulose acetate stearate, polysorbate 80, hydroxyethyl cellulose, sodium alginate, gums, for example, tragacanth gum, acacia gum, guar gum, xanthan such as xanthan gum, sugars, cellulose-based, for example, sodium carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, etc., polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, etc.

[0195] The "surfactant" includes sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate monooleate polysorbate, poloxamer, bile salts, glycerin monostearate, copolymers of ethylene oxide and propylene oxide, for example, compounds such as Pluronic® (BASF). Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, for example, polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers, for example, octoxynol 10, octoxynol 40. In some embodiments, the surfactant is included to enhance physical stability or for other purposes.

[0196] Examples of the "viscosity enhancer" include, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, and combinations thereof.

[0197] Examples of the "wetting agent" include compounds such as oleic acid, glycerin monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, Tween80, vitamin E TPGS, ammonium salts, and the like.

Example

[0198] IV. Example The following examples are included for illustrative purposes only and are not intended to limit the scope of the present invention.

[0199] Example 1: Single-cell deconvolution of the action of tropidyl in the substantia nigra pars compacta of rats with Parkinson's disease demonstrates the regulation of neuronal expression of dopamine 1 receptor Male Sprague Dawley rats (n = 25) were made parkinsonian by unilateral administration of 6-hydroxydopamine (“6-OHDA”) into the medial forebrain bundle. After a 2-week recovery from surgery, the rats were divided into three groups and received either 1) levodopa (6 mg / kg) / benserazide (15 mg / kg) and vehicle (BID) (n = 5), 2) levodopa (6 mg / kg) / benserazide (15 mg / kg) and tropidyl (7.5 mg / kg, BID) (n = 10), or 3) levodopa (6 mg / kg) / benserazide (15 mg / kg) and tropidyl (15 mg / kg, BID) (n = 10) by intraperitoneal administration daily for 2 weeks. On day 14, the rats were sacrificed after the final drug administration, and the striatum ipsilateral to the lesion was collected. RNA was extracted from the tissue bulk. Preparation steps were completed to perform RNA-seq on an Illumina sequencer. Samples were sequenced, and an average of approximately 28 million reads per sample were obtained. After the quality control step, the reads of each sample were aligned to the mouse genome (using STAR), counted (using HTseq), and differential expression was calculated (using DESeq2).

[0200] The results of RNA-seq of the tissue body were computationally deconvolved into predictive effects on individual cell types using an algorithm developed in recent years (Frishberg et al., Nature Methods 2019) and single-cell RNA-seq reference data from the mouse striatum (Gokce et al., Cell Reports 2016). By deconvolving the tissue body data into 11 cell types (including neurons expressing dopamine receptor 1 or dopamine receptor 2, astrocytes, oligodendrocytes, immune cells, and vascular cells), we evaluated which cell types had gene expression changes due to trapidil. The only cell type expression significantly activated by trapidil was neurons expressing dopamine receptor 1 (Figure 1). Such a change in the expression of neurons expressing dopamine receptor 1 is consistent with dopamine agonists that activate dopamine receptor 1 (Gerfen et al., Science 1990). Since trapidil is not an activator or inhibitor of dopamine receptors, this finding is surprising (Example 2).

[0201] Since cognitive impairment in Parkinson's disease may be due to defects in dopaminergic signaling, trapidil may be therapeutically useful.

[0202] Example 2: Trapidil does not activate, inhibit, or modulate dopamine receptors In cell-based pharmacological assays, trapidil was tested at relevant physiological concentrations (up to 20 μM) for dopamine receptors (D1, D2s, D3, D4, and D5). No significant effects (threshold set at 50% activation or 50% inhibition) were observed at any of the four concentrations used (Figure 2).

[0203] Example 3: Initial dosing levels of trapidil for non-human primate studies Efficacy tests often generate data that is impossible to interpret due to inappropriate dosing. The human plasma PK profile and rat plasma PK profile of SB-0107 can be obtained, but the dose-exposure relationship of trapidil in non-human primates cannot be obtained. The plasma levels of trapidil during oral dosing were characterized at four different doses of 3, 10, 15, and 20 mg / kg in non-human primates with Parkinson's disease lesioned by MPTP. Blood was collected before and after drug compound administration (10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours) for analysis. The calculated pharmacokinetic parameters are shown in Table 1. Finally, oral doses of 10 mg / kg and 15 mg / kg were used in the efficacy test (Example 4).

[0204]

Table 1

[0205] Example 4: Efficacy of Trapidil in Treating Cognitive Dysfunction in a Non-Human Primate Model Lesioned by Long-Term Low-Dose MPTP To test the in vivo efficacy of trapidil in treating the cognitive dysfunction of Parkinson's disease in a non-human primate model lesioned by long-term low-dose MPTP, trapidil was administered using the dosage determined from Example 3.

[0206] Animals develop mild cognitive dysfunction due to long-term low-dose toxin MPTP, but do not develop motor dysfunction, so it is possible to evaluate the same areas of cognitive dysfunction observed in patients, including attention, working memory, and executive function. The ability of trapidil to improve cognitive tests with or without using a low dose of levodopa (which has a minimal effect on cognitive function) was tested and compared with a high dose of levodopa (which begins to impair cognitive function).

[0207] Five male non-human primates were used and randomly subjected to eight treatments in a partial Latin square design (Table 2). Prior to the lesion, the animals were pre-trained to complete several cognitive tasks, including the variable delay response (VDR). The VDR is a spatial working memory task in which the NHP is rewarded for remembering the position on the screen after a variable delay period (ranging from 2 to 60 seconds, DP1 - DP5). If the period is short (i.e., DP1, DP2), only an attentional component is required, but if the delay period is long, additional memory components are involved (i.e., D4, D5). This task was specifically selected due to its cognitive domains (spatial working memory and attention), as these tasks are improved by dopamine D1 receptor agonism in a cognitive impairment model, impaired by high-dose levodopa in the model, and cognitive function is impaired in Parkinson's disease patients.

[0208]

Table 2

[0209] After long-term low-dose MPTP, the five primates showed significant deficits in their ability to accurately complete all five VDR tasks at all delay periods (Figure 3), thus demonstrating cognitive deficits in the areas of spatial working memory, executive function, and attention. When the animals were administered levodopa (5 - 20 mg / kg, groups 6 - 8), there was a tendency to complete the VDR test with lower accuracy, especially at the shorter delay periods (DP1 and DP2) (Figure 4).

[0210] Trapidil, at a dose of 10 mg / kg, can significantly improve the response accuracy of VDR in two short delay periods (Figure 5). This means improving cognition in the areas of spatial working memory, executive function, and attention. Furthermore, the response accuracy in the treatment group using a combination of low-dose levodopa (5 mg / kg) and trapidil further shows that trapidil improves the response to the VDR task in short delay periods (Figure 6). Finally, trapidil shows a significant improvement in the correct response in DP1 and DP2, with or without using levodopa (Figure 7). In Figures 5 - 7, the "optimal dose" refers to the best of either 10 mg / kg or 15 mg / kg for each of the 5 primates in terms of the response to treatment with trapidil.

[0211] Furthermore, the improvement in the delay periods DP1 and DP2 using monotherapy with 10 mg / kg of trapidil was investigated in more detail because it had the strongest effect among any of the treatment effects. In particular, it was observed that when using trapidil (10 mg / kg), the total reaction time of the primates (from the stimulus cue to the primate's response) was significantly reduced (Figure 8). This reduction suggests an improvement in motivation and incentive, and in some cases, may correct the associated mental disorder of apathy in Parkinson's disease. Apathy in Parkinson's disease has been shown to be highly correlated with cognitive impairment in Parkinson's disease, and apathy is also a predictor of potential cognitive decline. The degree of reduction in reaction time is along the maximum reduction in reaction time by any dose of levodopa, which is a known drug with an anti-apathy effect. However, the primates not only completed the task faster with trapidil but also did so in a more accurate manner than with levodopa (Figure 7).

[0212] Example 5: Efficacy of Trapidil in the Treatment of Cognitive Impairment in a Mouse Model of Pimozide-Induced Schizophrenia Short-term administration of phencyclidine (PCP) is an established model of schizophrenia in rodents for assessing various types of deficits, including cognition. This is a common model for evaluating potential pharmacological treatments for schizophrenia. Mice and rats exhibit cognitive deficits that can be detected using various behavioral evaluations, including the spontaneous alternation test in the Y-maze, which is an assessment of the cognitive ability of working memory.

[0213] In the dose-setting study, C57BL / 6J mice were divided into several treatment groups (Table 3). Short-term administration of PCP (7.5 mg / kg, IP) induced deficits in working memory, as detected by a decrease in the percentage of spontaneous alternation behavior (Figure 9A). Oral administration of trapidil was able to correct the deficits observed in the percentage of spontaneous alternation behavior induced by several different doses of PCP. These results were consistent with clozapine (2.5 mg / kg, IP), an atypical antipsychotic used as a positive control. Also, to evaluate confounding factors, the total number of entries into the Y-maze was catalogued. No significant differences were present in the number of entries compared to the PCP group, so such confounding factors were not detected (Figure 9B).

[0214]

Table 3

[0215] Example 6. Treatment of Dementia with Trapidil A patient diagnosed with dementia is administered a therapeutically effective dose of trapidil, a derivative of trapidil, a metabolite of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharmaceutically acceptable salt of trapidil. In some embodiments, the therapeutically effective dose of trapidil, a metabolite of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharmaceutically acceptable salt of trapidil is 200 milligrams or less, administered three times a day.

[0216] In some embodiments, the patient is also diagnosed with Parkinson's disease. In this example, the dementia is not caused by Parkinson's disease. In some embodiments, to treat Parkinson's disease, the patient is also administered a therapeutically effective dose of a dopamine precursor (e.g., levodopa) or a dopamine agonist, with or without the use of adjunctive therapy (e.g., carbidopa). In some embodiments, when administered in combination with a dose of tropidyl, a derivative of tropidyl, a metabolite of tropidyl, a prodrug of tropidyl, an analog of tropidyl, or a pharmaceutically acceptable salt of tropidyl, the dose of levodopa is a preclinical dose.

[0217] In some embodiments, the patient is also diagnosed with schizophrenia. In some embodiments, to treat schizophrenia, the patient is also administered a therapeutically effective dose of an antipsychotic (e.g., aripiprazole). In some embodiments, when administered in combination with a dose of tropidyl, a derivative of tropidyl, a metabolite of tropidyl, a prodrug of tropidyl, an analog of tropidyl, or a pharmaceutically acceptable salt of tropidyl, the dose of aripiprazole is a preclinical dose.

[0218] Example 7. Treatment of Apathy with Tropidyl A patient diagnosed with apathy is administered a therapeutically effective dose of tropidyl, a derivative of tropidyl, a metabolite of tropidyl, a prodrug of tropidyl, an analog of tropidyl, or a pharmaceutically acceptable salt of tropidyl. In some embodiments, the therapeutically effective dose of tropidyl, a metabolite of tropidyl, a prodrug of tropidyl, an analog of tropidyl, or a pharmaceutically acceptable salt of tropidyl is 200 milligrams or less, administered three times a day.

[0219] In some embodiments, the patient is also diagnosed with Parkinson's disease. In this example, the lethargy is not caused by Parkinson's disease. In some embodiments, to treat Parkinson's disease, the patient is administered a therapeutically effective dose of a dopamine precursor (e.g., levodopa) or a dopamine agonist, with or without the use of adjunctive therapy (e.g., carbidopa). In some embodiments, when administered in combination with a dose of tropidyl, a derivative of tropidyl, a metabolite of tropidyl, a prodrug of tropidyl, an analog of tropidyl, or a pharmaceutically acceptable salt of tropidyl, the dose of levodopa is a preclinical dose.

[0220] In some embodiments, the patient is also diagnosed with schizophrenia. In some embodiments, to treat schizophrenia, the patient is also administered a therapeutically effective dose of an antipsychotic drug (e.g., aripiprazole). In some embodiments, when administered in combination with tropidyl, a derivative of tropidyl, a metabolite of tropidyl, a prodrug of tropidyl, an analog of tropidyl, or a pharmaceutically acceptable salt of tropidyl, the dose of aripiprazole is a preclinical dose.

[0221] Example 8. Treatment or prevention of drug-induced cognitive deficits in Parkinson's disease patients In Parkinson's disease patients, cognitive deficits are caused or exacerbated by the administration of clinical doses of levodopa and / or carbidopa for the treatment of Parkinson's disease. To treat the cognitive deficits, the patient is administered a therapeutically effective amount of tropidyl, a derivative of tropidyl, a metabolite of tropidyl, a prodrug of tropidyl, an analog of tropidyl, or a pharmaceutically acceptable salt of tropidyl. After administration of a therapeutically effective amount of a derivative of tropidyl, a metabolite of tropidyl, a prodrug of tropidyl, an analog of tropidyl, or a pharmaceutically acceptable salt of tropidyl, the patient's cognitive function improves.

[0222] In some embodiments, trapidil, a prodrug of trapidil, an analog of trapidil, or a pharmaceutically acceptable salt of trapidil enhances the therapeutic action of levodopa and / or carbidopa for the treatment of Parkinson's disease in a patient, such that over time, lower (sub-clinical) dosages of levodopa and / or carbidopa are needed to treat Parkinson's disease. Thus, administration of trapidil, a prodrug of trapidil, an analog of trapidil, or a pharmaceutically acceptable salt of trapidil is effective in preventing cognitive deficits in a patient that are caused by or exacerbated by administering clinical dosages of levodopa and / or carbidopa.

Claims

1. A method for treating or preventing a cognitive impairment or mental illness of a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts.

2. The method further comprises (a) an antidepressant, (b) an antipsychotic, (c) an anxiolytic, (d) a dopamine precursor, (e) a dopamine agonist, or (f) any combination of (a) to (e) administering to the subject a further therapeutic agent comprising, the method according to claim 1.

3. The dopamine precursor is levodopa, the method according to claim 2.

4. The cognitive impairment or the mental illness is not caused by Parkinson's disease, the method according to claim 1.

5. The mental illness includes anxiety disorder, depression, asthenia, anhedonia, or psychosis, the method according to claim 1.

6. The cognitive impairment includes cognitive dysfunction, the method according to claim 1.

7. The cognitive dysfunction includes mild cognitive impairment or dementia, the method according to claim 6.

8. Dementia includes Alzheimer's disease, senile dementia, or Lewy body dementia, the method according to claim 7.

9. The cognitive dysfunction includes defects in attention, working memory, executive function, visuospatial function, or memory, or any combination thereof, the method according to claim 6.

10. The cognitive dysfunction is mental dullness, dull conversation, difficulty in word finding, or any combination thereof, the method according to claim 6.

11. The trapidil is N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine, the method according to claim 1.

12. The derivatives of trapidil are AR12455 【Chemical 1】 , AR12456 【Chemical 2】 , AR12460 【Chemical Formula 3】 , AR12463 【Chemical Formula 4】 , AR12464 【Chemical Formula 5】 , AR12465 【Chemical Formula 6】 , AR12565 【Chemical Formula 7】 , or 5-piperidino-7-(N-(n-amyl)-N-(β-hydroxyethyl)-amino)-s-triazolo(1,5-a)pyrimidine) 【Chemical Formula 8】 comprising, the method according to claim 1.

13. The metabolites of trapidil are desethyl-trapidil, 5-piperidin-4'-olyl-7-[N-pentyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, 5-piperidin-4'-olyl-7-[N-pent-4'-olyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, a hydroxy derivative or a ketopentyl derivative, piperidinol or piperidinone, TP-1 【Chemical Formula 9】 or TP-2 【Chemical 10】 The method according to claim 1, comprising the same.

14. The method according to claim 1, wherein the pharmaceutically acceptable salt comprises a salt with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid.

15. The method according to claim 1, wherein the trapidil, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt is administered orally, intravenously, or subcutaneously.

16. The method according to claim 2, wherein the trapidil, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt, and the further therapeutic agent are administered simultaneously.

17. The method according to claim 2, wherein the trapidil, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt, and the further therapeutic agent are administered sequentially.

18. The method according to claim 1, wherein the trapidil, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt treats or prevents the cognitive impairment or the mental disorder of the subject by at least partially activating neurons expressing dopamine 1 receptors in the subject.

19. The method according to claim 1, wherein the therapeutically effective dose comprises about 200 milligrams or less.

20. A combination for administration for use in a treatment method for treating or preventing a cognitive impairment or a mental disorder of a subject in need thereof, the combination for administration comprising (a) trapidil, its derivative, metabolite, prodrug, analog, or pharmaceutically acceptable salt, and (b) a further therapeutic agent, comprising (i) an antidepressant, (ii) an antipsychotic, (iii) an anxiolytic, (iv) a dopamine precursor, (v) a dopamine agonist, or (vi) a further therapeutic agent comprising any combination of (i) to (v) A combination of administrations, comprising a combination of therapeutic agents.

21. The combination of administrations according to claim 20, wherein the cognitive impairment or the mental disorder is not caused by Parkinson's disease.

22. The combination of administrations according to claim 20, wherein the mental disorder includes anxiety disorder, depression, anergia, anhedonia, or psychosis.

23. The combination of administrations according to claim 20, wherein the cognitive impairment includes cognitive dysfunction.

24. The combination of administrations according to claim 23, wherein the cognitive dysfunction is mild cognitive impairment or dementia.

25. The combination of administrations according to claim 24, wherein the dementia includes Alzheimer's disease, senile dementia, or Lewy body dementia.

26. The combination of administrations according to claim 24, wherein the cognitive dysfunction includes defects in attention, working memory, executive function, visuospatial function, or memory, or any combination thereof.

27. The combination of administrations according to claim 24, wherein the cognitive dysfunction is slowness of thinking, slowness of conversation, difficulty in word finding, or any combination thereof.

28. The combination of administrations according to claim 20, wherein the dopamine precursor is levodopa.

29. The combination of administrations according to claim 20, wherein the tropidyl is N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine.

30. The derivative of tropidyl is AR12455 【Chemical 11】 , AR12456 【Chemical Formula 12】 , AR12460 【Chemical Formula 13】 , AR12463 【Chemical 14】 , AR12464 【Chemical Formula 15】 , AR12465 【Chemical 16】 , AR12565 【Chemical 17】 , or 5-piperidino-7-(N-(n-amyl)-N-(β-hydroxyethyl)-amino)-s-triazolo(1,5-a)pyrimidine) 【Chemical 18】 The combination of administrations according to claim 20, comprising.

31. The metabolite of tropidyl is desethyl-tropidyl, 5-piperidine-4'-oril-7-[N-pentyl-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, 5-piperidine-4'-oril-7-[N-pent-4-oril-N-(β-hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine, a hydroxy derivative or a ketopentyl derivative, piperidinol or piperidinone, TP-1 【Chemical 19】 or TP-2 【Chemical 20】 The combination of administrations according to claim 20, comprising.

32. The pharmaceutically acceptable salt of trapidil includes salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, oxalic acid, malonic acid, or tartaric acid, and the combination of administrations according to claim 20.

33. The trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts are administered orally, intravenously, or subcutaneously, and the combination of administrations according to claim 20.

34. The additional therapeutic agent is administered orally, intravenously, or subcutaneously, and the combination of administrations according to claim 20.

35. The trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts, and the additional therapeutic agent are administered simultaneously, and the combination of administrations according to claim 20.

36. The trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts, and the additional therapeutic agent are administered sequentially, and the combination of administrations according to claim 20.

37. The combination of administrations according to claim 20 further includes at least one pharmaceutically acceptable excipient, carrier, or diluent.

38. The dosage of the trapidil, its derivatives, metabolites, prodrugs, analogs, or pharmaceutically acceptable salts present in the combination of therapeutic agents is about 200 milligrams or less, and the combination of administrations according to claim 20.

Images