Compositions and methods for treating synucleinopathies

Abstract

Methods and compositions for treating synucleinopathies are provided. The method comprises administering an effective daily dose of a 5HT3-antagonist, preferably ondansetron hydrochloride dihydrate, in combination with a therapeutically effective daily dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine.

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 477,187, filed on March 27, 2017 and U.S. Provisional Patent Application No. 62 / 528,228, filed on July 3, 2017, the disclosures of which are hereby incorporated by reference in their entirety.

[0002] Field of the Invention The present invention relates to the treatment of synucleinopathies, i.e., neurodegenerative disorders of the human central nervous system, particularly to the field of treatment of neurotoxic processes caused by oligomer formation and aggregation of alpha-synuclein.

[0003] Object of the Invention The present invention relates to novel combinations, compositions and methods for treating synucleinopathies, comprising a combination of a serotonin receptor subtype 3 antagonist (a "5HT3-antagonist") and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine.

[0004] Definitions - "CNS": Central Nervous System. - "IR": Immediate release of the active ingredient from the composition. - "ER": Sustained release of the active ingredient from the composition. - "GI": Gastrointestinal. - "AE": Adverse effect. - "SNCA": Synuclein-alpha or alpha-synuclein. - "MSA": Multiple System Atrophy. - "PD": Parkinson's Disease. - "LBD": Lewy Body Dementia. - "AD": Alzheimer's Disease. - "Synucleinopathy": A disease characterized by abnormal accumulation, processing, and propagation of alpha-synuclein in the brain. That is, alpha-synuclein deposits in the central nervous system, peripheral nervous system, and autonomic nervous system. Synucleinopathy (also called alpha-synucleinopathy) is a neurodegenerative disease including, but not limited to, Parkinson's disease, Lewy body dementia (LBD) or dementia with Lewy bodies (DLB), Alzheimer's disease, Lewy body variant of AD, multiple system atrophy, neurodegeneration with brain iron accumulation, and Parkinsonian disorders associated with glucocerebrosidase (GBA) mutations. - "TTS": Transdermal therapeutic system. - "Effective daily dose of 5HT3 antagonist": As used herein, this phrase refers to the dose of the 5HT3 antagonist that is at least the same as the dose for preventing or treating nausea and vomiting in pediatric or adult patients undergoing cancer chemotherapy according to the current protocol for such treatment. The daily dose is usually 1 μg to 300 mg. - "6-Propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine": A chiral compound available as a racemate, chemically (R,S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, as the (R)-stereoisomer, chemically (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine ("dexpramipexole", INN), and as the (S)-stereoisomer, chemically (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine. R-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine ( "pramipexole", INN). These three chemical substances are basic substances that can be isolated as their acid addition salts and solvates respectively. Pramipexole dihydrochloride monohydrate is also known as USAN "pramipexole hydrochloride". As used herein ,"6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol- 2-amine" refers, unless otherwise specified, to a member selected from the group consisting of pramipexole, its racemate, and pramipe xole / dexpramipexole mixtures, a general term used herein. - "(R) / (S)-mixture": This term refers to a physical mixture of dextropramipexole / pramipexole used as an active ingredient according to the present invention . - "(S)-enantiomer": With respect to the dose (per day or per unit form) of 6-propylamino-4,5,6,7-tetrahydro -1,3-benzothiazol-2-amine, this term as used herein refers to the (S) -stereoisomer contained in said dose, which is the main cause of the dopamine action offset by 5HT3-antagon ists in said 6-propylamino-4,5,6,7 -tetrahydro-1,3-benzothiazol-2-amine. More specifically, the S-enantiomer refers to the S- -stereoisomer present as a racemate or a pharmaceutically acceptable salt thereof in order to distinguish it from prami pexole used alone, and similarly, to the pramipexole or a pharmaceutically acceptable salt thereof present as the (S)-constituent substance in the (R) / (S)-mixture, as used herein . - 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole -2-amine", "(R)-6-propylamino-4,5,6,7-tetrahydro-1, 3-Benzothiazol-2-amine", "Dexpramipexole", "Pramipexole "(S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzo[b]pyridine" Thiazol-2-amine", "(S)-enantiomer", "racemic" and "(R) The term "(S)-mixture" refers to the free base and pharma- ceutical Relative dosages (per day or per unit form) including acceptable salts are: It is given in doses equivalent to xol dihydrochloride monohydrate. - "Active pramipexole dose / unit form" or "Active (S)-enantiomer Dose / unit form: 0.125mg to 42mg of pramipexole dihydrochloride monohydrate Pramipexole or a pharma- ceutically acceptable salt thereof, or (S)-enantiomer Dose per unit form of an antimer or a pharma- ceutically acceptable salt thereof. As described above and as used herein, "pramipexole" and "(S)-enantiomer" are used interchangeably herein. The term "(S)-enantiomer" generally refers to the same chemical entity, whereas the term "(S)-enantiomer" generally refers to the same chemical entity. It is used to describe racemic and mixture compositions. [Background technology]

[0005] 140 amino acids encoded by the SNCA (synuclein-alpha) gene Alpha-synuclein, a protein composed of especially in the cortex, hippocampus, substantia nigra and cerebellum (where SNCA contributes to the regulation of neurotransmitter release). In the neuron terminals in (the process of), it is mainly found and enters the blood (Marques and Outeiro, 2012), and is packaged into exosomes of CNS origin ( Shi et al., 2014).

[0006] Under normal circumstances, this soluble protein is thought to form a stable folded tetramer that resists aggregation. However, in certain pathological conditions, for unknown reasons, alpha -synuclein oligomerizes and aggregates (with the formation of fibrils). At some point in this abnormal pathway, it also passes through the peripheral circulation and migrates into exosomes, where toxic synucle in species are thought to be formed.

[0007] The oligomerization and aggregation of abnormal alpha-synuclein are thought to be the cause of synucleinopathies, especially Parkinson's disease (PD), Lewy body dementia (LBD), Parkinsonian disorders associated with glucocerebrosidase (GBA) mutations, multiple system atrophy (MSA), some forms of Alzheimer's disease, and several other disorders collectively referred to as "synucleinopathies". Alpha- synuclein is an abundant ubiquitous protein in the brain and is claimed to play a central role in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease, and other neurodegenerative disorders (Kim et al., 2004).

[0008] An abnormal ratio of monomeric and oligomeric synuclein species in plasma exosomes of patients has been proposed to be a prominent feature in the diagnosis of synucleinopathies.

[0009] PD was first reported in 1817 by James Parkinson, a ​Parkinson's disease (PD) is a common neurodegenerative disorder of the central nervous system (CNS). It is characterized by three main clinical symptoms: resting tremor, bradykinesia, and muscle rigidity. In addition, postural instability and various neurobehavioral and learning disabilities can occur. In the United States alone, more than one million individuals are estimated to be suffering from this relentless progressive disorder. Moreover, the prevalence of PD continues to increase with the general aging of the American population. The symptoms of Parkinson's disease are currently thought to largely reflect the progressive loss of dopaminergic neurons within the substantia nigra pars compacta. The cause of this degenerative process remains poorly understood, but abnormal misprocessing of alpha-synuclein into neurotoxic species is currently thought to be involved.

[0010] Lewy body dementia (LBD) is one of the most common types of progressive dementia. Central features of LBD include progressive cognitive decline, visual hallucinations, and Parkinsonian motor symptoms such as bradykinesia, gait difficulty, and muscle rigidity. Some cases may also be associated with depression. The symptoms of LBD are presumably caused by the selective loss of neurons, a result of misprocessing of synuclein, and are associated with the accumulation of Lewy bodies, spherical accumulations of synuclein within many degenerating neurons. Researchers do not know why alpha-synuclein accumulates in Lewy bodies or how synuclein species may cause the symptoms of LBD. Although the development of LBD is considered a marker for PD, LBD has also been observed in up to 60% of both sporadic and familial cases of Alzheimer's disease (AD) (Al-Mansoor et al., 2013). ​(Year). Therefore, the aggregation of α-synuclein is strongly associated as an important step in the development of neurodegenerative diseases (Al-Mansoor et al., 2013).

[0011] Parkinson's disease (PD) or brainstem-predominant Lewy body disease (LBD), and dementia with Lewy bodies (DLB ) are the two most frequent α-synucleinopathies, which are progressive multisystem neurodegenerative disorders associated with the widespread presence of α-synuclein deposited in the central nervous system, peripheral nervous system, and autonomic nervous system (Jellinger KA, 2008). According to reports, both are frequently associated with Alzheimer-type pathologies, and there is a considerable clinical and pathological overlap between PD (with or without dementia) and DLB (or LBD) corresponding to Braak LB stages 5 and 6 (Jellinger KA, 2008). Dementia is often not correlated with the progression stage of the LB pathology but may also be associated with the accompanying Alzheimer's disease lesions or mixed pathologies (Jellinger KA, 2008a ).

[0012] Alzheimer's disease (AD) has been reported to be characterized by the deposition of β-amyloid peptide, phosphorylation of tau protein (3- and 4-repeat tau), and α-synuclein (aSyn) deposition (Jellinger KA, 2008b). Lewy body diseases (LBD) such as sporadic Parkinson's disease (PD) and dementia with Lewy bodies (DLB) show aSyn positive depositions in neurons, neurites, glia, and presynaptic terminals, while frontotemporal dementia is tau positive and tau negative, ubiquitin and and TDP-43-positive neurons and glial inclusions are present (Jellinger KA, 2008b). The main proteins that can occur in different distribution patterns in the same brain The intermolecular interactions between are associated with different phenotypes and mixed pathologies, such as AD with aSyn pathology in the brainstem and amygdala , PD and DLB with AD lesions, and frontotemporal dementia associated with depositions of various mixtures, while others are characterized by other lesions absent and are characterized by one major pathology (e.g., tangle-predominant dementia, pure idiopathic PD, brainstem-predominant LBD) (Jellinger KA, 2008b). MSA with orthostatic hypotension is the current term for the neurological disorder that was previously called Shy-Drager syndrome

[0013] It is a progressive disorder of the central and autonomic nervous systems, characterized by orthostatic hypotension (an excessive drop in blood pressure when standing up) that causes dizziness or fainting. Multiple system atrophy can occur without orthostatic hypotension, but instead, there is urinary tract involvement (urgency / incontinence). Neurologists classify this disorder into three types: a Parkinsonian type that includes symptoms of Parkinson's disease such as slowness of movement, muscle rigidity, and tremors ; a cerebellar type that causes problems with coordination and speech; and a combined type that includes symptoms of both parkinsonism and cerebellar insufficiency . Problems due to urinary incontinence, constipation, and sexual dysfunction in men occur early in the course of the disease . Other symptoms include general weakness, double vision or other visual disturbances , breathing and swallowing difficulties, sleep disorders, and decreased sweating. This disease has common points with other diseases, so an accurate diagnosis may take several years .

[0014] ​​​Mutations in the glucocerebrosidase gene (GBA) can lead to Gaucher disease, an autosomal recessive genetic disorder. A variety of lines of evidence suggest that mutant GBA may be a risk factor for Parkinson's disease. GBA mutations are currently thought to be the single greatest risk factor for the development of idiopathic PD. Clinically, imaging, and pharmacologically, GBA PD is nearly identical to idiopathic PD (O’Regan et al., 2017). The molecular mechanisms by which this increases the risk of PD in GBA mutation carriers are not fully understood, but it has been shown to be involved in the accumulation of synuclein (Soria et al., 2017). Several other disorders, although at a lower frequency, are also considered synucleinopathies. These include Hallervorden–Spatz syndrome, neuroaxonal dystrophy, and some cases of traumatic brain injury. In cases of Hallervorden–Spatz syndrome, symptoms include parkinsonism, dystonia, dysphagia / dysarthria, limb contractures / rigidity, dementia, and spasticity. Currently, much is thought to be centered on the processes that lead to the aggregation of synuclein, which may be central to the neuronal injury and destruction that occurs in these synucleinopathy disorders. The mechanisms of aggregation in these synucleinopathies remain uncertain. Current evidence suggests that the conversion of the alpha-helical structure to a beta-pleated conformation, and subsequent oligomer formation, may be pathogenic precursors to the fibrillation and aggregation of synuclein. (O’Regan et al., 2017). In GBA mutation carriers, the molecular mechanisms by which this leads to an increased risk of PD are not fully understood, but it has been shown to be involved in the accumulation of synuclein (Soria et al., 2017). (Soria et al., 2017).

[0015] These include Hallervorden–Spatz syndrome, neuroaxonal dystrophy, and some cases of traumatic brain injury. In cases of Hallervorden–Spatz syndrome, symptoms include parkinsonism, dystonia, dysphagia / dysarthria, limb contractures / rigidity, dementia, and spasticity.

[0016] Currently, much is thought to be centered on the processes that lead to the aggregation of synuclein, which may be central to the neuronal injury and destruction that occurs in these synucleinopathy disorders.

[0017] The mechanisms of aggregation in these synucleinopathies remain uncertain. Current evidence suggests that the conversion of the alpha-helical structure to a beta-pleated conformation, and subsequent oligomer formation, may be pathogenic precursors to the fibrillation and aggregation of synuclein. ​​​suggests something. These features are similar to abnormal processing of the prion protein Prion-like protein, which can also be highly neurotoxic. Phosphorylation of alpha-synuclein at serine-129 residue has been implicated as a factor (Chen et al., 2016). According to these authors, the prion form of alpha-synuclein may be a cause, in particular, of multiple system atrophy. Prions are small proteins that can also misfold, form oligomers, aggregate and be transmitted to other cells. The results in the brain are widespread and a transmissible neurotoxic process.

[0018] Therefore, inhibiting the initial misfolding, oligomer formation and aggregation of synuclein may be beneficial in delaying or even halting the progression of synucleinopathy disorders.

[0019] As described above, alpha-synuclein is readily excreted into the extracellular space and has been identified in cerebrospinal fluid, blood, urine and saliva (Marques and Outeiro, 2012). The mechanism of alpha-synuclein excretion is not fully understood, but studies have demonstrated that at least a fraction of alpha-synuclein is excreted into exosomes, which are endocytosis-derived membrane vesicles of 40 - 100 nm (reviewed in Shi et al., 2014). The ratio of monomer to oligomer species of alpha-synuclein in plasma exosomes derived from the CNS correlates with disease severity (Shi et al., 2014), thus suggesting that alpha-synuclein species in plasma exosomes may be useful for monitoring disease progression. Correlates with the severity of functional impairment in the cross-section of samples from patients (Stuendl et al., 20 16).

[0020] Based on the above, drugs that normalize the ratio of monomeric and oligomeric alpha-synuclein species in plasma exosomes derived from the brain should delay or even halt the processes associated with synucleinopathy-related neurodegeneration.

[0021] Various compositions for the treatment of PD-related synucleinopathy and related disorders have been proposed that target the initial oligomerization and aggregation of alpha-synuclein. The processes discovered are mainly involved in cellular and animal models of prion and alpha-synuclein-induced neurodegeneration (Prusiner et al., 2015). Unfortunately, these models have not been validated and are currently all regarded as uncertain predictors of effects in humans. Nevertheless, these models continue to be widely used in the absence of better discovered techniques.

[0022] Pharmaceuticals currently proposed for consideration include, for example, low-molecular-weight substances such as pramipexole and its analogs.

[0023] Pramipexole is a synthetic aminothiazole derivative described in U.S. Patent No. 4,886,812, the content of which is hereby incorporated by reference in its entirety. It is approved for the treatment of motor symptoms of Parkinson's disease (PD) at a dose in the range of 0.375 mg / day to 4.5 mg / day, administered in three equally divided doses (package insert for Mirapex (registered trademark), July 2016), a non-ergoline class ​​​​​​​​​ is a dopamine agonist (Schneider CS and Mierau J, 1987). Pramipexole is available as immediate-release tablets containing 0.125 mg, 0.25 mg, 0.5 mg, 1 m g and 1.5 mg of pramipexole dihydrochloride monohydrate, and sustained-release tablets containing 4.5 mg of pramipexole dihydrochloride monohydrate as.

[0024] Pramipexole is widely used for the relief of symptoms of Parkinson's disease, but its potential as a disease-modifying agent has made pramipexole the subject of considerable research .

[0025] According to reports, pramipexole reduces the formation of oligomers of synuclein in vitro (Ono et al., 2013). Related studies have shown that pramipexole inhibits the toxic effects of rotenone on dopaminergic neurons in a mouse PD model while reducing immunoreactivity to alpha -synuclein, and in addition, pramipexole has been shown to reduce the in vitro oligomer formation of human wild-type alpha-synuclein by H2O2 and cytochrome c (Inden et al., 2009). Pramipe xole has also been observed to inhibit the aggregation of alpha-synuclein in SH-SY5Y cells, a human neuroblastoma (Kakimura et al., 2009). Importantly, it has been found that the relative expression of alpha-synuclein in serum exosomes decreases during prami pexole treatment in PD-type patients (Luo et al., 2016). xole in

[0026] ​​In addition, pramipexole has begun to be reported to exhibit a neuroprotective effect in various in vitro cell models and in vivo animal models of PD. The mechanism by which these neuroprotective effects may occur remains uncertain. Unfortunately, the protective effect of pramipexole in animal models is generally small and requires higher doses than would be considered safe and tolerable for human administration. Therefore, it is hardly surprising that pramipexole at doses approved for the treatment of PD motor symptoms was unable to demonstrate neuroprotective (i.e., disease-modifying) activity in a randomized comparative clinical trial involving 535 PD patients (Schapira AH, 2013)

[0027] A (R) / (S) mixture comprising a therapeutically effective amount of dextropramipexole or a pharmaceutically acceptable salt and solvate thereof, and a therapeutically effective amount of pramipexole or a pharmaceutically acceptable salt and solvate thereof, which is useful for the treatment of PD, is disclosed in U.S. Patent Application Publication No. 2008 / 0014259, the contents of which are hereby incorporated by reference in their entirety

[0028] According to U.S. Patent Application Publication No. 2008 / 0014259, both enantiomers can confer a neuroprotective effect by virtue of their ability to accumulate in cells of the brain, spinal cord, and mitochondria, which exerts a positive effect on nerve function independent of the dopamine agonist activity of pramipexole. In particular, the document discloses the composition as a neuroprotective agent and, in combination with up to 5000 mg of dextropramipexole, about ​​​​​​​​​​​A therapeutically effective dose of pramipexole ranging from 0.0625 mg to about 6 mg is proposed. However, this document is a reference to the same article in the almost identical International Publication No. WO 2008 / 113003. As confirmed by the applicant, the dopaminergic effects of pramipexole They emphasize the adverse effects of sedatives and tend to privilege low doses of pramipexole. The contents of this patent are incorporated herein by reference in their entirety.

[0029] No. 2013 / 013362, the contents of which are incorporated by reference herein in their entirety. According to No. 116292, dexpramipexole or a pharma- ceutically acceptable salt thereof and and solvates may be used to slow the progression of neuronal degeneration and / or to improve neuronal function. It works by preventing cell death. No further mention of the possible noteworthy effects of appears in the document.

[0030] Dexpramipexole and its pharma- ceutically acceptable salts, in particular Dexpramipexole The synthesis of benzoyl dihydrochloride monohydrate is described in U.S. Patent Application Publication No. 2012 / 0253047. No. 6,399,633, the contents of which are incorporated herein by reference in their entirety.

[0031] Unfortunately, there are limitations associated with administering pramipexole to patients with synucleinopathy. , pramipexo at potentially higher neuroprotective doses predicted by multiple animal models. First, its putative beneficial effects in synuclein-related neurotoxicity may limit its use. The mechanisms explaining this effect continue to elude complete understanding. Second, animal model studies The magnitude of the effect in [context not provided] tends to be small and occurs only at relatively high drug dosages. Both situations are also seen in the above reports on pramipexole-induced changes in synuclein in exosomes in PD patients, which are associated with administration of the maximum approved dosage of pramipexole of 4.5 mg / day (Mirapex package insert; revised July 2016). In the report by Luo et al. (2016), treatment of Parkinson's patients with approved therapeutic dosages of pramipexole significantly decreased the relative expression of alpha-synuclein (compared to pre-treatment values), but the magnitude of the effect was small. Higher dosages of pramipexole may be more effective, but side effects such as vomiting and severe nausea make the use of higher dosages impossible. For example, Corrigan et al. (2000) reported that a dosage of pramipexole of 5 mg / day, which is only slightly higher than the maximum recommended dosage of 4.5 mg / day (FDA-approved package insert for pramipexole), caused nausea in 76% of patients and vomiting in 39% of patients. Furthermore, 36% of patients were unable to complete the study due to presumably unacceptable GI adverse events.

[0032] U.S. Patent Application Publication No. 2014 / 0024644 discloses a series of indole (or indazole)-carboxylic acid esters or amides, azabicycloalkyl, oxabicycloalkyl or oxaazabicycloalkyl group esters or N-substituted forms that impart 5HT3-antagonist activity and are thus useful for the treatment of a number of diseases treatable by inhibition of the 5HT3 receptor. In particular, this document discloses 5HT3-antagonists.

[0033] ​​​​​​​​​​​ A series of disorders that can be treated with nicotine include vomiting, migraine, drug abuse and dependence, neurodegeneration and mental disorders (including Parkinson's disease), gastrointestinal disorders, immune disorders, atherosclerosis and inflammation are listed. This document also discloses the possible combinations of the 5HT3-antagonist with a number of active agents including pramipexole without any further information.

[0034] In a different therapeutic context, the inventors have disclosed the possibility of increasing the dose of an acetylcholinesterase inhibitor by combining it with an antiemetic containing a 5TH3-antagonist in US Patent Application Publication No. 2011 / 0071135.

[0035] In conclusion, despite a very large number of existing documents, particularly Willner et al., 1994, Corrigan et al., 2000 and the disclosures of US Patent Application Publication Nos. 2008 / 0014259, US Patent Application Publication No. 2011 / 0071135 and US Patent Application Publication No. 2014 / 00 24644, no one has successfully and safely increased the efficacy of pramipexole, and pramipexole currently provides only minimal activity in the treatment of Parkinson's disease.

[0036] Thus, the problem of providing a safe, long-term and effective treatment for patients suffering from synucleinopathy with pramipexole remains unsolved.

Summary of the Invention

[0037] The present invention increases the therapeutic concentration range of pramipexole and provides, in patients with PD-like disorders, to delay onset and / or progression of symptoms to a clinically significant extent and to enable the full neuroprotective effect thereof safely to such an extent as to safely enable its full neuroprotective effect

[0038] A 5HT3-antagonist such as ondansetron or a pharmaceutically acceptable salt or solvate thereof has been found herein to have the potential to modify synucleinopathy of pramipexole by reducing or even suppressing the GI side effects of high-dose pramipexole to afford

[0039] 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in combination with a 5HT3-antagonist such as ondansetron or a pharmaceutically acceptable salt or solvate thereof acts by normalizing the otherwise abnormal ratio of monomeric and oligomeric synuclein species in plasma exosomes derived from the CNS as also found herein

[0040] A 5HT3-receptor antagonist, also simply referred to as a 5HT3-antagonist when used in a defined combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine makes it possible to treat patients suffering from synucleinopathy with minimal adverse effects while maintaining a therapeutically effective daily dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof as further found herein herein

[0041] In addition, said 5HT3-antagonist is useful for alleviating the motor symptoms of Parkinson's disease​​ Higher than the maximum recommended daily dose of pramipexole and potentially much higher, the (S)- enantiomer dose, including a daily dose of 6-propylamino-4,5,6,7-tetrahydro- 1,3-benzothiazol-2-amine, has been found to enable safe administration. Therefore, an improvement in the condition of patients suffering from synucleinopathy, particularly PD, Lewy body disease, Parkinson's disorders and MSA related to glucocerebrosidase (GBA) mutations has been achieved.

[0042] In particular, the protective effect of said 5HT3-antagonist has been found to enable increasing the maximum recommended and approved dose by at least 4-fold, up to 10-fold or even more, the daily dose of pramipexole.

[0043] A combination of ondansetron or a pharmaceutically acceptable salt or solvate thereof as component (a), such as a 5HT3-antagonist, and 6-propylamino-4,5,6, 7-tetrahydro-1,3-benzothiazol-2-amine as component (b) acts in a way that results in normalization of the abnormal ratio of monomeric and oligomeric synuclein species in plasma exosomes derived from the CNS of patients suffering from synucleinopathy.

[0044] Accordingly, the present invention provides a combination of a 5HT3-antagonist and 6-propylamino- 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine that acts in a way that tends to normalize the abnormal ratio of monomeric and oligomeric synuclein species in plasma exosomes derived from the CNS for use in the treatment of synucleinopathy. -4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine. ​​​​​​

[0045] The present invention provides a method for treating a patient suffering from synucleinopathy, the method comprising treating the patient with an effective daily dose of a 5HT3-antagonist in combination with a therapeutically effective daily dose of 6-propylamino -4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine. Also provided is a method comprising such treatment.

[0046] According to certain embodiments, the 5HT3-antagonist and the 6-propylamino -4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine are each formulated into a pharmaceutical composition admixed with a pharmaceutical carrier and are administered separately to a patient in need of treatment with the combination.

[0047] According to another embodiment, the 5HT3-antagonist and 6-propylamino-4 ,5,6,7-tetrahydro-1,3-benzothiazol-2-amine are mixed together and formulated into a pharmaceutical composition (fixed-dose combination) admixed with a pharmaceutical carrier for administration to a patient in need of such treatment.

[0048] Any 5HT3-antagonist that has been shown to be effective, preferably approved, for preventing or treating nausea and vomiting following cancer chemotherapy can be used in combination at a dose equal to or higher than the dose of 6-propylamino-4,5,6,7-tetrahydro -1,3-benzothiazol-2-amine currently commonly used for treating neurodegenerative diseases, or at a dose currently used for treating neurodegenerative diseases. Long-term use of this combination may result in the 6-propylamino-4,5,6,7-tetrahydro Induced by the S-enantiomer present in -1,3-benzothiazol-2-amine By simultaneously reducing or even eliminating the harmful effects Improve the symptoms of synucleinopathy.

[0049] As described in the definition, 6-propylamino-4,5,6,7-tetrahydro-1 ,3-benzothiazol-2-amine represents the active ingredient independently of its salts or solvates.

[0050] In this specification, the phrase "its salts or solvates" and the cited 5HT3-antagonist Or 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothia The phrase "its salts or solvates" with respect to any of zole-2-amine indicates that any of the salts of the cited 5HT3-antagonist or the said 6-propylamino-4,5,6,7- Tetrahydro-1,3-benzothiazol-2-amine can be solvated with a solvent, generally , water.

[0051] According to the present invention, preferably, the 5HT3-antagonist used is one that is approved for preventing or treating nausea and vomiting after cancer chemotherapy. In fact, Surprisingly, known 5HT3 receptor inhibitors for preventing or treating nausea, vomiting and diarrhea induced by chemotherapeutic agents, especially when administered at high doses, do not affect their effectiveness in the treatment of said synucleinopathy and also prevent the gastrointestinal side effects of the S-enantiomer contained in the said 6-propylamino- 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine. 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine.

[0052] The severity of the disease, as well as both 5HT3-antagonists and 6-propylamino-4,5, 6,7-tetrahydro-1,3-benzothiazol-2-amine, had been two lines of products in their respective use with their own efficacy for over 10 years. Nevertheless, by combining an effective amount of a 5HT3-antagonist with an effective amount of 6-propylamino-4,5,6,7-tetra hydro-1,3-benzothiazol-2-amine, it has been found that the therapeutic dose of the said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, particularly the dose of the S-enantiomer contained in the dose of pramipexole dihydrochloride monohydrate, can be increased, thereby safely improving the condition of patients suffering from synucleinopathy. No one has ever considered this before, and this finding is surprising considering the seemingly simple solution discovered by the inventors of the present invention.

[0053] More specifically, in the case of pramipexole dihydrochloride monohydrate, the combination of a 5HT3-antagonist with the said pramipexole dihydrochloride monohydrate enables the administration of a therapeutically effective dose of pramipexole that significantly exceeds the maximum recommended dose (4.5 mg / day) of pramipexole dihydrochloride monohydrate for the treatment of PD symptoms in many patients, thereby increasing its effectiveness in the treatment of patients

[0054] suffering from synucleinopathy such as PD, including an unexpected and substantial For a patient in need thereof, administering a therapeutically effective daily dose of a 5HT3 antagonist in combination with a therapeutically effective daily dose of 6- propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is provided.

[0055] According to the above definition, the phrase "therapeutically effective daily dose of pramipexole" refers to the at least approved daily dose of pramipexole dihydrochloride monohydrate for the treatment of Parkinson's disease, i.e., the equivalent (i.e., equal) effective daily dose of pramipexole for pediatric or adult patients. However, the "therapeutically effective daily dose of pramipexole" as defined above in combination with a 5HT3 antagonist not only allows for the safe administration of the approved daily dose of pramipexole dihydrochloride monohydrate for the treatment of Parkinson's disease without any adverse effects, but also allows for the safe administration of a higher or even higher daily dose of pramipexole dihydrochloride monohydrate, which is described in detail herein. For Parkinson's disease treatment, the "therapeutically effective daily dose of pramipexole" is defined as the approved daily dose of pramipexole dihydrochloride monohydrate, which is equivalent to the effective daily dose of pramipexole for pediatric or adult patients. However, in combination with a 5HT3 antagonist, the "therapeutically effective daily dose of pramipexole" allows for the safe administration of the approved daily dose of pramipexole dihydrochloride monohydrate without any adverse effects and also allows for the safe administration of a higher or even higher daily dose of pramipexole dihydrochloride monohydrate, as described in detail herein. refers to the effective daily dose of pramipexole for pediatric or adult patients that is equivalent (i.e., equal) to at least the approved daily dose of pramipexole dihydrochloride monohydrate for the treatment of Parkinson's disease. However, the "therapeutically effective daily dose of pramipexole" as defined above in combination with a 5HT3 antagonist not only allows for the safe administration of the approved daily dose of pramipexole dihydrochloride monohydrate for the treatment of Parkinson's disease without any adverse effects, but also allows for the safe administration of a higher or even higher daily dose of pramipexole dihydrochloride monohydrate, which is described in detail herein. However, the "therapeutically effective daily dose of pramipexole" as defined above in combination with a 5HT3 antagonist not only allows for the safe administration of the approved daily dose of pramipexole dihydrochloride monohydrate for the treatment of Parkinson's disease without any adverse effects, but also allows for the safe administration of a higher or even higher daily dose of pramipexole dihydrochloride monohydrate, which is described in detail herein. "therapeutically effective daily dose of pramipexole" as defined above in combination with a 5HT3 antagonist not only allows for the safe administration of the approved daily dose of pramipexole dihydrochloride monohydrate for the treatment of Parkinson's disease without any adverse effects, but also allows for the safe administration of a higher or even higher daily dose of pramipexole dihydrochloride monohydrate, which is described in detail herein. For the treatment of Parkinson's disease, the "therapeutically effective daily dose of pramipexole" allows for the safe administration of the approved daily dose of pramipexole dihydrochloride monohydrate without any adverse effects and also allows for the safe administration of a higher or even higher daily dose of pramipexole dihydrochloride monohydrate, as described in detail herein. higher than or even higher than the approved dose, and the safe administration of a higher daily dose of pramipexole dihydrochloride monohydrate is described in detail herein. is described in detail herein.

[0056] Generally, according to the present invention, the "effective daily dose of pramipexole" is 0.375 mg to 42 mg. In the case of the (R) / (S) mixture, the "effective daily dose of the S-enantiomer" is 0.375 mg to 42 mg, and applies to the daily dose of the (S)-enantiomer present in and thus administered with the (R) / (S) mixture. For the (R) / (S) mixture, the "effective daily dose of the S-enantiomer" is 0.375 mg to 42 mg, which applies to the daily dose of the (S)-enantiomer present in and thus administered with the (R) / (S) mixture. The "effective daily dose of pramipexole" is generally 0.375 mg to 42 mg according to the present invention. In the case of the (R) / (S) mixture, the "effective daily dose of the S-enantiomer" is 0.375 mg to 42 mg, and applies to the daily dose of the (S)-enantiomer present in and thus administered with the (R) / (S) mixture. applies to the daily dose of the (S)-enantiomer present in and thus administered with the (R) / (S) mixture.

[0057] Pharmaceutically acceptable salts of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine are also included in the present invention. Examples of these salts include hydrochloride -amine are also included in the present invention. Examples of these salts include hydrochloride , mineral acids such as hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or formic acid, acetic acid , propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, apple acid, tartaric acid, citric acid, carbonic acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid and the like, and acid addition salts with organic acids. The solvent substance is generally water .

[0058] According to certain embodiments, the present invention has been shown to be effective for the prevention or treatment of postoperative nausea and vomiting, or for the prevention of nausea and vomiting induced by chemotherapy or, alternatively, approved, a 5HT3 - antagonist of at least the same dose as that for pediatric or adult doses of component (a) and 6 - propylamino - 4,5, 6,7 - tetrahydro - 1,3 - benzothiazol - 2 - amine of effective dose of component (b), to provide a pharmaceutical combination .

[0059] According to another embodiment, the present invention is also mixed with a pharmaceutical carrier or vehicle and administered in combination with 6 - propylamino - 4,5,6,7 - tetrahydro - 1,3 - benzothiazol - 2 - amine in a pharmaceutical composition, a 5HT 3 - antagonist provided in a pharmaceutical composition containing the 5HT3 - antagonist as an active ingredient and mixed with a pharmaceutical carrier or vehicle for administration. According to this embodiment, the 5HT3 - antagonist is mixed with a pharmaceutical carrier for use in preventing or curing the adverse effects of pramipexole in the treatment of Parkinson's disease, and for the prevention or treatment of postoperative nausea and vomiting, or for the prevention of nausea and vomiting induced by chemotherapy

[0060] According to this embodiment, the 5HT3 - antagonist is mixed with a pharmaceutical carrier for use in preventing or curing the adverse effects of pramipexole in the treatment of Parkinson's disease, and for the prevention or treatment of postoperative nausea and vomiting, or for the prevention of nausea and vomiting induced by chemotherapy body, and for the prevention or treatment of postoperative nausea and vomiting, or for the prevention of nausea and vomiting induced by chemotherapy Approved for the prevention of nausea and vomiting, pediatric or adult dosage / unit form and in an amount / unit form of at least the same height, present in the composition. 5HT in the composition The amount / unit dose of the 3 - antagonist is from 1 μg to 300 mg.

[0061] According to the same embodiment, the 6 - propylamino - 4,5,6,7 - tetrahydro - 1 ,3 - benzothiazole - 2 - amine is in an amount / unit form of 0.125 mg to 3000 mg and is present in the composition. The 6 - propylamino - 4,5,6,7 - tetrahydro -1,3 - benzothiazole - 2 - amine, when it is pramipexole or a pharmaceutically acceptable salt thereof, the pramipexole or its pharmaceutically acceptable salt is present in the composition in an amount equivalent to 0.125 mg to 42 mg, 0.125 mg to 20 mg, 1.5 mg to 20 m g of pramipexole dihydrochloride monohydrate.

[0062] In particular, according to this embodiment, the present invention (a) Azasetron hydrochloride in an amount / unit form equivalent to 5 mg to 10 mg, mixed with a pharmaceutical carrier or medium and its pharmaceutically acceptable salts and solvates, in particular its hydrochloride; Dolasetron in an amount / unit form equivalent to 1.5 mg to 200 mg of dolasetron mesylate and its pharmaceutically acceptable salts and solvates, in particular, its mesylate monohydrate; Granisetron in an amount / unit form equivalent to 0.5 mg to 2 mg of granisetron base and its pharmaceutically acceptable salts and solvates, in particular, its hydrochloride; Ondansetron in an amount / unit form equivalent to 2 mg to 32 mg, usually 2 mg to 16 mg of ondansetron base Ondansetron and its pharmaceutically acceptable salts and solvates, in particular, the dihydrochloride dihydrate ; paroxetine base in an amount equivalent to 0.1 mg to 2 mg, usually 0.25 mg to 0.5 mg of paroxetine and its pharmaceutically acceptable salts and solvates, in particular its hydrochloride; ramelteon in an amount equivalent to 2.5 μg to 100 mcg, usually 5 μg to 20 μg of ramelteon hydrochloride and its pharmaceutically acceptable salts and solvates, in particular its hydrochloride; and tropisetron in an amount equivalent to 2.5 mg to 5 mg of tropisetron base of tropisetron and its pharmaceutically acceptable salts and solvates, in particular its hydrochloride, comprising a 5HT3 antagonist selected from the group consisting of as an active ingredient a pharmaceutical composition in unit dosage form; and (b) Pramipexole or a pharmaceutically acceptable salt thereof mixed with a pharmaceutical carrier or vehicle as an active ingredient, in an amount per unit form equivalent to 0.125 mg to 42 mg, or 0.125 mg to 20 mg of pramipexole dihydrochloride monohydrate, of pramipexole or a pharmaceutically acceptable salt or solvate thereof in a pharmaceutical composition; provides a pharmaceutical combination. In particular, for use at the start of treatment, said pramipexole or a pharmaceutically acceptable salt or solvate thereof of component (b) is preferably present in said composition in an amount equivalent to 1.5 mg to

[0063] 20 mg, 1.6 mg to 20 mg, 1.625 mg to 20 mg, 3 mg to 20 mg, 4. more than 5 mg to 20 mg, more than 6 mg to 20 mg, or 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate.

[0064] ​​For administration of pramipexole at higher dosages, the pramipexole is present in the composition in an amount equivalent to a wider range selected from the group consisting of greater than 1.5 mg to 45 mg, 1.6 mg to 45 mg, 1.625 mg to 45 mg, 3 mg to 45 mg, greater than 4.5 mg to 45 mg, greater than 6 mg to 45 mg, and 6.5 mg to 4 5 mg. Preferably, the pramipexole is present in the composition in an amount equivalent to a wider range selected from the group consisting of greater than 1.5 mg to 42 mg, 1.6 mg to 42 mg, 1.625 mg to 42 mg, 3 mg to 42 mg, greater than 4.5 mg to 42 mg, 6 mg greater than to 42 mg, and 6.5 mg to 42 mg. It may be present in an equivalent amount.

[0065] In the combination, the pramipexole or a pharmaceutically acceptable salt or solvate thereof is mixed in the pharmaceutical composition with a pharmaceutical carrier or vehicle for immediate release formulations and may be present in an amount per unit form equivalent to 1.6 mg to 10 mg or 6.5 mg to 10 mg of pramipexole dihydrochloride monohydrate. For administration of pramipexole at higher dosages, the amount per IR unit form is equivalent to 1.6 mg to 21 mg or 6.5 mg to 21 mg of pramipexole dihydrochloride monohydrate. In the combination, the pramipexole or a pharmaceutically acceptable salt or solvate thereof is also mixed in the pharmaceutical composition with a pharmaceutical carrier or vehicle for sustained release formulations and may be present in an amount per unit form equivalent to greater than 4.5 mg to 20 mg or greater than 6 mg to 20 mg of pramipexole dihydrochloride. For higher dosages of pramipexole

[0066] For administration, the amount per ER unit form is greater than 4.5 mg to 45 mg or 6. It is equivalent to 5 mg to 45 mg of pramipexole dihydrochloride monohydrate. Preferably, the amount per ER unit form is greater than 4.5 mg to 42 mg or 6.5 mg to 42 mg of pramipexole dihydrochloride monohydrate.

[0067] According to this embodiment, the present invention relates to the component (b) in the above pharmaceutical composition of the dose per unit form as described above. The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, in combination with a pharmaceutical carrier or vehicle for the treatment of synucleinopathy, is also mixed with a pharmaceutical carrier or vehicle to provide the above 5HT3-antagonist of component (a) in the above pharmaceutical composition of the dose per unit form.

[0068] According to another aspect of this embodiment, the present invention provides (a) A 5HT3-antagonist contained as an active ingredient in a pharmaceutical composition mixed with a pharmaceutical carrier or vehicle, in an amount of at least the same height as the dose / unit form, for the prevention or treatment of postoperative nausea and vomiting, or for the prevention of nausea and vomiting induced by chemotherapy; and (b) Pramipexole dihydrochloride monohydrate in a pharmaceutical composition mixed with a pharmaceutical carrier or vehicle, in an amount of at least the same height as the dose / unit form, which is approved for the treatment of Parkinson's disease, contained as an active ingredient in a pharmaceutical composition containing pramipexole dihydrochloride monohydrate.

[0069] In the above combination, component (a) is present in the composition in an amount of 1 μg to 300 mg. is present, and pramipexole dihydrochloride monohydrate of component (b) is present in an amount of 0.125 mg to 45 mg or is present in an amount of 1.5 mg to 22.5 mg. Preferably, component (a) is present in the composition in an amount of 1 μg to 300 mg, and pramipexole dihydrochloride monohydrate of component (b) is present in an amount of 0.125 mg to 42 mg or 1.5 mg to 20 mg.

[0070] According to a further embodiment, the present invention is for preventing or curing the harmful effects of 6-propyl amino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt and / or solvate thereof and is shown to be effective for preventing or treating postoperative nausea and vomiting, or for preventing nausea and vomiting induced by chemotherapy when mixed with a pharmaceutical carrier, or is approved, and provides the use of a 5HT3-antagonist in the preparation of a medicament comprising a pharmaceutical composition containing, as an active ingredient, a 5HT3-antagonist in an amount / unit form at least as high as that of a pediatric or adult dose and having at most 6 times said dose. As described above, the amount / unit form of the 5HT3-antagonist is shown to be effective for preventing or treating postoperative nausea and vomiting or for preventing nausea and vomiting induced by chemotherapy, or is approved, and is at least as high as that of a pediatric or adult dose

[0071] and can be at most 6 times said dose. Or according to a further embodiment, the present invention is mixed with a pharmaceutical carrier or vehicle, and as component ( a), for preventing and treating postoperative nausea and vomiting, or for preventing nausea and vomiting induced by chemotherapy and is shown to be effective for preventing or treating postoperative nausea and vomiting, or for preventing nausea and vomiting induced by chemotherapy

[0072] or is approved, and is at least as high as that of a pediatric or adult dose and can be at most 6 times said dose. shown to be effective or approved for the prevention of nausea and vomiting, a 5HT3-antagonist in an amount / unit form at least as high as that of a pediatric or adult dose, and as component (b), a pharmaceutical composition containing 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine in an effective dose / unit form. Provide a fixed-dose formulation containing. The dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine per IR unit form is in the range of 1.5 mg to 1500 mg depending on safety and tolerance (in combination with a 5HT3-antagonist). The above range includes a wider range of doses, including lower doses of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine per IR unit form. The wider range of doses per unit form of the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine can be 0.125 mg to 1500 mg, preferably 1.5 mg to 1500 mg, and preferably 1.6 mg to 1500 mg. The dose of (R) / (S)-mixed 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine per IR unit form is in the range of 50 mg to 1500 mg depending on safety and tolerance (in combination with a 5HT3-antagonist). The above range includes the amount of 0.125 mg to 10 mg of the (S)-enantiomer per IR unit form. For administration of pramipexole at higher doses, is provided.

[0073] per IR unit form in combination with a 5HT3-antagonist is in the range of including lower doses of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine can be included in a wider range of doses The wider range of doses per unit form of the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is 0.125 mg to 1500 mg, preferably 1.5 mg to 1500 mg, preferably

[0074] per IR unit form in combination with a 5HT3-antagonist is in the range of 50 mg to 1500 mg including the amount of 0.125 mg to 10 mg of the (S)-enantiomer per IR unit form. For administration of pramipexole at higher doses, The dosage range is 0.125 mg to 21 mg, preferably 6.5 mg to 21 mg, per IR unit form.

[0075] Generally, when the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothia zole-2-amine is pramipexole dihydrochloride monohydrate, the dosage range is (5 (in combination with an HT3-antagonist)) depending on safety and tolerability, 0.125 mg to 10 mg, preferably 1.5 mg to 10 mg or 6. 5 mg to 10 mg, per IR unit form. For the administration of pramipexole at higher dosages, the dosage range is 0.125 mg to 21 mg, usually 6.5 mg to 21 mg.

[0076] When the 5HT3-antagonist is ondansetron hydrochloride dihydrate, in combination with pramipexole dihydrochloride monohydrate, the dosage of ondansetron per IR unit form is 2 mg to 32 mg, 4 mg to 32 mg, or equivalent to 4 mg to 16 mg of ondansetron base.

[0077] The dosage of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine in ER formulations including transdermal therapeutic systems such as sustained release compositions and transdermal patches is in the range of 3 mg to 3000 mg (in combination with a 5HT3-antagonist), depending on tolerability.

[0078] The (R) / (S) mixture of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine in ER formulations including transdermal therapeutic systems such as sustained release compositions and transdermal patches The dosage / unit form of thiazole-2-amine is, in combination with a 5HT3-antagonist, depending on tolerance, 0.375 mg to 45 mg, or more than 6 mg to 45 mg of pramipexole dihydrochloride monohydrate, preferably, a dosage / unit form of the (S)-enantiomer equivalent to 0.375 mg to 42 mg, or more than 6 mg to 42 mg of pramipexole dihydrochloride monohydrate, and is in the range of 150 mg to 3000 mg, usually 300 mg to 3000 m g of pramipexole dihydrochloride monohydrate. Usually, when the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothia zole-2-amine is pramipexole dihydrochloride monohydrate, the dosage range / ER unit

[0079] form is 3 mg to 20 mg. Advantageously, when the 6-propylamino-4,5,6, 7-tetrahydro-1,3-benzothiazole-2-amine is pramipexole or a pharmaceutically acceptable salt thereof, the said dosage range / ER unit form is more than 4.5 mg to 45 mg, or more than 6 mg to 45 mg, in some cases, more than 4.5 mg to 22. 5 mg, preferably, more than 6 mg to 22.5 mg, or 6.5 mg to 22.5 mg of pramipexole dihydrochloride monohydrate equivalent. Preferably, the said dosage range / ER unit form is more than 4.5 mg to 42 mg, or more than 6 mg to 42 mg, in some cases more than 4.5 mg to 20 mg, preferably, more than 6 mg to 20 mg, or 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate equivalent. When the 5HT3-antagonist is ondansetron, the dosage / ER unit form is in the range of 8 mg to 32 mg.

[0080] ​​​​

[0081] When the 5HT3-antagonist is dolasetron, the dose / unit form in the combination with 6- propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is in the range of 1.5 mg to 200 mg, preferably 2 0 mg to 200 mg (in the case of dolasetron mesylate).

[0082] Generally, in the method (or use) for the treatment of synucleinopathy according to the present invention, 6-propylamino-4,5, 6,7-tetrahydro-1,3-benzothiazol-2-amine, which is mixed with a pharmaceutical carrier or medium and is usually in a pharmaceutical composition, is administered to a patient in need of said treatment at a daily dose of 1.5 mg to 300 0 mg. In practice, said daily dose is - a daily dose of pramipexole equivalent to 1.5 mg to 42 mg of pramipexole dihydrochloride monohydrate; or a pharmaceutically acceptable salt thereof; - a daily dose of a racemate of pramipexole dihydrochloride monohydrate of 3 mg to 84 mg or a pharmaceutically acceptable salt thereof (thus, clearly, including a daily dose of (S)-6-propylamino-4,5, 6,7-tetrahydro-1,3-benzothiazol-2-amine equivalent to 1.5 mg to 42 mg of pramipexole dihydrochloride monohydrate, and a daily dose of (R)-6-propylamino-4,5, 6,7-tetrahydro-1,3-benzothiazol-2-amine equivalent to 1.5 mg to 42 m g of pramipexole dihydrochloride monohydrate); and and - a daily dose of (R) / (S)-enantiomer mixture of 150 mg to 3000 mg including a daily dose of (S)-enantiomer equivalent to 1.5 mg to 42 mg of pramipexole dihydrochloride monohydrate ​​​ The mixture (and thus, clearly, the daily dose is 1.5 mg to 42 mg of pramipexole dihydrochloride monohydrate equivalent (S)-enantiomer dose, and 150 m g to 3000 mg minus (1.5 mg to 42 mg) of pramipexole dihydrochloride monohydrate equivalent (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine dose). It is selected from the group consisting of

[0083] In a method (or use) for the treatment of synucleinopathy according to the present invention, 6 as an (R) / (S)-mixture -propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, which is mixed with a pharmaceutical carrier or vehicle and is usually in a pharmaceutical composition, contains a daily dose of (S)-enantiomer equivalent to 0.375 mg to 45 mg and preferably contains a daily dose of (S)-enantiomer of pramipexole dihydrochloride monohydrate of more than 6 mg to 45 mg, or 6.5 mg to 45 mg, more preferably contains a daily dose of (S)-enantiomer equivalent to 0.375 mg to 42 mg, more than 6 mg to 42 mg, or 6.5 mg to 42 mg of pramipexole dihydrochloride monohydrate, and is administered to a patient in need of said treatment at a daily dose of 1.5 mg to 30 00 mg, or 3.0 mg to 3000 mg. In another embodiment, in a method (or use) for the treatment of synucleinopathy according to the present invention, 6-propylamino-4,5,6,7 -tetrahydro-1,3-benzothiazol-2-amine as an (R) / (S)-mixture is a sustained-release pharmaceutical composition or a transdermal

[0084] composition ​​​​In a transdermal therapeutic system such as a patch, containing a daily dose of (S)-enantiomer equivalent to 0.375 mg to 42 mg, preferably, more than 6 mg to 42 mg, or 6.5 mg to 42 mg of the (S)-enantiomer of pramipexole dihydrochloride monohydrate, and being administered to a patient in need of said treatment at a daily dose of 150 mg to 3000 mg, or 300 mg to 3000 mg. In the method (or use) according to the present invention, 6- propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is administered to said patient in combination with a 5HT3-antagonist. Due to the presence of the 5HT3-antagonist in the combination, advantageously, the range of said daily dose is more than 4.5 mg to 42 mg, preferably, more than 6 mg to 42 mg of the (S)-enantiomer equivalent to pramipexole dihydrochloride monohydrate. According to a particular embodiment, in the method (or use), said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate administered to said patient at a daily dose of more than 4.5 mg to 42 mg, preferably, more than 6 mg to 42 mg, or 6.5 mg to 42 mg. According to this embodiment, in the method (or use), 6-propylamino-4,5,6,7-tetra hydro-1,3-benzothiazol-2-amine is administered to said patient in combination with a 5HT3-antagonist. When the 5HT3-antagonist is ondansetron, said ondansetron is

[0085] administered to said patient at a daily dose of more than 4.5 mg to 42 mg, preferably, more than 6 mg to 42 mg, or 6.5 mg to 42 mg in combination with pramipexole dihydrochloride monohydrate.

[0086] administered to said patient in combination with pramipexole dihydrochloride monohydrate at a daily dose of more than 4.5 mg to 42 mg, preferably, more than 6 mg to 42 mg, or 6.5 mg to 42 mg. administered to the patient as ondansetron hydrochloride dihydrate in a daily dose equivalent to 4 mg to 32 mg of ondansetron base

[0087] When the 5HT3 - antagonist is droperidol, the droperidol is administered to the patient as droperidol mesylate monohydrate in a daily dose of 1.5 mg to 200 mg, preferably an oral dose of 20 mg to 200 mg (in droperidol mesylate).

[0088] In this specification, the range of the dose of pramipexole per unit form includes the effective dose of pramipexole currently used in the treatment of PD, and particularly includes the low dose that can be administered in the case of the initial dose setting of the daily dose of pramipexole. However, according to the present invention, the therapeutically effective usage of pramipexole or its pharmaceutically acceptable salt or solvate in the safe treatment of synucleinopathy including a fixed - dose formulation may be equivalent to more than 4.5 mg / day and more than 6 mg / day (up to 45 mg / day) of pramipexole dihydrochloride monohydrate. Therefore, the present invention provides a dose of pramipexole or its pharmaceutically acceptable salt or solvate per IR unit form equivalent to more than 6 mg to 21 mg of pramipexole dihydrochloride monohydrate, mixed with a pharmaceutical carrier or vehicle; and a dose of pramipexole or its pharmaceutically acceptable salt or solvate per ER unit form equivalent to more than 6 mg to 42 mg of pramipexole dihydrochloride monohydrate

[0089] ​​​​​​​​​​​​Also provided is a new pharmaceutical composition in unit dosage form, comprising an active ingredient selected from the group consisting of

[0090] The present invention relates to a mixture with a pharmaceutical carrier or vehicle - an IR unit form equivalent to more than 6 mg to 22.5 mg of pramipexole dihydrochloride monohydrate per dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof; and and - an ER unit form equivalent to more than 6 mg to 45 mg of pramipexole dihydrochloride monohydrate per dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof Also provided is a new pharmaceutical composition in unit dosage form, comprising an active ingredient selected from the group consisting of

DETAILED DESCRIPTION OF THE INVENTION

[0091] As outlined above, the present invention provides a combination comprising a 5HT3-antagonist of component (a) and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine of component (b), in a fixed-dose formulation, and its use for the treatment of sinuclaropathy in a patient. In particular, the present invention provides - A method for treating a patient suffering from sinuclaropathy, the method comprising treating the patient with a 5HT3-antagonist in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine; - A 5HT3-antagonist for use in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in the treatment of a patient suffering from sinuclaropathy; - 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine for use in combination with a 5HT3-antagonist in the treatment of a patient suffering from sinuclaropathy; - A method for treating a patient suffering from sinuclaropathy, the method comprising treating the patient with a 5HT3-antagonist in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine; - A 5HT3-antagonist for use in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in the treatment of a patient suffering from sinuclaropathy; - A method for treating a patient suffering from sinuclaropathy, the method comprising treating the patient with a 5HT3-antagonist in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine; - A 5HT3-antagonist for use in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in the treatment of a patient suffering from sinuclaropathy; - For use in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in the treatment of a patient suffering from sinuclaropathy, a 5HT3-antagonist; - 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol- Use of a 5HT3 antagonist for the preparation of a medicament for treating synucleinopathy in a patient in need of said treatment in combination with a 2-amine; and - a fixed-dose formulation comprising a pharmaceutical composition in unit dosage form, containing a 5HT3 antagonist as component (a) and 6-propylamino-4 ,5,6,7-tetrahydro-1,3-benzothiazol-2-amine as component (b), mixed with a pharmaceutical carrier or vehicle. Provide.

[0092] 5HT3 antagonist As described above, any 5HT3 antagonist disclosed in the literature can be used in combination with the daily dose of 6-propylamino-4,5,6,7-tetrahydro-1,3- benzothiazol-2-amine as defined above in the present specification.

[0093] Long-term use of this combination reduces or even eliminates the adverse effects induced by pramipexole, such as the (S)-enantiomer in the racemate or (R) / (S)-mixture, delays the progression of synucleinopathy disorders, thereby enabling the use of higher doses and thus more neuroprotective doses of pramipexole.

[0094] The 5HT3 antagonist is usually selected from those shown to be effective or approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of nausea and vomiting induced by chemotherapy.

[0095] The 5HT3 antagonist is preferably 5-methyl-2-[(4-methyl-1H-imidazol-5-yl)methyl] disclosed in U.S. Patent No. 5,360,800 -2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-1-one ( alosetron), and its pharmaceutically acceptable salts and solvates, especially its hydrochloride ; (±)-6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(quinucidinyl)-2H-1,4-benzoxazine-8-carboxamide (azasetron), as disclosed in U.S. Patent No. 4,892,872, and its pharmaceutically acceptable salts and solvates, especially its hydrochloride; [(1S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] 3,5-dichlorobenzoate (bemesetron, CAS : 40796-97-2); (10R)-10-[(2-methyl-1H-imidazol-1-yl)methyl]-5,6,9,10-tetrahydro-4H-pyrido(3,2,1-jk)carbazol-11-one (seroton) as disclosed in U.S. Patent No. 4,939,136, and its pharmaceutically acceptable salts and solvates, especially its hydrochloride monohydrate; (3R)-10-oxo-8-azatricyclo[5.3.1.03,8]undec-5-yl 1H-indole-3-carboxylate (dolasetron) as disclosed in U.S. Patent No. 4,906,755, and its pharmaceutically acceptable salts and solvates, especially its monomethanesulfonate monohydrate; (+)-(R)-8,9-dihydro-10-methyl-7-[(5-methylimidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (fasetron) as disclosed in U.S. Patent No. 5,141,945, and its pharmaceutically acceptable salts and solvates, especially its hydrochloride; ; solvates, especially its hydrochloride monohydrate; ; (3R)-10-oxo-8-azatricyclo[5.3.1.03,8]undec-5-yl 1H-indole-3-carboxylate (dolasetron) as disclosed in U.S. Patent No. 4,906,755, and its pharmaceutically acceptable salts and solvates, especially its monomethanesulfonate monohydrate; ; (+)-(R)-8,9-dihydro-10-methyl-7-[(5-methylimidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (fasetron) as disclosed in U.S. Patent No. 5,141,945, and its pharmaceutically acceptable salts and solvates, especially its hydrochloride; ; (+)-(R)-8,9-dihydro-10-methyl-7-[(5-methylimidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (fasetron) as disclosed in U.S. Patent No. 5,141,945, and its pharmaceutically acceptable salts and solvates, especially its hydrochloride; solvates, especially its hydrochloride; Hydrochloride or maleate; 1-methyl-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-indazole-3-carboxamide (granisetron) disclosed in U.S. Patent No. 4,886,808, as well as its pharmaceutically acceptable salts and solvates, particularly its hydrochloride; 2,3-dihydro-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)-2-oxo-1H-benzimidazole-1-carboxamide (itacetron) disclosed in U.S. Patent No. 5,223 ,511, as well as its pharmaceutically acceptable salts and solvates, particularly its hydrochloride; 1-phenylmethyl-2-(1-piperazinyl)-1H-benzimidazole (lerisetron) disclosed in U.S. Patent No. 5,256,665, as well as its pharmaceutically acceptable salts and solvates, particularly , its hydrochloride; and the transdermal preparation disclosed in U.S. Patent No. 6,1 36,807; 6-fluoro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indol-1-one (lurasetron, CAS 128486- 54-4), as well as its pharmaceutically acceptable salts and solvates, particularly its mesylate (GR87442N); (±)1, 2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (ondansetron) disclosed in U.S. Patent No. 4,695,578, as well as its pharmaceutically acceptable salts and solvates, particularly its hydrochloride dihydrate; (3aS)-2-[(S)-1-azabicyclo[2.2 disclosed in U.S. Patent No. 5,20 2,333; H-pyrido[4,3-b]indol-1-one (lurasetron, CAS 128486- 54-4), as well as its pharmaceutically acceptable salts and solvates, particularly its mesylate (GR87442N); (±)1, 2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (ondansetron) disclosed in U.S. Patent No. 4,695,578, as well as its pharmaceutically acceptable salts and solvates, particularly its hydrochloride dihydrate; (3aS)-2-[(S)-1-azabicyclo[2.2 -yl)methyl]-4H-carbazol-4-one (ondansetron) disclosed in U.S. Patent No. 4,695,578, as well as its pharmaceutically acceptable salts and solvates, particularly its hydrochloride dihydrate; (3aS)-2-[(S)-1-azabicyclo[2.2 -yl)methyl]-4H-carbazol-4-one (ondansetron) disclosed in U.S. Patent No. 4,695,578, as well as its pharmaceutically acceptable salts and solvates, particularly its hydrochloride dihydrate; (3aS)-2-[(S)-1-azabicyclo[2.2 2,333; .2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1 H-benzo[de]isoquinoline (palonosetron), and its pharma- ceutically acceptable derivatives Salts and solvates thereof, particularly the hydrochloride salt; as disclosed in U.S. Pat. No. 5,344,927. 1-Methylindol-3-yl)-[(5R)-4,5,6,7-tetrahydro- 3H-benzimidazol-5-yl]methanone (ramosetron), and its pharmaceutical uses and the acceptable salts and solvates thereof, in particular the fumarate salt thereof; endo-N-(8-methyl-8 -Azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethyl Indole-1-carboxamide (3,3-dimethyl-N-1αH,5αH-tropa 3α-yl-1-indolinecarboxamide, licasetron (CAS117086- 68-7), and pharma- ceutically acceptable salts and solvates thereof, in particular the hydrochlorides thereof; 1H-indole-3-carboxylic acid, as disclosed in Japanese Patent No. 4,789,673 (3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (3-tropanylindole-3-carboxylate, tropisetron), and , in particular the hydrochloride salt thereof; and U.S. Pat. No. 5,531,633. 5-chloro-2,2-dimethyl-N-(8-methyl- 8-Azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-1-benzofuran Ran-7-carboxamide (zatosetron), and its pharma- ceutically acceptable salts, solvates thereof, particularly maleates thereof; The disclosures of all U.S. patents are incorporated herein by reference in their entireties.

[0096] Advantageously, the 5-HT3 antagonist is azasetron and its pharmaceutically acceptable salts and solvates, dolasetron and its pharmaceutically acceptable salts and solvates, granisetron and its pharmaceutically acceptable salts and solvates, ondansetron and its pharmaceutically acceptable salts and solvates, palonosetron and its pharmaceutically acceptable salts and solvates, ramosetron and its pharmaceutically acceptable salts and solvates, and tropisetron and its pharmaceutically acceptable salts and solvates, selected from the group consisting of.

[0097] Examples of pharmaceutically acceptable salts of these advantageous 5-HT3 antagonists include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid, etc. The solvating substance is generally water.

[0098] For the prevention or treatment of postoperative nausea and vomiting, or for the prevention of nausea and vomiting induced by chemotherapy, antagonists of the 5-HT3 receptor, in particular, according to the present invention, are useful. In particular, azasetron hydrochloride commercially available as 10 mg tablets and 10 mg vials for intravenous injection; dolasetron monomethanesulfonate monohydrate (also referred to as dolasetron mesylate) commercially available as tablets with a maximum dose of 200 mg and 12.5 m g / 0.625 ml vials; tablets with a maximum dose of 2.24 mg as Granisetron hydrochloride commercially available in tablets with a maximum dose of 10 mg and as a 2 mg / ml (as ondansetron base) solution in multi-dose vials; ondansetron hydrochloride dihydrate commercially available in 0.56 mg tablets and 0.075 mg / 1.5 ml or 0.25 mg / 5 ml (as palonosetron base) vials; palonosetron hydrochloride commercially available as 0.15 mg / ml for injection and 0.1 mg oral tablets; lamotrigine hydrochloride commercially available as 5.64 mg capsules, 2.256 mg / 2 ml vials for intravenous injection and 5.64 mg vials for intravenous and subcutaneous injection; tropisetron hydrochloride is a particularly advantageous 5HT3-antagonist. commercially available as a 2 mg / ml (as ondansetron base) solution in multi-dose vials ondansetron hydrochloride dihydrate commercially available in 0.56 mg tablets and 0.075 mg / 1.5 ml or 0.25 mg / 5 ml (as palonosetron base) vials palonosetron hydrochloride commercially available as 0.15 mg / ml for injection and 0.1 mg oral tablets lamotrigine hydrochloride commercially available as 5.64 mg capsules, intravenous injection 2.256 mg / 2 ml vials and 5.64 mg vials for intravenous and subcutaneous injection tropisetron hydrochloride commercially available as 5.64 mg capsules, 2.256 mg / 2 ml vials for intravenous injection and 5.64 mg vials for intravenous and subcutaneous injection is a particularly advantageous 5HT3-antagonist.

[0099] According to the present invention, the 5HT3-antagonist is mixed with a pharmaceutical carrier or vehicle and used in a pharmaceutical composition containing the 5HT3-antagonist as an active ingredient in an amount per unit form of 1 μg to 300 mg, and is administered in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in a daily dose of 3 mg to 3000 mg, and particularly, in combination with pramipexole dihydrochloride monohydrate in a daily dose of 0.375 mg to 45 mg, preferably 0.375 mg to 42 mg.

[0100] Thus, for example, an oral pharmaceutical composition according to the present invention administered over a long period in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is administered in a daily dose equivalent to 15 mg to 40 mg of azasetron hydrochloride, 5m ​​​​​​​Azasetron in an amount per unit form equivalent to 10 mg or less of azasetron hydrochloride and its pharmaceutically acceptable salts and solvates; Dolasetron mesylate in an amount per unit form equivalent to a daily dose of 75 mg to 200 mg of dolasetron mesylate and dolasetron in an amount per unit form equivalent thereto, and its pharmaceutically acceptable salts and solvates; Granisetron in an amount per unit form equivalent to a daily dose of 1.5 mg to 8 mg of granisetron base and granisetron in an amount per unit form equivalent to 0.5 mg to 2 mg of granisetron base, and its pharmaceutically acceptable salts and solvates; Ondansetron in an amount per unit form equivalent to a daily dose of 6 mg to 64 mg, usually 6 mg to 32 mg of ondansetron base and ondansetron in an amount per unit form equivalent to 0.5 mg to 16 mg, usually 2 mg to 8 mg of ondansetron base, and its pharmaceutically acceptable salts and solvates; Palonosetron in an amount per unit form equivalent to a daily dose of 0.75 mg to 2 mg of palonosetron base and palonosetron in an amount per unit form equivalent to 0.25 mg to 0.5 mg of palonosetron base, and its pharmaceutically acceptable salts and solvates; Ramosetron hydrochloride in an amount per unit form equivalent to a daily dose of 0.05 mg to 0.2 mg of ramosetron hydrochloride and ramosetron in an amount per unit form equivalent thereto, and its pharmaceutically acceptable salts and solvates; Tropisetron in an amount per unit form equivalent to a daily dose of 7.5 mg to 20 mg of tropisetron base and tropisetron in an amount per unit form equivalent to 2.5 mg to 5 mg of tropisetron base, and its pharmaceutically acceptable salts and solvates, and may contain a 5HT3 antagonist selected

[0101] Preferably, the 5HT3 - antagonist is azasetron salt in a daily dose equivalent to 15 mg to 40 mg, and the amount per unit form equivalent to 5 mg to 10 mg of azasetron hydrochloride; the amount per unit form equivalent to 75 mg to 200 mg of daily dose of dolasetron mesylate, which is administered in a daily dose equivalent to 25 mg to 200 mg of dolasetron mesylate; granisetron hydrochloride in an amount per unit form equivalent to 0.5 mg to 2 mg of granisetron base, which is administered in a daily dose equivalent to 1.5 mg to 16 mg, usually 2 mg to 8 mg; ondansetron hydrochloride dihydrate in an amount equivalent to 0.5 mg to 32 mg, usually 2 mg to 32 mg, 2 mg to 16 mg or 2 mg to 8 mg of ondansetron base, which is administered in a daily dose equivalent to 6 mg to 64 mg, usually 6 mg to 32 mg of ondansetron base; palonosetron hydrochloride in an amount equivalent to 0.25 mg to 0.5 mg of palonosetron base, which is administered in a daily dose equivalent to 0.75 mg to 2 mg of palonosetron base; ramosetron hydrochloride in an amount per unit form equivalent to 0.05 mg to 0.2 mg, which is administered in a daily dose equivalent to 0.05 mg to 0.2 mg; and tropisetron hydrochloride in an amount equivalent to 2.5 mg to 5 mg of tropisetron base, which is administered in a daily dose equivalent to 7.5 mg to 20 mg of tropisetron base, selected from the group consisting of. The composition containing the 5HT3 - antagonist described above is combined with 6 - propylamino - 4, 5,6,7 - tetrahydro - 1,3 - benzothiazol - 2 - amine, and further, the amount per unit form equivalent to 0.125 mg to 3000 mg of the 6 - propylamino - 4,5,6,7 - tetrahydro - 1,3 - benzothiazol - 2 - amine, particularly, ([

[0102] ​​​​​​​​​​​​​​​ As a (R) / (S)-mixture, pramipexole dihydrochloride monohydrate in an amount equivalent to 50 mg to 3000 mg per unit form, and the amount per unit form is 0.125 mg to 4 5 mg, including an amount of the (S)-enantiomer equivalent to 5 mg of pramipexole dihydrochloride monohydrate, as a racemate, in an amount equivalent to 0.25 mg to 90 mg of pramipexole dihydrochloride monohydrate, or as pramipexole or a pharmaceutically acceptable salt thereof, in an amount equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate, a pharmaceutical composition in unit dosage form, which is intended to be administered to a patient suffering from synucleinopathy. Preferably, the amount per unit form is an amount of the (S)-enantiomer equivalent to 0.125 mg to 42 mg of pramipexole dihydrochloride monohydrate, as a racemate, in an amount equivalent to 0.25 mg to 84 mg of pramipexole dihydrochloride monohydrate, or as pramipexole or a pharmaceutically acceptable salt thereof, in an amount equivalent to 0.125 mg to 42 mg of pramipexole dihydrochloride monohydrate. The pharmaceutical composition in unit dosage form containing the 5HT3-antagonist described above is mixed with another active ingredient, particularly in a fixed-dose formulation, with a pharmaceutical carrier or vehicle, and co-formulated with the 5HT3-ant agonist, and may contain 6-propylamino-4,5,6,7-tetrahydro-1, 3-benzothiazol-2-amine. 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2- amine As described in the above definition, 6-propylamino-4,5,6,7-tetrahydro-

[0103] The pharmaceutical composition in unit dosage form containing the 5HT3-antagonist described above is mixed with another active ingredient, particularly in a fixed-dose formulation, with a pharmaceutical carrier or vehicle, and co-formulated with the 5HT3-ant agonist, and may contain 6-propylamino-4,5,6,7-tetrahydro-1, 3-benzothiazol-2-amine. 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-

[0104] amine amine As described in the above definition, 6-propylamino-4,5,6,7-tetrahydro- ​1,3-Benzothiazol-2-amine is - Pramipexole, that is, (S)-6-propylamino-4,5,6,7-tetra hydro-1,3-benzothiazol-2-amine, and pharmaceutically acceptable salts and solvates thereof; - Racemate, that is, (R,S)-6-propylamino-4,5,6,7-tetrahydro -1,3-benzothiazol-2-amine, and pharmaceutically acceptable salts and solvates thereof; and - (S) / (R) mixture, that is, (R)-6-propylamino-4,5,6,7- tetrahydro-1,3-benzothiazol-2-amine and (S)-6-propylamino -4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine mixture ( mixed with a pharmaceutical carrier or medium and usually in a pharmaceutical composition, for example, as described in US Patent Application Publication No. 2 008 / 0014259, a mixture containing a therapeutically effective amount of the (S)-enantiomer) selected from the group consisting of .

[0105] Examples of pharmaceutically acceptable salts or solvates of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, acetic acid, propionic acid, stearic acid, glycolic acid, oxalic acid, succinic acid, lactic acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid , 2-acetoxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethane sulfonic acid (isethionic acid), p-toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-Amino-benzenesulfonic acid (sulfanilic acid), 2,6-naphthalenedisulfonic acid , 1,5-naphthalenedisulfonic acid and pamonic acid (embonic acid) and other inorganic or organic acids. The solvent for solvation is generally water.

[0106] In the case of pramipexole or a pharmaceutically acceptable salt or solvate thereof, the commercially available pramipexole dihydrochloride monohydrate is preferably 6-propylamino-4,5,6 ,7-tetrahydro-1,3-benzothiazol-2-amine. For example, both of them are incorporated herein by reference in their entirety, International Publication No. 2012 / 0140604 and the stable pharmaceutical composition containing pramipexole dihydrochloride monohydrate disclosed in International Publication No. 2008 / 122638, incorporated herein by reference in its entirety and the sustained release composition containing pramipexole dihydrochloride monohydrate disclosed in U.S. Patent No. 8,399,016 incorporated herein by reference in its entirety may be useful for use in combination with a 5HT3-antagonist for the treatment of synucleinopathy.

[0107] The racemate and pramipexole described in U.S. Patent No. 4,886, 812, the contents of which are incorporated herein by reference in their entirety, are each 5HT3-A n antagonist in combination, a useful 6-prop ylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine for the treatment of synucleinopathy .

[0108] (S) / (R)-mixture, i.e., the content of which is incorporated herein by reference in its entirety, disclosed in U.S. Patent Application Publication No. 2008 / 0014259 a therapeutically effective amount (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol -ol-2-amine or a pharmaceutically acceptable salt and solvate thereof, and a therapeutically effective amount of (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol -ol-2-amine or a pharmaceutically acceptable salt and solvate thereof, is also a pharmaceutical composition containing 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine useful for the treatment of synucleinopathy .

[0109] For the treatment of synucleinopathy, in combination with a 5HT3 antagonist as described in the above item "5HT3 antagonist", 6-propylamino- 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is mixed with a pharmaceutical carrier or vehicle and formulated into a pharmaceutical composition containing an amount of said 6-propylamino- 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine equivalent to 0.125 mg to 3000 mg. The composition is administered to a patient in need of said treatment at a daily dose of 0.375 mg to 3000 mg, in combination with a 5HT3 antagonist at a daily dose of 1 μg to 300 mg . . . .

[0110] According to the present invention, 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is preferably - Pramipexole dihydrochloride monohydrate in an amount of 0.125 mg to 45 mg, preferably 0. 125 mg to 42 mg of pramipexole dihydrochloride monohydrate, and the amount per unit form equivalent to that of (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol . -ol Zol-2-amine (INN: Pramipexole) and its pharmaceutically acceptable salts and solvates, in particular its dihydrochloride monohydrate (USAN: Pramipexole hydrochloride); - A dose per unit form equivalent to 0.25 mg to 90 mg of pramipexole dihydrochloride monohydrate (therefore, clearly, a dose per unit form of (S)-6-propylamino-4,5,6,7-tetrahydro-1, 3-benzothiazol-2-amine equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate, and a dose per unit form of (R)-6-propylamino-4, 5,6,7-tetrahydro-1,3-benzothiazol-2-amine equivalent to 0.125 mg to 4 5 mg of pramipexole dihydrochloride monohydrate, and including) preferably, a dose per unit form equivalent to 0.25 mg to 84 mg of pramipexole dihydrochloride monohydrate (therefore, clearly, a dose per unit form of (S)-6-propylamino-4,5,6, 7-tetrahydro-1,3-benzothiazol-2-amine equivalent to 0.125 mg to 42 mg of pramipexole dihydrochloride monohydrate, and a dose per unit form of (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine equivalent to 0.125 mg to 42 mg of pramipexole dihydrochloride monohydrate, and including) of (R,S)-6-propylamino-4,5,6 7-tetrahydro-1,3-benzothiazol-2-amine (racemate) and its pharmaceutically acceptable salts and solvates; and - A (R) / (S) mixture, i.e., a dose per unit form equivalent to 50 mg to 3000 mg, preferably 150 m g to 3000 mg of pramipexole dihydrochloride monohydrate ,7-tetrahydro-1,3-benzothiazol-2-amine (racemate) and its pharmaceutically acceptable salts and solvates; and - A (R) / (S) mixture, i.e., a dose per unit form equivalent to 50 mg to 3000 mg, preferably 150 m g to 3000 mg of pramipexole dihydrochloride monohydrate , the amount per unit form is 0.125 mg to 45 mg of pramipexole dihydrate monohydrate and contains an amount of the (S)-enantiomer equivalent to that of pramipexole dihydrate monohydrate (thus, clearly, the amount per unit form is composed of an amount of the (S)-enantiomer equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate and, from 50 mg, preferably from 150 mg to 3000 mg minus (0.125 mg to 45 mg) of pramipexole dihydrochloride monohydrate equivalent amount per unit form of (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine), preferably 0 .125 mg to 42 mg of pramipexole dihydrochloride monohydrate equivalent amount per unit form (thus, clearly, the amount per unit form is composed of an amount of the (S)-enantiomer equivalent to 0.125 mg to 42 mg of pramipexole dihydrochloride monohydrate and also, from 50 mg, preferably from 150 mg to 3000 mg minus (0.125 mg to 42 mg) of pramipexole dihydrochloride monohydrate equivalent amount per unit form of (R)- 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine), and is selected from the group consisting of pharmaceutical compositions in unit dosage forms containing 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine. In said unit form, the amount of pramipexole per unit form, or the amount of the (S)-enantiomer in the racemate or in the (R) / (S)-mixture is usually more than 1.5 mg to 45 mg, preferably more than 1.5 mg to 42 mg, advantageously more than 4.5 mg to 45 m g.

[0111] g. Preferably, it is more than 4.5 mg to 42 mg, more preferably more than 6 mg to 45 mg, preferably more than 6 mg to 42 mg, even more preferably more than 6.5 mg to 45 mg, preferably more than 6.5 mg to 42 mg, which is equivalent to pramipexole dihydrochloride monohydrate.

[0112] Thus, according to the first embodiment, the present invention provides an appropriate unit form of pramipexole , usually mixed with a pharmaceutical carrier or medium, - Pramipexole dihydrochloride monohydrate of more than 6 mg to 22.5 mg, or 6.5 mg to 22.5 mg, and preferably pramipexole dihydrochloride monohydrate of more than 6 mg to 21 mg, or 6.5 mg to 21 mg, and the dosage of pramipexole or its pharmaceutically acceptable salt or solvate per IR unit form equivalent thereto; and - Pramipexole dihydrochloride monohydrate of more than 6 mg to 45 mg, or 6.5 mg to 45 mg, and preferably pramipexole dihydrochloride monohydrate of more than 6 mg to 42 mg, or 6.5 mg to 42 mg, and the dosage of pramipexole or its pharmaceutically acceptable salt or solvate per ER unit form equivalent thereto amount to provide a pharmaceutical composition in unit dosage form containing an active ingredient selected from the group consisting of .

[0113] According to the first aspect of this first embodiment, the present invention provides a pharmaceutical carrier in an IR formulation or an amount per unit form of pramipexole dihydrochloride monohydrate selected from the group consisting of 6.5 mg, 7 mg, 8 mg, 9.5 mg, 10 mg, 12 mg , 14 mg, 15 mg, 17.5 mg, 21 mg and 22.5 mg, mixed with the medium, and pramipexole or a pharmaceutical composition in unit dosage form containing its pharmaceutically acceptable salt as an active ingredient . to provide

[0114] According to the second aspect of this first embodiment, the present invention relates to a pharmaceutical carrier or vehicle in an ER formulation, mixed with 6.5 mg, 7 mg, 8 mg, 9.5 mg, 10 mg, 11 mg , 13.5 mg, 15 mg, 16.5 mg, 18 mg, 20 mg, 22.5 mg, 25 m g, 27 mg, 30 mg, 32 mg, 35 mg, 37 mg, 40 mg, 42 mg and 4 5 mg, and provides a pharmaceutical composition in unit dosage form containing pramipexole or a pharmaceutically acceptable salt thereof as an active ingredient, in an amount per unit form of pramipexole dihydrochloride monohydrate selected from the group consisting of. As described above, according to the present invention, the daily dose of pramipexole or a pharmaceutically acceptable salt thereof is equivalent to 0.375 mg to 42 mg of pramipexole dihydrochloride monohydrate. The said daily dose range is - Low dose, usually equivalent to the currently approved dose of 0.375 mg to 1.5 mg administered to patients with synucleinopathy in combination with a 5HT3 - antagonist during the dose - setting period at the start of treatment;

[0115] - Equivalent to the currently approved dose, usually safely administered to patients in combination with a 5HT3 - antagonist according to the current protocol, and does not cause adverse events due to the presence of the 5HT3 - antagonist, 1.5 mg to 4.5 mg; - Higher (usually above 4.5 mg to 6 mg), or even higher (usually above 6 mg to 45 mg, preferably above 6 mg to 42 mg) doses that can objectively improve the condition of the said patient and provide neuroprotective activity pre - confirmed by studies in animal models, and is equivalent. - Low dose, usually, during the dose - setting period at the start of treatment, in combination with a 5HT3 - antagonist, administered to patients with synucleinopathy, 0.375 mg to 1.5 m g, equivalent to the currently approved dose; - Equivalent to the currently approved dose, usually, safely administered to patients in combination with a 5HT3 - antagonist according to the current protocol, and does not cause adverse events due to the presence of the 5HT3 - antagonist, 1.5 mg to 4.5 mg; - Higher (usually above 4.5 mg to 6 mg), or even higher (usually above 6 mg to 45 mg, preferably above 6 mg to 42 mg) doses that can objectively improve the condition of the said patient and provide neuroprotective activity pre - confirmed by studies in animal models, and is equivalent. - Equivalent to the currently approved dose, usually, safely administered to patients in combination with a 5HT3 - antagonist according to the current protocol, and does not cause adverse events due to the presence of the 5HT3 - antagonist, 1.5 mg to 4.5 mg; - Higher (usually above 4.5 mg to 6 mg), or even higher (usually above 6 mg to 45 mg, preferably above 6 mg to 42 mg) doses that can objectively improve the condition of the said patient and provide neuroprotective activity pre - confirmed by studies in animal models, and is equivalent. - Higher (usually above 4.5 mg to 6 mg), or even higher (usually above 6 mg to 45 mg, preferably above 6 mg to 42 mg) doses that can objectively improve the condition of the said patient and provide neuroprotective activity pre - confirmed by studies in animal models, and is equivalent including.

[0116] According to the second embodiment, the present invention provides a unit form of appropriate (R,S)-6-propylamino-4,5 ,6,7-tetrahydro-1,3-benzothiazol-2-amine (racemate), usually mixed with a pharmaceutical carrier or vehicle, - a dose of the racemate or a pharmaceutically acceptable salt or solvate thereof per IR unit form of more than 12 mg to 45 mg, or 13 mg to 45 mg, preferably more than 12 mg to 42 mg, or 13 mg to 42 mg of pramipexole dihydrochloride monohydrate equivalent; and - a dose of the racemate or a pharmaceutically acceptable salt or solvate thereof per ER unit form of more than 12 mg to 90 mg, or more than 13 mg to 90 mg, preferably more than 12 mg to 8 4 mg, or 13 mg to 84 mg of pramipexole dihydrochloride monohydrate equivalent, and - a dose of the racemate or a pharmaceutically acceptable salt or solvate thereof per ER unit form of more than 12 mg to 90 mg, or more than 13 mg to 90 mg, preferably more than 12 mg to 8 4 mg, or 13 mg to 84 mg of pramipexole dihydrochloride monohydrate equivalent, wherein the pharmaceutical composition contains an active ingredient selected from the group consisting of - a dose of the racemate or a pharmaceutically acceptable salt or solvate thereof per ER unit form of more than 12 mg to 90 mg, or more than 13 mg to 90 mg, preferably more than 12 mg to 8

[0117] According to the present invention, the daily dose of (R,S)-6-propylamino-4,5,6,7-tetrahydro- 1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt (racemate) thereof is equivalent to 0.75 mg to 90 mg, preferably 0.75 mg to 84 mg of pramipexole dihydrochloride monohydrate. - a dose of the racemate or a pharmaceutically acceptable salt or solvate thereof per ER unit form of more than 12 mg to 90 mg, or more than 13 mg to 90 mg, preferably more than 12 mg to 8

[0118] According to the third embodiment, the present invention provides a pharmaceutical composition containing (R)-6 -propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine and (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benz othiazol-2-amine as active ingredients, mixed with a pharmaceutical carrier or vehicle, in an amount of 50 mg to 3000 mg, preferably 1 mg to 3000 mg, preferably 1 It contains in a total amount per unit form of 50 mg to 3000 mg, and the total amount per unit form is pramipexole dihydrochloride in an amount of more than 6 mg to 45 mg, preferably more than 6 mg to 42 mg and comprises a pharmaceutical composition in unit dosage form containing an amount of the (S)-enantiomer equivalent to the monohydrate, providing a suitable (R) / (S) mixture.

[0119] According to the aspect of this third embodiment, the present invention - (R)-6-propylamino -4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine and (S) -6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine as an active ingredient, contained in a total amount per unit form of 50 mg to 1500 mg, preferably 150 mg to 150 0 mg, and the total amount per unit form is more than 6 mg to 2 2.5 mg, preferably more than 6 mg to 21 mg of pramipexole dihydrochloride monohydrate and the same amount of the (S)-enantiomer, a pharmaceutical composition in unit dosage form; and - (R)-6-propylamino -4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine and (S) -6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine as an active ingredient, contained in a total amount per unit form of 50 mg to 3000 mg, preferably 150 mg to 300 0 mg, and the total amount per unit form is more than 6 mg to 4 5 mg, preferably more than 6 mg to 42 mg of pramipexole dihydrochloride monohydrate and equivalent (S)-enantiomer amount, a pharmaceutical composition in unit dosage form Provide a suitable (R) / (S) mixture selected from the group consisting of.

[0120] The daily dose of the (R) / (S)-mixture is 150 mg to 3000 mg, preferably, 300 mg to 3000 mg, and the daily dose is 0.375 mg to 42 mg, advantageously is more than 6 mg to 45 mg, preferably more than 6 mg to 42 mg, even more advantageously, 6. More than 5 mg to 45 mg, preferably 6.5 mg to 42 mg of pramipexole dihydrochloride monohydrate equivalent to the daily dose of (S)-6-propylamino-4,5,6,7-tetrahydro-1,3- benzothiazol-2-amine is included.

[0121] According to a particular embodiment, the 6-propylamino-4,5,6,7-tetrahydro- 1,3-benzothiazol-2-amine is mixed with a pharmaceutical carrier or vehicle, 6 mg More than that to 42 mg, or 6.5 mg to 42 mg of pramipexole di hydrochloride monohydrate per unit form as the active ingredient, formulated into a unit dosage form of a pharmaceutical composition, pramipe xole dihydrochloride monohydrate. The composition is combined with a 5HT3-antagonist In combination, at a daily dose of more than 6 mg to 42 mg, it is to be administered to patients suffering from synucleinopathy as planned.

[0122] According to another particular embodiment, the 6-propylamino-4,5,6,7-tetrahydro ro-1,3-benzothiazol-2-amine is mixed with a pharmaceutical carrier or vehicle, 6 mg more to 45 mg, or 6.5 mg to 45 mg of pramipexole l dihydrochloride monohydrate per unit form as the active ingredient, formulated into a unit dosage form of a pharmaceutical composition, pra It is mipaxolol dihydrochloride monohydrate. The composition is combined with a 5HT3 - antagonist and is to be administered to patients suffering from synucleinopathy at a daily dose of more than 6 mg to 45 mg. In combination, it is scheduled to be administered to patients suffering from synucleinopathy at a daily dose of more than 6 mg to 45 mg. It is to be administered.

[0123] Preferably, the 5HT3 - antagonist is one of the approved 5HT3 - antagonists described in the "5HT3 - antagonist" section in the amount per unit form described in the above section. In certain embodiments, it is ondansetron or a pharmaceutically acceptable salt or solvate thereof, or dolasetron or a pharmaceutically acceptable salt or solvate thereof. In the amount of the "5HT3 - antagonist" described in the above section per unit form. One of the approved 5HT3 - antagonists, and in certain embodiments, it is ondansetron or a pharmaceutically acceptable salt or solvate thereof, or dolasetron or a pharmaceutically acceptable salt or solvate thereof. Or a pharmaceutically acceptable salt or solvate thereof, or dolasetron or a pharmaceutically acceptable salt or solvate thereof. It is.

[0124] The first aspect of the present invention According to the first aspect, the present invention provides a method for safely delaying or even reversing the progression of the disease in patients suffering from synucleinopathy, which comprises treating the patient with 6 - propylamino - 4,5,6,7 - tetrahydro - 1,3 - benzothiazol - 2 - amine by administering a 5HT3 - antagonist to the patient simultaneously or for a long term. More specifically, the present invention provides a method for treating synucleinopathy in a patient, which comprises administering to the patient in need of such treatment an effective daily dose of a 5HT3 - antagonist in combination with an effective daily dose of 6 - propylamino - 4,5,6,7 - tetrahydro - 1,3 - benzothiazol - 2 - amine or a pharmaceutically acceptable salt or solvate thereof. By administering a 5HT3 - antagonist to the patient simultaneously or for a long term. It provides a method of treatment.

[0125] More particularly, the present invention provides a method for treating synucleinopathy in a patient, which Comprises administering to the patient in need of such treatment an effective daily dose of a 5HT3 - antagonist, In combination with an effective daily dose of 6 - propylamino - 4,5,6,7 - tetrahydro - 1,3 - benzothiazol - 2 - amine or a pharmaceutically acceptable salt or solvate thereof. Or a pharmaceutically acceptable salt or solvate thereof. It provides a method comprising administering.

[0126] In the practice of the method of the present invention, the daily dose of these 5HT3 - antagonists is the above - mentioned According to the current protocol for treatment or prevention, it is used to prevent or treat nausea and vomiting in pediatric or adult patients who have undergone surgery or cancer chemotherapy, and is at least as high as the same. The daily dose is usually 1 μg to 300 mg.

[0127] As described above, 6-propylamino-4,5,6,7-tetrahydro-1,3 -benzothiazol-2-amine is selected from the group consisting of racemates, pramipexole and (R) / (S) -mixtures, as well as pharmaceutically acceptable salts and solvates thereof.

[0128] The dose per unit form and the daily dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine are as described above in the section "6-propylamino-4,5,6 ,7-tetrahydro-1,3-benzothiazol-2-amine". The dose per unit form of the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine is 0.125 mg to 42 mg, preferably consisting of or including an amount per unit form of the (S)-enantiomer equivalent to more than 6 mg to 42 mg of pramipexole dihydrochloride monohydrate. The daily dose of the 6-propylamino-4, 5,6,7-tetrahydro-1,3-benzothiazol-2-amine consists of or includes a daily dose of the (S)-isomer equivalent to 0. 375 mg to 42 mg of pramipexole dihydrochloride monohydrate. Preferably, the daily dose of the 6-propylamino-4,5, 6,7-tetrahydro-1,3-benzothiazol-2-amine is more than 6 mg to 42 mg of the therapeutically effective daily dose of the (S)-isomer equivalent to pramipexole dihydrochloride dihydrate. dose.​​​​​ comprises or contains the dosage.

[0129] The dosage per unit form of the said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine may consist of or contain an amount equivalent to 0.125 mg to 45 mg, preferably more than 6 mg to 45 mg of the (S)-isomer per unit form of pramipexole dihydrochloride monohydrate. The daily dosage of the said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine may consist of or contain a daily dosage equivalent to that of 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate of the (S)-isomer. Preferably, the daily dosage of the said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine consists of or contains a therapeutically effective daily dosage equivalent to that of more than 6 mg to 45 mg of the (S)-isomer of pramipexole dihydrochloride dihydrate. According to an embodiment, 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is administered at a daily dosage equivalent to 0.375 mg to 20 mg, preferably more than 6 mg to 20 mg, or 6.5 mg to

[0130] 20 mg of pramipexole dihydrochloride monohydrate, and is 0.125 mg to 20 mg of the dosage / unit form equivalent to pramipexole dihydrochloride monohydrate of the (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine (INN: pramipexole) and its pharmaceutically acceptable salts, in particular its dihydrochloride monohydrate (USAN: pramipexole hydrochloride); ​​​​​- 0.375 mg to 22.5 mg, preferably more than 6 mg to 22.5 mg, or 6. administered in a daily dose equivalent to 0.375 mg to 22.5 mg of pramipexole dihydrochloride monohydrate dose / unit form of (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzo thiazol-2-amine (INN: pramipexole) and its pharmaceutically acceptable salts, in particular its dihydrochloride monohydrate (USAN: pramipexole hydrochloride); - 0.25 mg to 84 mg of dose / unit form of (R,S)-6-propylamino-4, 5,6,7-tetrahydro-1,3-benzothiazol-2-amine (racemate) and its pharmaceutically acceptable salts, said dose being 0.375 mg to 42 mg, preferably more than 12 mg to 42 mg, or 13 mg to 42 mg of pramipexole dihydrochloride monohydrate and the same daily dose, 0.125 mg to 42 mg, preferably more than 12 mg to 42 mg, or 13 mg to 42 mg of pramipexole dihydrochloride monohydrate equivalent S-enantiomer per unit form containing; - 50 mg to 3000 mg, preferably 150 mg to 3000 mg per unit form dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol- 2-amine-containing pharmaceutical composition of unit dosage form (S) / (R)-mixture, said dose is 0.375 mg to 20 mg, preferably more than 6 mg to 20 mg, or more than 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate equivalent (S)-enantiomer daily dose, 150 mg to 300 mg, preferably 300 mg to 3000 mg, or ​​Administered at a daily dose of 450 mg to 3000 mg, 0.125 mg to 20 mg, preferably more preferably, more than 6 mg to 20 mg, or 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate in an amount per unit form of the S-enantiomer equivalent thereto; selected from the group consisting of.

[0131] Generally, in a method (or use) for the treatment of synucleinopathy according to the present invention, 6-propylamino-4,5,6, 7-tetrahydro-1,3-benzothiazol-2-amine in a pharmaceutical composition mixed with a pharmaceutical carrier or vehicle is administered to a patient in need of said treatment at a daily dose of 1.5 mg to 3000 m g. In said method (or use), 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol -2-amine is administered to said patient in combination with a 5HT3-antagonist. As described above, said 6-propylamino-4,5,6,7-tetrahydro-1,3 -benzothiazol-2-amine can be pramipexole, a racemate or an (R) / (S) -mixture.

[0132] For this administration, 6-propylamino-4,5,6, 7-tetrahydro-1,3-benzothiazol-2-amine and (R) / (S)-mixture 6-propylamino-4,5,6,7-tetrahydro-1, 3-benzothiazol-2-amine selected from the group consisting of pramipexole, racemic 6-propylamino-4,5,6, 7-tetrahydro-1,3-benzothiazol-2-amine and (R) / (S)-mixture is formulated into a unit dosage form of a pharmaceutical composition containing the aforementioned individual amount ranges per unit form thereof, each mixed with a pharmaceutical carrier or vehicle. Said composition is described, for example, in International Publication No. 2012 / 0140604, International JP 2008 / 122638 A, US 2013 / 01162924 A1, US 7,285,669 B2 and US 2008 / 0014259 A1 (US 8,017,598 B2), and may be manufactured according to the known techniques described in the patent documents, and all of these disclosures are hereby incorporated by reference in their entirety. In accordance with one embodiment, the 5-HT3 antagonist is selected from the group consisting of azasetron in a daily dose equivalent to 15 mg to 20 mg of azasetron hydrochloride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; dolasetron in a daily dose equivalent to 75 mg to 200 mg of dolasetron mesylate and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate monohydrate; granisetron in a daily dose equivalent to 1.5 mg to 8 mg of granisetron base and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; ondansetron in a daily dose equivalent to 6 mg to 32 mg of ondansetron base and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate; palonosetron in a daily dose equivalent to 0.1 mg to 2 mg, preferably 0.25 mg to 0.5 mg of palonosetron base and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; ramosetron in a daily dose equivalent to 75 mcg to 100 mcg of ramosetron hydrochloride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; and tropisetron in a daily dose equivalent to 7.5 mg to 20 mg of tropisetron base and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; and

[0133] In accordance with one embodiment, the 5-HT3 antagonist is azasetron in a daily dose equivalent to 15 mg to 20 mg of azasetron hydrochloride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; dolasetron in a daily dose equivalent to 75 mg to 200 mg of dolasetron mesylate and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate monohydrate; granisetron in a daily dose equivalent to 1.5 mg to 8 mg of granisetron base and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; ondansetron in a daily dose equivalent to 6 mg to 32 mg of ondansetron base and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate; palonosetron in a daily dose equivalent to 0.1 mg to 2 mg, preferably 0.25 mg to 0.5 mg of palonosetron base and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; ramosetron in a daily dose equivalent to 75 mcg to 100 mcg of ramosetron hydrochloride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; and tropisetron in a daily dose equivalent to 7.5 mg to 20 mg of tropisetron base and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; and is selected from the group consisting of; and In accordance with one embodiment, the 5-HT3 antagonist is azasetron in a daily dose equivalent to 15 mg to 20 mg of azasetron hydrochloride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; dolasetron in a daily dose equivalent to 75 mg to 200 mg of dolasetron mesylate and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate monohydrate; granisetron in a daily dose equivalent to 1.5 mg to 8 mg of granisetron base and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; ondansetron in a daily dose equivalent to 6 mg to 32 mg of ondansetron base and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate; palonosetron in a daily dose equivalent to 0.1 mg to 2 mg, preferably 0.25 mg to 0.5 mg of palonosetron base and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride; The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole -2-amine is 0.375 mg to 42 mg, particularly more than 6 mg to 42 mg, or 6.5 mg or more to 42 mg of pramipexole or a pharmaceutically acceptable salt thereof having the same daily dose as pramipexole dihydrochloride monohydrate, or the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole -2-amine is 0.375 mg to 45 mg, particularly more than 6 mg to 45 mg, or 6.5 mg or more to 45 mg of pramipexole or a pharmaceutically acceptable salt thereof having the same daily dose as pramipexole dihydrochloride monohydrate.

[0134] Specifically, the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole -2-amine is 0.375 mg to 20 mg, particularly 1.5 mg to 20 mg, advantageously 1.6 mg to 20 mg, more advantageously more than 4.5 mg to 20 mg, preferably more than 6 mg to 20 mg, or 6.5 mg to 20 mg of pramipexole or a pharmaceutically acceptable salt thereof having the same daily dose as pramipexole dihydrochloride monohydrate.

[0135] Specifically, the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole -2-amine is 0.375 mg to 22.5 mg, particularly 1.5 mg to 22. 5 mg, advantageously 1.6 mg to 22.5 mg, more advantageously more than 4.5 mg to 21 mg , preferably more than 6 mg to 22.5 mg, or 6.5 mg to 22.5 mg of pramipexole or a pharmaceutically acceptable salt thereof having the same daily dose as pramipexole dihydrochloride monohydrate.

[0136] ​​​​​ According to an advantageous embodiment, in the method of the present invention, the 5HT3-antagonist is on dolasetron hydrochloride dihydrate, 6-propylamino-4,5,6,7-tetrahydro -1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate. According to a specific embodiment, in the said method (or use), the said 6-propylamino

[0137] -4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is in a daily dose of 1.5 m g to 42 mg, and in some cases 1.5 mg to 20 mg, of pramipexole dihydrochloride monohydrate administered to the said patient. According to this embodiment, in the said method ( or use), 6-propylamino-4,5,6,7-tetrahydro-1,3- benzothiazol-2-amine is administered to the said patient in combination with a 5HT3-antagonist. According to an advantageous aspect of this specific embodiment, pramipexole dihydrochloride monohydrate is in a pharmaceutical composition in unit form containing more than 4.5 mg to 21 mg, preferably more than 6 mg to 21 mg, or 6.5 mg to 21 mg, of pramipexole dihydrochloride monohydrate per unit form, mixed with a pharmaceutical carrier or vehicle in an IR formulation. The said composition is administered to the said patient in combination with a 5HT3-antagonist, 1 or 2 or 3 times a day, up to a maximum daily dose of 4

[0138] 2 mg of pramipexole dihydrochloride monohydrate. Another advantageous aspect of this specific embodiment is that it is mixed with a pharmaceutical carrier or vehicle in an IR formulation .

[0139] Another advantageous aspect of this specific embodiment is that it is mixed with a pharmaceutical carrier or vehicle in an IR formulation Combined, more than 4.5 mg to 22.5 mg, preferably more than 6 mg to 22.5 mg, or The amount of pramipexole dihydrochloride monohydrate per unit form containing 6.5 mg to 22.5 mg In a pharmaceutical composition in unit dosage form containing pramipexole dihydrochloride monohydrate as an active ingredient Including. The composition is combined with a 5HT3 - antagonist and administered to the patient 2 or 3 times a day Up to a maximum daily dose of 45 mg of pramipexole dihydrochloride monohydrate To be administered.

[0140] According to another advantageous aspect of this particular embodiment, pramipexole dihydrochloride monohydrate is Mixed with a pharmaceutical carrier or medium in an ER formulation, more than 4.5 mg to 42 mg, preferably More than 6 mg to 42 mg, or 6.5 mg to 42 mg, per unit form In a pharmaceutical composition in unit dosage form containing the above - mentioned pramipexole dihydrochloride monohydrate as an active ingredient There is. The composition is administered to the patient once a day in combination with a 5HT3 - antagonist To be administered.

[0141] Another advantageous aspect of this particular embodiment is that it is mixed with a pharmaceutical carrier or medium in an ER formulation Combined, more than 4.5 mg to 45 mg, preferably more than 6 mg to 45 mg, or 6.5 m g to 45 mg, per unit form, of pramipexole dihydrochloride monohydrate as an active ingredient Including pramipexole dihydrochloride monohydrate in a pharmaceutical composition in unit dosage form. The above - mentioned The composition is administered to the patient once a day in combination with a 5HT3 - antagonist .

[0142] Preferably, in a method for treating synucleinopathy in a patient according to the present invention wherein the 5HT3 antagonist is ondansetron hydrochloride dihydrate in an effective daily dose of 4 mg to 32 mg (in ondansetron), and the 6-propylamino- 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate in an effective daily dose of 1.5 mg to 42 mg, and in some cases, 1 .5 mg to 20 mg. More specifically, in the method, the pramipexole dihydrochloride monohydrate is more than 6 mg to 42 mg, or 6.5 mg to 42 mg, and in some cases, more than 6 mg to 20 mg, or 6.5 mg to 20 mg of a therapeutically effective daily dose and is administered to a patient suffering from synucleinopathy.

[0143] Second aspect of the present invention According to a second aspect, the present invention provides a 5HT3 antagonist for use in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in the treatment of synucleinopathy in a patient in need of treatment.

[0144] In particular, the second aspect of the present invention provides a 5HT3 antagonist in an amount of 1 μg to 300 mg for use in combination with a daily dose of 0.375 mg to 3000 mg of said 6-propylamino-4,5,6,7 -tetrahydro-1,3-benzothiazol-2-amine for the treatment of synucleinopathy in a patient in need of treatment.

[0145] According to an embodiment, usually, the amount of the 5HT The 3 - antagonist is for use in combination as an (R) / (S) - mixture with a daily dose of 50 mg to 3000 mg, 15 0 mg to 3000 mg, or 300 mg to 3000 mg of 6 - propylamino -4,5,6,7 - tetrahydro - 1,3 - benzothiazol - 2 - amine, and said daily dose comprises a dose of the (S) - enantiomer equivalent to 0.375 mg to 42 mg, preferably more than 6 mg to 42 mg, or 6.5 mg to 42 mg of pramipexole dihydrochloride monohydrate. The 6 - propylamino - 4,5,6,7 - tetrahydro - 1,3 - benzothiazol -2 - amine may also be a racemate with a daily dose equivalent to 0.75 mg to 84 mg, preferably more than 12 mg to 42 mg,

[0146] or 13 mg to 42 mg of pramipexole dihydrochloride monohydrate. The 6 - propylamino - 4,5,6,7 - tetrahydro - 1,3 - benzothiazol -2 - amine may also be a racemate with a daily dose equivalent to 0.75 mg to 90 mg, preferably more than 12 mg to 45 mg, or 13 mg to 45 mg of pramipexole dihydrochloride monohydrate.

[0147] Preferably, the 6 - propylamino - 4,5,6,7 - tetrahydro - 1,3 - benzothiazol -2 - amine is 1.5 mg to 20 mg, advantageously more than 4.5 mg to 20 m g, more advantageously 4.8 g to 20 mg, preferably more than 6 mg to 20 mg of pramipexole or a pharmaceutically acceptable salt or solvate thereof equivalent to the daily dose of pramipexole dihydrochloride monohydrate.

[0148] Preferably, the 6 - propylamino - 4,5,6,7 - tetrahydro - 1,3 - ben zothiazol - 2 - amine is 1.5 mg to 20 mg, advantageously more than 4.5 mg to 20 m g, more advantageously 4.8 g to 20 mg, preferably more than 6 mg to 20 mg of pramipexole or a pharmaceutically acceptable salt or solvate thereof equivalent to the daily dose of pramipexole dihydrochloride monohydrate. is a pharmaceutically acceptable salt or solvate thereof.

[0149] According to this second aspect, the pharmaceutical combination is for the prevention or treatment of postoperative nausea and vomiting. have been shown to be effective for the treatment or prevention of chemotherapy-induced nausea and vomiting. at least as high as the currently prescribed or approved pediatric or adult dose. and an effective dose of 6-propylamino-4,5, Contains 6,7-tetrahydro-1,3-benzothiazol-2-amine.

[0150] Advantageously, in said combination, said 5HT3-antagonist is azasetron and pharmaceutical salts and solvates thereof, dolasetron and pharmaceutical salts and solvates thereof solvates, granisetron and its pharmaceutical salts and solvates, ondansetron and its pharmaceutical salts and solvates, Palonosetron and its pharmaceutical salts and solvates hydrates, ramosetron and its pharma- ceutically acceptable salts and solvates, and troponin and pharmaceutical salts and solvates thereof, Pyramino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is , a daily dose equivalent to 0.375 mg to 42 mg, preferably greater than 6 mg to 42 mg, is safely administered to patients with synucleinopathy at therapeutically effective daily doses of 6.5 mg to 42 mg. pramipexole or a pharma- ceutically acceptable salt or solvate thereof is administered. .

[0151] In said combination with said 5HT3-antagonist, pramipexole or The pharma- ceutically acceptable salt thereof may, in some cases, be in the range of 1.5 mg to 20 mg, 1.6 mg ~20mg, 1.625mg~20mg, 3mg~20mg, >4.5mg~20mg, 4.8 mg to 20 mg, 6 mg to 20 mg, or 6.5 mg to 20 mg of pramipexole administered to patients suffering from synucleinopathy in a daily dose equivalent to pramipexole dihydrochloride monohydrate.

[0152] For these administrations for the treatment of synucleinopathy, 5HT3-antagonists and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine are each formulated into a pharmaceutical composition mixed with a pharmaceutical carrier or medium.

[0153] In particular, according to this second aspect, the pharmaceutical combination is mixed with a pharmaceutical carrier or medium, (a) azasetron in an amount / unit form equivalent to 5 mg to 10 mg of azasetron hydrochloride mixed with a pharmaceutical carrier or medium, as well as its pharmaceutically acceptable salts and solvates, in particular, its hydrochloride; dolasetron in an amount / unit form equivalent to 1.5 mg to 200 mg of dolasetron mesylate, as well as its pharmaceutically acceptable salts and solvates, in particular, its mesylate monohydrate; granisetron in an amount / unit form equivalent to 0.5 mg to 2 mg of granisetron base, as well as its pharmaceutically acceptable salts and solvates, in particular, its hydrochloride; ondansetron in an amount / unit form equivalent to 2 mg to 32 mg, usually 2 mg to 16 mg of ondansetron base, as well as its pharmaceutically acceptable salts and solvates, in particular, dihydrochloride dihydrate; palonosetron in an amount / unit form equivalent to 0.1 mg to 2 mg, usually 0.25 mg to 0.5 mg of palonosetron base, as well An amount / unit form of lamotrigine equivalent to the hydrochloride salt, and its pharmaceutically acceptable salts and solvates, particularly its hydrochloride salt; and an amount / unit form of tropisetron equivalent to 2.5 mg to 5 mg of tropisetron base, and its pharmaceutically acceptable salts and solvates, particularly , its hydrochloride salt; a 5HT3 antagonist selected from the group consisting of the above, containing the 5HT3 antagonist as an active ingredient in a pharmaceutical composition in unit dosage form; and (b) Pramipexole or a pharmaceutically acceptable salt thereof in an amount per unit form equivalent to 0.125 mg to 42 mg, usually more than 1.5 mg to 42 mg, more than 4.5 mg to 42 mg, more than 6 mg to 42 mg, or 6.5 mg to 42 mg of pramipexole dihydrochloride monohydrate, or pramipexole or a pharmaceutically acceptable salt thereof in an amount per unit form equivalent to 0.125 mg to 45 mg, usually more than 1.5 mg to 45 mg, more than 4.5 mg to 45 mg, more than 6 mg to 42 mg, or 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate, or pramipexole or a pharmaceutically acceptable salt thereof in a pharmaceutical composition containing the same as an active ingredient or solvate, or Pramipexole or a pharmaceutically acceptable salt thereof in an amount per unit form equivalent to 0.125 mg to 45 mg, usually more than 1.5 mg to 45 mg, more than 4.5 mg to 45 mg, more than 6 mg to 42 mg, or 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate, or pramipexole or a pharmaceutically acceptable salt thereof in a pharmaceutical composition containing the same as an active ingredient or solvate, is included as a component. The pharmaceutical composition thus obtained is administered to a patient suffering from synucleinopathy, either simultaneously or consecutively. The use according to the present invention is carried out under the conditions described above in this specification for carrying out a method of treatment.

[0154]

[0155]

[0155]

[0156] According to a third aspect, the present invention provides a 5HT3-antagonist for the preparation of a medicament for the treatment of synucleinopathy in a patient in need of treatment, in combination with an effective dose of 6-propylamino-4,5,6,7-tetrahydro -1,3-benzothiazol-2-amine. Any 5HT3-antagonist disclosed in the "5HT3-antagonist" section can be used for the preparation of the above-mentioned medicament to be administered to the patient in combination with an effective dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2- amine as described in the "6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine" section.

[0157] Preferably, the 5HT3-antagonist is selected from the group consisting of azasetron and its pharmaceutically acceptable salts and solvates, dolasetron and its pharmaceutically acceptable salts and solvates, granisetron and its pharmaceutically acceptable salts and solvates, ondansetron and its pharmaceutically acceptable salts and solvates, palonosetron and its pharmaceutically acceptable salts and solvates, ramosetron and its pharmaceutically acceptable salts and solvates, and tropisetron and its pharmaceutically acceptable salts and solvates, and 6-propylamino-4,5,6,7- tetrahydro-1,3-benzothiazol-2-amine is pramipexole or its pharmaceutically acceptable salt or solvate. In combination with the 5HT3-antagonist in the pharmaceutical composition, pramipexole or its pharmaceutically acceptable salt is from 0.375 mg to 42 mg, preferably 4.5 mg.

[0158] mg.

[0159] mg to 36 mg. mg to 36 mg.

[0159] In combination with the 5HT3-antagonist in the pharmaceutical composition, pramipexole or its pharmaceutically acceptable salt is from 0.375 mg to 42 mg, preferably 4.5 mg to 36 mg. more than 42 mg, preferably more than 6 mg to 42 mg, or 6.5 mg to 42 mg of the same daily dose, or in some cases 1.5 mg to 20 mg, 1.6 mg to 20 m g, 1.625 mg to 20 mg, 3 mg to 20 mg, more than 4.5 mg, 4.8 mg to 20 m g, more than 6 mg to 20 mg, or 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate equivalent daily dose, and is safely administered to patients suffering from synucleinopathy.

[0160] For these administrations for the treatment of synucleinopathy, 5HT3 - antagonists and 6 - propylamino - 4,5,6,7 - tetrahydro - 1,3 - benzothiazole - 2 - amine are each formulated into a pharmaceutical composition mixed with a pharmaceutical carrier or vehicle .

[0161] The pharmaceutical composition thus obtained is administered to patients suffering from synucleinopathy, either simultaneously or sequentially.

[0162] Therefore, according to this third aspect, the present invention provides a 5HT3 - antagonist in a pharmaceutical composition mixed with a pharmaceutical carrier or vehicle, which is administered simultaneously or sequentially in combination with 6 - propylamino - 4,5,6,7 - tetrahydro - 1,3 - benzothiazole - 2 - amine in a pharmaceutical composition mixed with a pharmaceutical carrier or vehicle for the treatment of synucleinopathy in a patient in need of treatment. propylamino - 4,5,6,7 - tetrahydro - 1,3 - benzothiazole - 2 - amine in a pharmaceutical composition mixed with a pharmaceutical carrier or vehicle and containing a 5HT3 - antagonist as an active ingredient, which is administered simultaneously or sequentially. According to this aspect, the 5HT3 - antagonist is mixed with a pharmaceutical carrier or vehicle and is present in the pharmaceutical composition in an amount per unit form of 1 μg to 300 mg, respectively, in the pharmaceutical composition.

[0163] According to this aspect, the 5HT3 - antagonist is mixed with a pharmaceutical carrier or vehicle and is present in the pharmaceutical composition in an amount per unit form of 1 μg to 300 mg, respectively, in the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine is mixed with a pharmaceutical carrier or vehicle and is present in the said composition in an amount of 0.125 mg to 3000 mg. More specifically, the dosage, i.e., the amount of said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine per unit form, is in the range of 0.125 mg to 1500 mg in IR unit form, preferably 1.5 mg to 1500 mg, more preferably 1.6 mg to 1500 mg, preferably 1.625 mg to 1500 mg, and in the range of 3 mg to 3000 mg in ER unit form.

[0164] For the efficacy thereof in the treatment of synucleinopathy in combination with said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, preferred 5HT3-antagonists in said pharmaceutical composition are azasetron in an amount / unit form equivalent to 5 mg to 10 mg of ondansetron hydrochloride and its pharmaceutically acceptable salts and solvates, especially its hydrochloride; dolasetron in an amount / unit form equivalent to 20 mg to 200 mg of dolasetron mesylate and its pharmaceutically acceptable salts and solvates, especially its mesylate monohydrate; granisetron in an amount / unit form equivalent to 0.5 mg to 2 mg of granisetron base and its pharmaceutically acceptable salts and solvates, especially its hydrochloride; ondansetron in an amount / unit form equivalent to 2 mg to 32 mg, usually 2 mg to 16 mg of ondansetron base Paroxetine in an amount / unit form equivalent to paroxetine base and its pharmaceutically acceptable salts and solvates, in particular its hydrochloride; Ramoxetine hydrochloride in an amount / unit form equivalent to 2.5 μg to 100 mcg of ramoxetine hydrochloride and its pharmaceutically acceptable salts and solvates, in particular its hydrochloride; and Tropisetron in an amount / unit form equivalent to 2.5 mg to 5 mg of tropisetron base and its pharmaceutically acceptable salts and solvates, in particular its hydrochloride, selected from the group consisting of.

[0165] The pharmaceutical composition comprising the preferred 5-HT3 antagonist is preferably selected from the group consisting of pemipexole and its pharmaceutically acceptable salts and solvates, and, in the pharmaceutical composition, the pemipexole in an amount per unit form equivalent to pemipexole dihydrochloride monohydrate in the range selected from the group consisting of 0.125 mg to 42 mg, usually 1.5 mg to 42 mg, 1.6 mg to 42 mg, 1.625 mg to 42 mg, 3 mg to 42 mg, greater than 4.5 mg to 42 mg, greater than 6 mg to 42 mg, and 6.5 mg to 42 mg, mixed with a pharmaceutical carrier or vehicle, and its pharmaceutically acceptable salts and solvates, in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, is administered to a patient suffering from synucleinopathy, either simultaneously or sequentially.

[0166] The pharmaceutical composition comprising the preferred 5-HT3 antagonist is preferably selected from the group consisting of pemipexole and its pharmaceutically acceptable salts and solvates, Also, in the pharmaceutical composition, 0.125 mg to 45 mg, mixed with a pharmaceutical carrier or vehicle , usually 1.5 mg to 45 mg, 1.6 mg to 45 mg, 1.625 mg to 45 mg, 3 mg to 45 mg, more than 4.5 mg to 45 mg, more than 6 mg to 45 mg, and 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate in an amount equivalent to the unit form per unit, and its pharmaceutically acceptable salts and solvates containing 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is administered simultaneously or consecutively to patients suffering from synucleinopathy.

[0167] According to certain embodiments, in particular, for use at the start of treatment, the pramipexole in the pharmaceutical composition is 0.125 mg to 21 mg, or in an amount equivalent to 0.125 mg to 20 mg of pramipexole dihydrochloride monohydrate per unit form. In particular, the amount per unit form in the composition is 1.5 mg to 20 mg, 1.6 mg to 20 mg, 1.625 mg to 20 mg, 3 mg to 20 mg, 4 .5 mg more than to 20 mg, 6 mg more than to 20 mg and 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate selected from the group consisting of ranges equivalent. More particularly, the amount of pramipexole or its pharmaceutically acceptable salts is

[0168] In the IR formulation, it is equivalent to 0.125 mg to 21 mg, and preferably more than 1.5 mg to 2 1 mg, 1.6 mg to 21 mg, 1.625 mg to 21 mg, 3 mg to 21 mg, 4.5 mg more than to 21 mg, 6 mg more than to 21 mg, and 6.5 mg to 21 mg of pramipexole dihydrochloride monohydrate. equivalent to a range selected from the group consisting of pramipexole dihydrochloride monohydrate; In the ER formulation, 3 mg to 42 mg, more than 4.5 mg to 42 mg, more than 6 mg to 42 mg, and equivalent to a range selected from the group consisting of 6.5 mg to 42 mg of pramipexole dihydrochloride monohydrate.

[0169] The 5HT3-antagonist and 6-propylamino-4,5, 6,7-tetrahydro-1,3-benzothiazol-2-amine-containing composition according to this third aspect is also, as a ( R) / (S)-mixture, a daily dose of 150 mg to 3000 mg, usually 300 mg to 300 0 mg, for treating synucleinopathies with 6-propylamino-4,5,6,7-tetrahydro-1,3-benz othiazol-2-amine, said daily dose being 0 .375 mg to 42 mg, preferably more than 6 mg to 42 mg, or 6.5 mg to 42 m g and containing a daily dose of the (S)-enantiomer equivalent to pramipexole dihydrochloride monohydrate, wherein said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol- 2-amine is also in a unit dosage form of a medicament mixed with a pharmaceutical carrier or vehicle.

[0170] The 5HT3-antagonist and 6-propylamino-4, 5,6,7-tetrahydro-1,3-benzothiazol-2-amine-containing composition thus produced is also in the form of a racemate, a daily dose of 0.75 mg to 84 mg, preferably more than 12 mg to 84 mg, or also 13 mg to 84 mg of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine equivalent to pramipexole dihydrochloride monohydrate for treating synucleinopathies. ​intended to treat synucleinopathies, said 6-propylamino-4,5,6,7-tetra hydro-1,3-benzothiazol-2-amine is or is also in a pharmaceutical unit dosage form mixed with a pharmaceutical carrier or vehicle and is present in a pharmaceutical unit dosage form mixed with a pharmaceutical carrier or vehicle

[0171] These pharmaceutical compositions, which are used simultaneously in combination with each other, enable for the first time the use of pramipexole for the substantial and effective treatment of patients suffering from synucleinopathies such as Parkinson's disease, Lewy body dementia, Parkinsonian disorders associated with glucocerebrosidase (GBA) mutations and multiple system atrophy and multiple system atrophy and are for the substantial and effective treatment of patients suffering from synucleinopathies such as Parkinson's disease, Lewy body dementia, Parkinsonian disorders associated with glucocerebrosidase (GBA) mutations and multiple system atrophy and enable for the first time the use of pramipexole

[0172] When the 5HT3-antagonist is ondansetron, the dosage per tablet administered to a patient in combination with 6-propylamino-4 5,6,7-tetrahydro-1,3-benzothiazol-2-amine ranges from 2 mg to 16 mg, usually from 2 mg to 8 mg, or from 4 mg to 8 mg and is in the range of 4 mg to 8 mg

[0173] Ondansetron is also present in compositions for transdermal administration, subcutaneous administration, intravenous administration, sustained release tablets in sustained release compositions such as capsules, or in combination products as transdermal drug delivery systems (TDDS) such as patches, preferably matrix patches as described by Cho J-R et al. in 2016, in patch pumps, infusion pumps or micropumps; or in rapidly soluble buccal films such as those described by Koland M et al. in 2013 and can be present in patch pumps, infusion pumps or micropumps; or in rapidly soluble buccal films such as those described by Koland M et al. in 2013

[0174] In the treatment of synucleinopathies, the 5HT3-antagonist and 6-propylamino Minocyclo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is combined and used, and the two active ingredients are administered simultaneously or sequentially, or as a fixed-dose formulation comprising a pharmaceutical composition containing a 5HT3-antagonist and 6-propylamino-4,5,6,7- tetrahydro-1,3-benzothiazol-2-amine mixed with a pharmaceutical

[0175] carrier or vehicle, may be co-administered. The 5HT3-antagonist of component (a) and 6-propylamino-4, 5,6,7-tetrahydro-1,3-benzothiazol-2-amine of component (b) can be administered separately or together in any conventional oral or

[0176] parenteral unit dosage form such as capsules, tablets, powders, cachets, suspensions, solutions or transdermal devices. In the case of separate (simultaneous or sequential) administration of an effective amount of said 5HT3-antagonist per unit form, and an effective amount of said 6-propylamino-4,5,6,7-tetrahydro-1,3- benzothiazol-2-amine per unit form, each of these is the said 5HT3-antagonist mixed with a pharmaceutical carrier or vehicle in a

[0177] container; and said 6-propylamino-4,5,6,7-tetrahydro-1,3- benzothiazol-2-amine mixed with a pharmaceutical carrier or vehicle The 5HT3-antagonist is formulated into a pharmaceutical composition, and the 5HT3-antagonist is mixed with a pharmaceutical carrier or vehicle.

[0178] For these simultaneous administrations for the treatment of synucleinopathy, the 5HT3- antagonist and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, preferably pramipexole, may be combined and formulated into a pharmaceutical composition together with a pharmaceutical carrier or vehicle (fixed-dose formulation).

[0179] Fourth aspect of the present invention According to the fourth aspect, the present invention provides, as one of its active components, an effective amount of one of the 5HT3-antagonists or a pharmaceutically acceptable salt and solvate thereof; and as a second active component, an effective amount of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt and / or solvate thereof, in a pharmaceutical

[0180] composition comprising the 5HT3-antagonist and the 6-propylamino-4,5,6,7-tetrahydro- 1,3-benzothiazol-2-amine are combined and formulated into a fixed-dose formulation consisting of a pharmaceutical composition comprising the 5HT3- antagonist of component (a) and the 6-propylamino-4,5,6,7-tetrahydro-1,3- benzothiazol-2-amine of component (b) mixed with a pharmaceutical carrier or vehicle.

[0181] The fixed-dose formulation comprises a 5HT3-antagonist and 6-propylamino-4,5,6 Ensure the safe and simultaneous administration of 7-tetrahydro-1,3-benzothiazol-2-amine.

[0182] The dosage per unit form of the 5HT3-antagonist of component (a) is in the range of 1 μg to 300 m g, and the dosage per unit form of 6-propylamino-4,5,6,7-tetrahydro-1 ,3-benzothiazol-2-amine of component (b) is in the range of 0.125 mg to 30 00 mg.

[0183] In particular, according to this first aspect, the present invention provides a composition mixed with a pharmaceutical carrier or vehicle, (a) a 5HT3-antagonist in an amount per unit form of 1 μg to 300 mg; and (b) a racemate or a pharmaceutically acceptable salt thereof in an amount equivalent to 0.25 mg to 84 mg of pramipexole dihydrochloride monohydrate; pramipexole or a pharmaceutically acceptable salt thereof in an amount equivalent to 0.125 mg to 42 mg of pramipexole dihydrochloride monohydrate; and an (S)-enantiomer in an amount per unit form equivalent to 0.125 mg to 42 mg of pramipexole dihydrochloride monohydrate, comprising a 6-propylamino-4 ,5,6,7-tetrahydro-1,3-benzothiazol-2-amine selected from the group consisting of (R) / (S) mixtures in an amount per unit form of 50 mg to 3000 mg; or a racemate or a pharmaceutically acceptable salt thereof in an amount equivalent to 0.25 mg to 90 mg of pramipexole dihydrochloride monohydrate per unit form; pramipexole or a pharmaceutically acceptable salt thereof in an amount equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate ; and an (S)-enantiomer in an amount per unit form equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate, comprising a 6-propylamino-4 ,5,6,7-tetrahydro-1,3-benzothiazol-2-amine selected from the group consisting of (R) / (S) mixtures in an amount per unit form of 50 mg to 3000 mg; or a racemate or a pharmaceutically acceptable salt thereof in an amount equivalent to 0.25 mg to 90 mg of pramipexole dihydrochloride monohydrate per unit form; pramipexole or a pharmaceutically acceptable salt thereof in an amount equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate ; and an (S)-enantiomer in an amount per unit form equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate, comprising a 6-propylamino-4 ,5,6,7-tetrahydro-1,3-benzothiazol-2-amine selected from the group consisting of (R) / (S) mixtures in an amount per unit form of 50 mg to 3000 mg; or The (S)-enantiomer is contained in a unit form of 50 mg to 3000 mg. 6-propylamino-4,5, 6,7-Tetrahydro-1,3-benzothiazol-2-amine The present invention provides a pharmaceutical composition in unit dosage form comprising:

[0184] Preferably, the amount / unit form of the 5HT3-antagonist is selected to prevent postoperative nausea and vomiting. Effective for the prevention or treatment of chemotherapy-induced nausea and vomiting Doses shown or approved for use in children or adults that are less than or equal to the doses given. Both are the same dose and can be up to six times said dose.

[0185] In particular, according to a first embodiment, the present invention provides a pharmaceutical composition comprising a component, in admixture with a pharmaceutical carrier or vehicle. (a) Azasetron hydrochloride in an amount / unit equivalent to 5 mg to 10 mg 20 mg to 50 mg of phenylalanine and its pharma- ceutically acceptable salts and solvates, in particular its hydrochloride salt; Dolasetron in the form of 200 mg (in dolasetron mesylate) / unit and Pharmaceutically acceptable salts and solvates thereof, in particular the mesylate monohydrate thereof; 0.5 mg Granisetron in an amount / unit equivalent to ~2mg of granisetron base and its pharmaceutical formulations and its hydrochloride salts; 2 mg to 32 mg, usually 2 mg. Ondansetron in an amount / unit equivalent to 16 mg of ondansetron base and its equivalents 0.1 mg to 2 mg of pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate; Usually, palonosetron is administered in an amount / unit equivalent to 0.25 mg to 0.5 mg of palonosetron base. 2.5μ thoron and its pharma- ceutically acceptable salts and solvates, in particular its hydrochloride salt; A 5-HT3 antagonist selected from the group consisting of lamosetron in an amount / unit form equivalent to 100 mcg or less of lamosetron hydrochloride, and pharmaceutically acceptable salts and solvates thereof, particularly its hydrochloride; and tropisetron in an amount / unit form equivalent to 2.5 mg to 5 mg of tropisetron base, and pharmaceutically acceptable salts and solvates thereof, particularly its hydrochloride; and as component (b), a fixed-dose combination comprising a pharmaceutical composition in unit dosage form containing 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in an amount of 0.125 mg to 3000 mg per unit. Preferably, in the pharmaceutical composition, the 5-HT3 antagonist is ondansetron hydrochloride dihydrate in an amount per unit form equivalent to 2 mg to 32 mg of ondansetron base, and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is in an amount per unit form of 0.125 mg to 42 mg, or pramipexole dihydrochloride monohydrate in an amount per unit form of 0.125 mg to 45 mg. More specifically, the dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine per IR unit form of component (b) is usually 0.125 mg to 1500 mg, preferably 1.6 mg to 1500 mg, more preferably 1.625 mg to 1500 mg, depending on the safety and tolerability (in combination with the 5-HT3 antagonist of component (a)).

[0186]

[0187]

[0188] ​​​​​​​​​​​​​The dosage of 6-propylamino-4,5,6,7-tetrahydro-1,3- benzothiazole-2-amine per IR unit form is usually in the range of 1.5 mg to 1500 mg, depending on safety and tolerance (in combination with a 5HT3 antagonist).

[0189] According to this first embodiment, when the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine as component (b) of the fixed-dose formulation is pramipexole or a pharmaceutically acceptable salt or solvate thereof, the dosage range per unit form is, in combination with a 5HT3 antagonist, depending on safety and tolerance, from 0.125 mg to 42 mg, usually from 1.5 mg to 42 mg, 1.6 mg to 4 2 mg, 1.625 mg to 42 mg, 3 mg to 42 mg, greater than 4.5 mg to 42 mg, greater than 6 m g to 42 mg, and 6.5 mg to 42 mg, equivalent to the range selected from the group consisting of pramipexole dihydrochloride monohydrate.

[0190] In some cases, especially for use at the start of treatment, according to this first embodiment, the pramipexole in the pharmaceutical composition is, in combination with a 5HT3 antagonist, depending on safety and tolerance, in an amount per unit form equivalent to 0.125 mg to 21 mg, or in the dosage range per unit form equivalent to 0.125 mg to 10 mg, preferably 1.5 mg to 10 mg, more preferably 1.6 mg to 10 mg, preferably 1.625 mg to 10 mg of pramipexole dihydrochloride monohydrate.

[0191] ​​​​​​​In the case where 6-propylamino-4,5,6,7-tetrahydro- 1,3-benzothiazol-2-amine of component (b) of the fixed-dose combination agent is a (R) / (S)-mixture, the dose range per unit form is 50 mg to 3000 mg, containing an amount of the (S)-enantiomer per unit form equivalent to 0.125 mg to 42 mg of pramipexole dihydrochloride monohydrate is as follows.

[0192] The dose of 6-propylamino-4,5,6 ,7-tetrahydro-1,3-benzothiazol-2-amine as the (R) / (S)-mixture per IR unit form is 1.5 mg to 15 00 mg, depending on safety and tolerance (in combination with a 5HT3-antagonist). The above range may include a wider dose range including a lower dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine per IR unit form. The wider dose range per unit form of the above 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine may be 0.125 mg to 1500 mg, preferably 1.5 mg to 1500 mg, more preferably 1.6 mg to 1500 mg. In particular, as the (R) / (S)-mixture, the dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine per IR unit form is 50 mg to 3000 mg, containing an amount of the (S)-enantiomer equivalent to 0.125 mg to 21 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerance (in combination with a 5HT3-antagonist).

[0193] ​​​​​​​​​​​The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole -2-amine is pramipexole, the dosage range per IR unit form is, (in combination with a 5H T3-antagonist) depending on safety and tolerance, 0.12 5 mg to 21 mg, preferably more than 6 mg to 21 mg, or 6.5 mg to 21 mg of pr amipexole dihydrochloride monohydrate equivalent.

[0194] Generally, when the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothia zole-2-amine is pramipexole dihydrochloride monohydrate, the dosage range is, (5 in combination with an HT3-antagonist) depending on safety and tolerance, per IR single unit form, 0.125 mg to 10 mg, preferably 1.5 mg to 10 mg. When the 5 HT3-antagonist is ondansetron hydrochloride dihydrate, in combination with pramipexole dihydrochloride monohydrate, the dosage of ondansetron per IR unit form is 2 mg to 16 mg, or equivalent to 4 mg to 16 mg of ondansetron base. The dosage range of the above pramipexole dihydrochloride monohydrate can be included in a wider dosage range including a lower dosage of pramipexole dihydrochloride monohydrate per IR unit form. The wider dosage range of the pramipexole dihydrochloride monohydrate per unit form can be 0.125 mg to 10 mg, 1.5 mg to 10 mg, 1.6 mg ~10 mg, or 1.625 mg to 10 mg per IR unit form. ER formulations including transdermal therapeutic systems such as sustained release compositions and transdermal patches, the 6-propyl

[0195] in the ER formulation Dosage of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine / Unit form is, (in combination with a 5HT3-antagonist) depending on tolerance, in the range of 3 mg to 3000 mg.

[0196] When the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole -2-amine is pramipexole, the dosage range / ER unit form is 1.5 mg to equivalent to 42 mg of pramipexole dihydrochloride monohydrate. Advantageously, when the 6-prop ylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pr amipexole, the dosage range / ER unit form is greater than 4.5 mg to 42 mg preferably greater than 6 mg to 42 mg, and 6.5 mg to 42 mg, and is equivalent to the range selected from the group consisting of pramipexole di hydrochloride monohydrate.

[0197] Generally, when the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothia zol-2-amine is pramipexole dihydrochloride monohydrate, the dosage range / ER unit form is 1.5 mg to 20 mg, usually 3 mg to 20 mg. Advantageously, when the 6 -propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-a mine is pramipexole or a pharmaceutically acceptable salt thereof, the dosage range / ER unit form is greater than 4.5 mg to 20 mg, preferably greater than 6 mg to 20 mg of pramipe xole dihydrochloride monohydrate.

[0198] When the 5HT3-antagonist is ondansetron, the dosage / ER unit form is 4 mg to 32 mg, or in the range of 8 mg to 32 mg.

[0199] When the 5HT3 antagonist is dolasetron, 6- in the above dosage / unit form propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine The dosage / unit form in combination with is 1.5 mg to 200 mg, preferably in the range of 20 mg to 200 mg (in the case of dolasetron mesylate).

[0200] According to this first embodiment, the 6-propylamino of component (b) of the fixed-dose formulation -4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, in an ER formulation including a transdermal therapeutic system such as a sustained-release composition and a transdermal patch When it is a (R) / (S) mixture, the dosage range / ET unit is (in combination with a 5HT3 antagonist) depending on tolerance, 3 mg to 42 mg, preferably more than 6 mg to 42 mg, or 6 .5 mg to 42 mg, containing an amount per unit form of (S)-enantiomer equivalent to that of pramipexole dihydrochloride monohydrate, 150 mg to 3000 mg, advantageously 300 mg to 3 000 mg. 000 mg.

[0201] According to this first embodiment, the 6-propylamino of component (b) of the fixed-dose formulation -4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is a racemate When there is, the dosage range / ER unit form is more than 9 mg to 42 mg, preferably more than 12 m g to 42 mg, and equivalent to a range selected from the group consisting of 13 mg to 42 mg of pramipexole dihydrochloride monohydrate.

[0202] Furthermore, according to a further embodiment, the present invention provides a component mixed with a pharmaceutical carrier or medium​ (a) For the prevention and treatment of postoperative nausea and vomiting, or for the prevention of nausea and vomiting induced by chemotherapy, or is shown to be effective or approved for the prevention of nausea and vomiting induced by chemotherapy, a 5HT3-antagonist in an amount / unit form at least as high as that of pediatric or adult doses, and as component (b), an effective dose / unit form of 6-propylamino-4, 5,6,7-tetrahydro-1,3-benzothiazol-2-amine, or a pharmaceutical composition comprising the same, to provide a fixed-dose formulation. The advantageous pharmaceutical composition according to this fourth aspect of the present invention is mixed with a pharmaceutical carrier or vehicle, and (a) for the prevention and treatment of postoperative nausea and vomiting, or for the prevention or treatment of nausea and vomiting induced by chemotherapy, is shown to be effective or approved for the prevention of nausea and vomiting induced by chemotherapy, a 5HT3-antagonist in an amount at least as high as that of pediatric or adult doses; and

[0203] and (b) pramipexole dihydrochloride monohydrate in an amount at least as high as that of the dose approved for the treatment of Parkinson's disease. is included. (a) For the prevention and treatment of postoperative nausea and vomiting, or for the prevention or treatment of nausea and vomiting induced by chemotherapy, is shown to be effective or approved for the prevention or treatment of nausea and vomiting induced by chemotherapy, a 5HT3-antagonist in an amount at least as high as that of pediatric or adult doses; and and (b) pramipexole dihydrochloride monohydrate in an amount at least as high as that of the dose approved for the treatment of Parkinson's disease. is included. (b) pramipexole dihydrochloride monohydrate in an amount at least as high as that of the dose approved for the treatment of Parkinson's disease. is included. is included.

[0204] The preferred pharmaceutical composition according to this further aspect of the present invention is mixed with a pharmaceutical carrier or vehicle, and (a) a 5HT3-antagonist selected from the group consisting of ondansetron and pharmaceutically acceptable salts thereof in an amount of ondansetron in the range of 2 mg to 32 mg, 4 mg to 32 mg, or 4 mg to 16 mg; and (a) a 5HT3-antagonist selected from the group consisting of ondansetron and pharmaceutically acceptable salts thereof in an amount of ondansetron in the range of 2 mg to 32 mg, 4 mg to 32 mg, or 4 mg to 16 mg; and and (b) 0.125 mg to 42 mg, or particularly, at the start of treatment, 1.5 mg to 20 m is included. (b) 0.125 mg to 42 mg, or particularly, at the start of treatment, 1.5 mg to 20 m g, or an amount equivalent to pramipexole dihydrochloride monohydrate of more than 6 mg to 20 mg of prami mipexole and pharmaceutically acceptable salts and solvates thereof selected from the group consisting of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine is included.

[0205] More specifically, in the fixed-dose formulation, the 6-propylamino- 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine of component (b) is more than 4.5 mg to 21 mg, more than 6 mg to 21 mg, and a dose range per IR unit form selected from the group consisting of 6.5 mg to 21 mg of pramipexole di hydrochloride monohydrate, or a dose range per ER unit form selected from the group consisting of more than 4. 5 mg to 42 mg, more than 6 mg to 42 mg, and 6.5 mg to 42 mg of pramipexole di hydrochloride monohydrate which is .

[0206] Pharmaceutical composition 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine, for use contemplated in the treatment of synucleinopathies in combination with a 5HT3-antagonist is formulated into a pharmaceutical composition, said 5HT3-antagonist is mixed with a pharmaceutical carrier or vehicle.

[0207] In particular, as described above, according to the present invention, the aforementioned 5HT3-antagonist and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine, separately or together, are usually formulated into a pharmaceutical composition useful as a medicine for treating patients suffering from synucleinopathy.

[0208] The pharmaceutical composition may be formulated into an oral form such as tablets or gelatin capsules , 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine or a pharmaceutically acceptable salt or solvate thereof, or a 5HT3-antag onist, or both active ingredients, are mixed with a carrier or vehicle which may include diluents such as cellulose, dextrose, lactose, manni tol, sorbitol or sucrose; lubricants such as acids, calcium stearate or magnesium stearate, polyethylene glycol, silica or talc; and, if necessary, binders such as magnesium aluminum silicate, gelatin, methylcellulo se, sodium carboxymethylcellulose or polyvinylpyrrolidone.

[0209] The oral form may be tablets coated with sucrose or various polymers , or alternatively, the tablets may have an extended or delayed activity by gradually releasing a predetermined amount of 6-propylamino-4,5,6,7-tetrahydro-1, 3-benzothiazol-2-amine (or a pharmaceutically acceptable salt or solvate thereof ) or a 5HT3-antagonist, or both active ingredients, using carriers such as polymers and copolymers of acrylic acid and methacrylic acid; cellulose derivatives such as hydroxypropyl ethyl cellulose ; or other suitable materials. Oral formulations may also contain 6-propylamino-4,5,6,7-tetrahydro-1,3 -benzothiazol-2-amine (or a pharmaceutically acceptable salt or solvate thereof) Or a sustained release of a 5HT3-antagonist, or both active ingredients, may be in the form of a capsule agent.

[0210] The pharmaceutical composition may also be formulated into a TTS such as a patch preparation, and the active ingredient or the mixture of active ingredients may contain any auxiliary ingredients such as D-sorbitol, gelatin, kaolin, methylparaben, polysorb ate 80, propylene glycol, propylparaben, povidone, carboxymethylcell ulose sodium, sodium polyacrylate, tartaric acid, titanium dioxide and purified water. The patch preparation may also contain a skin penetration enhancer such as a lactate ester (e.g., lauryl lactate), triacetin or diethylene glycol monoethyl ether.

[0211] "Transdermal drug delivery system" provides transdermal delivery using a transdermal drug formulation, and a transdermal patch incorporating such a transdermal drug formulation. For example, a transdermal drug delivery system may include a composition in the form of a patch, cream, gel, lotion or paste containing a 5HT3-antagonist (such as ondansetron). Examples of transdermal formulations include, but are not limited to, those described in U.S. Patent No. 6,562,368, U.S. Patent No. 7, 029,694, U.S. Patent No. 7,179,483, U.S. Patent No. 8,241,662 and transdermal gel formulations described in U.S. Patent Application Publication No. 2009 / 0018190, International Publication No. 2005 / 039531, U.S. Patent Application Publication No. 2007 / 022379, U.S. Patent Application Publication No. 2010 / 0216880, U.S. Patent Application Publication No. 2014 / 003 7713 and liquid formulations, creams, described in U.S. Patent No. 8,652,491, lotions, Drug delivery topicals, such as lotions, sprays, ointments, gels, aerosols and patches Transdermal or transmucosal pharmaceutical compositions that can be used for transdermal or transmucosal application, International Publication No. 2003 / 0136662, No. 013 / 061969 and U.S. Patent Application Publication No. 2014 / 0271796. and transdermal preparations which have been described in US Pat. No. 6,399,343, the disclosures of which are incorporated herein by reference in their entirety. Transdermal patches are also disclosed in, but not limited to, U.S. Pat. The inherent stiff catheter and flexible mechanism described in US Pat. No. 9,782,536 and and / or a patch pump with a flexible catheter attachment, U.S. Pat. No. 9,771,633. No. 24,462; the selectively activatable patch pump described in U.S. Pat. No. 9,6 A patch pump connected to a wireless communication system as described in U.S. Pat. No. 23,173; The compliant patch pump described in U.S. Pat. No. 9,616,171, U.S. Pat. No. 8,915 No. 8,480,649; Portable infusion drug delivery, such as the microparticles described in U.S. Pat. No. 8,282,366. and the patch pump described in U.S. Pat. No. 7,828,771. and other similar techniques, the disclosures of which are incorporated herein by reference in their entireties. Patches include, but are not limited to, those described in U.S. Pat. No. 8,802,134. The adhesive layer composition contains oxybutynin and an acrylic polymer as an adhesive base. The acrylic polymer is incorporated into the copolymer of polymethyl methacrylate and polyacrylate. The patch is a polymer, and at least one of the polymers described in U.S. Pat. No. 8,877,235 is A patch consisting of a support layer and an adhesive layer disposed on the surface of the support layer, U.S. Pat. No. 5,443,333. Skin penetration enhancers described in U.S. Patent No. 4,174,0 and U.S. Patent No. 5,550,222 Patches that use monoglycerides or mixtures of monoglycerides of fatty acids as described in U.S. Patent No. 5,686,097, U.S. Patent No. 5,747,065, U.S. Patent No. 5,747, 065, U.S. Patent No. 5,750,137, and U.S. Patent No. 5,900,250, and patches that use monoglycerides or mixtures of monoglycerides and lactic acid esters as skin penetration enhancers described in U.S. Patent No. 5,614,211 and U.S. Patent No. 5,63 5,203, patches having a non-rate controlling tie layer on the skin proximal surface of a reservoir that does not affect drug release, as described in U.S. Patent No. 5,212,199, U.S. Patent No. 5,227,169, U.S. Patent No. 5,601,839, and U.S. Patent No. 5,834,0 10, patches that use triacetin as a penetration enhancer, as described in U.S. Patent No. 6 ,555,129, patches having a matrix body in the form of a self-adhesive layer, wherein the matrix body is composed of an ammonium group-containing (meth)acrylate copolymer, as described in U.S. Patent No. 6,743,441, U.S. Patent No. 7,081,249, U.S. Patent No. 7,081,250, U.S. Patent No. 7,081,251, U.S. Patent No. 7,081,252 and U.S. Patent No. 7,087,241 can be mentioned, and these disclosures are hereby incorporated herein by reference in their entirety. Preferably, the transdermal drug delivery system is a patch, a patch pump, an infusion pump, or a micropump.

[0212] In the above pharmaceutical composition, a preferred active ingredient of the 5HT3-antagonist is ondansetron.​ The active ingredient is ondansetron base or its hydrochloride dihydrate, or droperidol base or droperidol mesylate monohydrate, and preferably 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole base or pramipexole dihydrochloride monohydrate. In the pharmaceutical composition of the present invention for oral, subcutaneous, intravenous, transdermal or topical administration, the active ingredient is preferably administered in the form of a dosage unit mixed with a classical pharmaceutical carrier or vehicle.

[0213] The dosage, that is, the amount of the active ingredient in a single dose administered to the patient, can vary widely depending on the patient's age, weight and health condition. This dosage can be, depending on the strength of the dosage of each active ingredient, once to three times a day by intravenous, subcutaneous, oral or transdermal administration, and the dosage of each 5HT3-antagonist is 1 μg to 30 mg depending on the efficacy of the 5HT3-antagonist and the patient's age, and the dosage of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is 1.5 mg to 1500 mg depending on the patient's age. including administration.

[0214] When the 5HT3-antagonist is ondansetron hydrochloride dihydrate, the dosage is in the range of 2 mg to 32 mg, 4 mg to 32 mg, or 4 mg to 16 mg (in the case of ondansetron), and when 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, the dosage is 0.125 mg to 42 mg, preferably 1.5 mg to 42 mg, or particularly

[0215] At the start of treatment, it is in the range of 1.5 mg to 20 mg.

[0216] Advantageously, the preferred composition is more than 4.5 mg to 42 mg, advantageously more than 6 mg to 42 m g, or contains an amount of pramipexole or a pharmaceutically acceptable salt thereof equivalent to that of pramipexole dihydrochloride monohydrate in the range of 6.5 mg to 42 mg per unit form per unit form.

[0217] In the case of the first treatment, the pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount equivalent to that of more than 4.5 mg to 20 mg, more than 6 mg to 20 mg, or 6.5 mg to 2 0 mg of pramipexole dihydrochloride monohydrate.

[0218] The dosage range per unit form of all of the above pramipexole includes, in particular, the low dosages that can be used in the case of the first dosage setting of the daily dosage of pramipexole. However, according to the present invention, the therapeutically effective pramipexole or a pharmaceutically acceptable salt or solvate thereof in the treatment of synucleinopathy by the combination described above, including a fixed-dose formulation, is more than 4.5 mg / day to 42 mg / day, preferably equivalent to more than 6 mg / day to 42 mg / day of pramipexole dihydrochloride monohydrate.

[0219] The combination of the present invention also enables the full expression of the effectiveness of pramipexole by allowing the administration of a dosage of pramipexole higher than the maximum recommended dosage approved for the reduction of the motor symptoms of Parkinson's disease, and is useful for Parkinson's disease, Lewy body disease (LBD) or dementia with Lewy bodies (DLB), glucocerebrosidase (GBA) mutations or dementia with Lewy bodies (DLB), glucocerebrosidase (GBA) mutations or dementia with Lewy bodies (DLB), glucocerebrosidase (GBA) mutations Having related Parkinson's disorder, Alzheimer's disease, Lewy body variant of AD, brain iron accumulation New tools for the treatment of synucleinopathies such as neurodegeneration and multiple system atrophy are presented.

[0220] The pharmaceutical compositions of the present invention are formulated with classical excipients suitable for administration in different ways and are particularly advantageous in the form of tablets, multi-scored tablets, coated tablets, orally disintegrating tablets, sustained release tablets, hard or soft capsules, sustained release capsules, patches for transdermal administration, liquid oral solutions, syrups or suspensions in defined unit forms and vials for intravenous or subcutaneous administration. It is particularly advantageous to be formulated in this way.

[0221] Thus, for example, 0.375 mg to 42 mg, in some cases 3 mg to 20 mg, preferably a daily dose of more than 6 mg to 20 mg, 0.125 mg to 21 mg, preferably 3 mg to 21 mg of the amount / IR unit form, or in some cases 0.125 mg to 10 mg, usually 1.5 mg to 10 mg, preferably 1.6 mg to 10 mg of the amount / IR unit form of 6-propylamino-4,5,6,7-tetrahydro-1 ,3-benzothiazol-2-amine (preferably pramipexole dihydrochloride monohydrate ) administered in combination with the pharmaceutical composition according to the present invention is an aro serotonin hydrochloride in an amount of 0.25 mg to 2 mg / unit dose (in aroserotonin) administered in a daily dose of 0.25 mg to 3 mg ; azaserotonin hydrochloride in an amount of 5 mg to 10 mg / unit dose administered in a daily dose of 15 mg to 20 mg; droserotonin mesylate in an amount of 25 m g to 200 mg / unit dose (in droserotonin mesylate) administered in a daily dose of 75 mg to 200 mg Ruan acid salt monohydrate; granisetron hydrochloride in an amount / unit dose equivalent to 0.5 mg to 2 mg of granisetron base, administered at a daily dose of 1.5 mg to 8 mg; ondansetron hydrochloride dihydrate in an amount / unit dose equivalent to 2 mg to 8 mg of ondansetron base, administered at a daily dose of 6 mg to 32 mg; palonosetron hydrochloride in an amount / unit dose equivalent to 0.25 mg to 0.5 mg of palonosetron base, administered at a daily dose of 0.75 mg to 2 mg; ramosetron hydrochloride in an amount / unit dose equivalent to 50 μg to 20 mg, administered at a daily dose of 75 mcg to 40 mg; and tropisetron hydrochloride in an amount / unit dose equivalent to 2.5 mg to 5 mg of tropisetron base, administered at a daily dose of 7.5 mg to 20 mg may be included. .

[0222] In the case of pediatric or obese patients, the daily dose of the 5HT3 - antagonist may be determined based on body weight. Thus, for example, azasetron hydrochloride may be administered at a daily dose of 0.4 - 0.5 mg / kg, dolasetron mesylate may be administered at a daily dose of 9 - 9.5 mg / kg, granisetron hydrochloride may be administered at a daily dose of 0.09 - 0.11 mg / kg, ondansetron hydrochloride dihydrate may be administered at a daily dose of 0.45 - 0.55 mg / kg, palonosetron hydrochloride may be administered at a daily dose of 0.03 mg / kg, and tropisetron hydrochloride may be administered at a daily dose of 0.5 - 0.6 mg / kg. .

Example

[0223] The ability of 5HT3 - antagonists to prevent gastrointestinal (GI) adverse effects (AE) of pramipexole in humans was tested. ​​​​​​​​​​​

[0224] A Phase I trial was conducted in subjects administered a single oral dose of ondansetron hydrochloride dihydrate ("ondansetron") with or without a single oral dose of pramipexole dihydrochloride monohydrate ("pramipexole"). This trial was a single-site, single-blind study.

[0225] The purpose of the trial was to demonstrate that ondansetron could safely attenuate the gastrointestinal side effects of pramipexole administered at a dose equal to or greater than the dose approved for

[0226] treatment of Parkinson's disease or the dose shown in clinical trials to be effective for the treatment of depression. 1. Male and female subjects, including both ages 20 - 45. 2. Women of childbearing potential must abstain or agree to use any two of the following medically acceptable forms of contraception from screening through 14 days after the last visit of the trial: condom and spermicidal jelly, diaphragm or cervical cap and spermicidal jelly, or intrauterine device (IUD). Women with a vasectomized male partner must agree to use one additional form of medically acceptable contraception. Subjects must agree to use the above birth control methods for 14 days after the final visit as a safety measure. Not necessary. The reason is that it must be documented in the original materials. 4. Males with a female partner who is potentially fertile must agree to use a highly effective medically acceptable method of contraception from the screening period until 14 days after the last visit of the trial. Males who are surgically sterile (post-vasectomy) and have a female partner who is potentially fertile must agree to use condoms and spermicides for the same period. Male subjects must agree to implement the above birth control methods for 14 days after the final visit as a safety measure. 5. Subjects must have a medical history, including personal and family psychiatric history and the results of a health examination, an electrocardiogram (ECG), vital signs, and a good health status determined by clinical tests. Subjects with medical abnormalities may only be included if the researcher or designee determines that the abnormality does not pose a significant additional risk to the subject's health or interfere with the purpose of the trial. 6. Subjects must be able to clearly and reliably communicate any changes in their medical condition. 7. Subjects with a body mass index (BMI) between 19.0 and 32.0 kg / m 2 (including both). 8. Subjects who can swallow multiple tablets or capsules simultaneously. 9. Subjects must sign an informed consent indicating that they understand the purpose and necessary procedures of this trial, voluntarily participate in the trial, and comply with the trial procedures and restrictions.

[0227] Important exclusion criteria: ​​​​​​​​​​The criteria for excluding subjects from registration in this study were as follows: 1. Any clinically relevant acute or chronic disease that may interfere with the safety of the subject during the trial, expose the subject to excessive risks, or interfere with the purpose of the trial . 2. History or presence of diseases of the gastrointestinal tract, liver or kidneys, or other conditions known to interfere with the absorption, distribution, metabolism or excretion of the drugs in this trial . 3. History of drug abuse, dependence on known drugs, or positive test for drug abuse or alcohol . 4. History of drug or other major allergic reactions . 5. Known hypersensitivity to pramipexole, or to ondansetron or similar serotonin receptor antagonists, or to aprepitant or similar substance P / NK1 receptor antagonists . 6. Prolongation of the QT interval of the current, congenital long QT syndrome, electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmia, or history of other pharmaceuticals that cause QT prolongation or first-degree AV block in men at ≥ 450 QTcF and in women at ≥ 470 QTcF on day - 1 or before dosing . - 7. Treatment with centrally acting drugs or antiemetics within 1 month of trial entry . 8. Tobacco or nicotine users (except subjects who stopped using tobacco or nicotine more than 1 year before trial registration) . 9. Excessive daily consumption of xanthine-containing beverages (i.e., > 500 mg / day of caffeine) . 10. Subjects who dislike suppression of long-term intensive exercise during the trial period (from screening visit to final dosing of the trial drug) . 11. Positive test results for hepatitis B surface antigen and hepatitis C antibody. 12. Positive test results for serology of HIV-1 or -2. 13. During the test period, any medical or dental treatment may be required. 14. Use of any prescription or over-the-counter medications within 14 days before admission on day -1. In addition, any medication with central effects is prohibited for a period equal to 5 times the half-life of the drug before admission (day -1), and this period must be longer than 14 days. 15. Subjects who are likely to be uncooperative during the test and / or subjects who are suspected of being ineligible in the opinion of the researcher. 16. Subjects who cannot be contacted in case of acute illness. 17. Intake of investigational drug within 30 days of test entry. 18. Showing signs of suicidal ideation within the past 6 months as evaluated by the C-SSRS (Columbia Suicide Severity Rating Scale) at screening.

[0228] After registering for the test, participants were administered a single oral escalating dose of pramipexole once a day in the morning (Test Period 1). The starting dose of pramipexole was 0.5 mg, and this dose was increased by 0.5 mg increments daily. When the subject reached the subject's first intolerable dose (FID-1), the upward dose increase was stopped. The first intolerable dose (FID) was defined as follows: - 1(1) episode of vomiting; or - 2(2) episodes of nausea, or - 1(1) episode of severe nausea lasting more than 1 hour (Grade 3; defined as nausea that interferes with daily activities or inadequate oral calorie or fluid intake; requiring tube feeding, total parenteral nutrition, or hospitalization), or - 1(1) episode of dizziness; or - 1(1) episode of syncope; or - Continuous episodes (Grade 2; subjectively symptomatic but not interfering with activities of daily living) of moderate vomiting every 4 hours in 3(3), or - One (1) episode of moderate diarrhea (Grade 2; defined as 4 - 6 more stools than baseline) in 1(1).

[0229] When the subject reached FID - 1 for pramipexole alone, the subject was washed out for at least 5 days and then entered Period 2 of the study, during which the subject received a single oral daily dose of pramipexole starting at 0.5 mg and escalating in 0.5 mg increments until the subject reached the intolerable dose defined above, together with oral ondansetron hydrochloride dihydrate (equivalent to 10 mg, 8 mg of ondansetron base). The FID for oral pramipexole and oral ondansetron was designated FID - 2. (equivalent to 10 mg, 8 mg of ondansetron base).

[0230] If the subject reached FID - 2 during Period 2 at the same or lower dose as FID - 1 and the study responsible physician determined that there were no safety concerns and the subject consented, the subject received the same dose of pramipexole as the FID - 2 dose, together with a higher dose of oral ondansetron hydrochloride dihydrate (equivalent to 20 mg, 16 mg of ondansetron base), the next day. The protocol specified that the subject should continue the remainder of the dose titration with a higher dose of oral ondansetron hydrochloride dihydrate (equivalent to 20 mg, 16 mg of ondansetron base) until the subject reached the intolerable dose (FID2+). All other conditions of the protocol were kept unchanged. The assessments were the same as those planned for the dose increase day. ​​

[0231] On each test day, the subjects were followed up for AE, vital signs, and ECG up to 8 hours after drug administration. In addition, the test panel was obtained at the end of screening and the study.

[0232] Three subjects were enrolled in this study. The demographic characteristics of the subjects are summarized in Table 1 below.

[0233]

Table 1

[0234] All subjects reached FID-1 (pramipexole alone) during the study. Dose-limiting toxicity was gastrointestinal adverse events in all five subjects. For all subjects, FID-2 was higher than FID-1. During Period 2 of the study, three of the five subjects tolerated the maximum dose of pramipexole as defined by the 6 mg protocol and thus did not reach FID-2 (pramipexole and ondansetron). In other words, co-administration of ondansetron and pramipexole prevented the occurrence of gastrointestinal dose-limiting adverse events associated with high doses of pramipexole. Table 2 lists the values for each subject for FID-1 (pramipexole alone) and FID-2 (pramipexole + ondansetron).

[0235]

Table 2

[0236] As shown in Table 3 below, the maximum tolerated dose (MTD) during Period 2 was in all subjects.​​​​​​​​​​​ and higher than the MTD during Period 1, and in two subjects, MTD-2 increased up to more than three-fold .

[0237]

Table 3

[0238] Overall, the results indicate that co-administration of ondansetron and pramipexole attenuates the gastrointestinal dose-limiting adverse effects reported with pramipexole alone, and thus, 5HT3 antagonists enable the administration of pramipexole to humans at other intolerable doses when administered alone.

[0239] In conclusion, co-administration of ondansetron and pramipexole inhibits the occurrence of gastrointestinal AEs associated with administration of pramipexole alone, and thus, the dose of pramipexole can be safely and tolerably increased up to more than two-fold, thereby enabling much higher efficacy of this drug.

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Claims

1. A pharmaceutical composition for treating a synucleinopathy in a patient, comprising a therapeutically effective daily dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, or a pharma-ceutically acceptable salt or solvate thereof, in combination with an effective daily dose of ondansetron, or a pharma-ceutically acceptable salt or solvate thereof.

2. 2. The pharmaceutical composition of claim 1, wherein the effective daily dose of ondansetron or a pharma- ceutically acceptable salt or solvate thereof is from 1 μg to 300 mg.

3. 2. The pharmaceutical composition of claim 1, wherein the ondansetron or a pharma- ceutically acceptable salt or solvate thereof is ondansetron hydrochloride dihydrate.

4. The pharmaceutical composition of claim 1, wherein the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharma- ceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate.

5. 2. The pharmaceutical composition of claim 1, wherein said ondansetron or a pharma- ceutically acceptable salt or solvate thereof is ondansetron hydrochloride dihydrate in an effective daily dose of 4 mg to 32 mg and said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharma- ceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate in a therapeutically effective daily dose of 1.5 mg to 42 mg.

6. 2. The pharmaceutical composition of claim 1, wherein the ondansetron or a pharma- ceutically acceptable salt or solvate thereof and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharma- ceutically acceptable salt or solvate thereof are each formulated into a pharmaceutical composition in unit dosage form comprising the ondansetron or a pharma- ceutically acceptable salt or solvate thereof and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharma- ceutically acceptable salt or solvate thereof, respectively, in admixture with a pharmaceutical carrier or vehicle.

7. The ondansetron or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit dosage form equivalent to 2 mg to 32 mg of ondansetron base, and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit dosage form of 0.125 mg to 3000 mg, the pharmaceutical composition according to claim 6.

8. The pharmaceutical composition according to claim 7, wherein the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate in an amount per unit dosage form exceeding 4.5 mg to 42 mg.

9. The pharmaceutical composition according to claim 8, wherein the pramipexole dihydrochloride monohydrate is in an amount per unit dosage form exceeding 6 mg to 42 mg.

10. The pharmaceutical composition according to claim 8, wherein the pramipexole dihydrochloride monohydrate is in an amount per unit dosage form of 6.5 mg to 42 mg.

11. The ondansetron or a pharmaceutically acceptable salt or solvate thereof and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof are co-formulated into a unit dosage form of a pharmaceutical composition containing the ondansetron or a pharmaceutically acceptable salt or solvate thereof in an amount per unit dosage form equivalent to 2 mg to 32 mg of ondansetron base, and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof in an amount per unit dosage form of 0.125 mg to 3000 mg, mixed with a pharmaceutical carrier or vehicle. The pharmaceutical composition according to claim 1.

12. The pharmaceutical composition according to claim 11, wherein the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit dosage form equivalent to 0.125 mg to 42 mg of pramipexole dihydrochloride monohydrate.

13. The pharmaceutical composition according to claim 12, wherein the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate in an amount per unit dosage form of more than 4.5 mg to 42 mg.

14. The pharmaceutical composition according to claim 12, wherein the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate in an amount per unit dosage form of more than 6 mg to 42 mg.

15. The pharmaceutical composition according to claim 12, wherein the ondansetron or a pharmaceutically acceptable salt or solvate thereof is ondansetron hydrochloride dihydrate in an amount equivalent to 2 mg to 32 mg of ondansetron base per unit dosage form, and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate in an amount per unit dosage form of 0.125 mg to 42 mg.

16. The pharmaceutical composition according to claim 1, wherein the synucleinopathy is selected from the group consisting of Parkinson's disease, Lewy body dementia, mutations in the glucocerebrosidase gene, and multiple system atrophy.

17. (a) Ondansetron or a pharmaceutically acceptable salt or solvate thereof in an amount per unit dosage form of 1 μg to 300 mg, and (b) A 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit dosage form equivalent to 0.25 mg to 84 mg of pramipexole dihydrochloride monohydrate; pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit dosage form equivalent to 0.125 mg to 42 mg of pramipexole dihydrochloride monohydrate; and an (S)-enantiomer or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit dosage form equivalent to 0.125 mg to 42 mg of pramipexole dihydrochloride monohydrate, comprising a (R) / (S) mixture in an amount per unit dosage form of 50 mg to 3000 mg, selected from the group consisting of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, mixed with a pharmaceutical carrier or vehicle, a unit dosage form pharmaceutical composition for treating synucleinopathy in a patient. **Claim 18** The composition according to claim 17, wherein the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is pramipexole or a pharmaceutically acceptable salt thereof in an amount per unit dosage form equivalent to more than 4.5 mg to 42 mg of pramipexole dihydrochloride monohydrate. **Claim 19** The composition according to claim 17, wherein the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is pramipexole or a pharmaceutically acceptable salt thereof in an amount per unit dosage form equivalent to more than 6 mg to 42 mg of pramipexole dihydrochloride monohydrate. **Claim 20** The composition according to claim 17, wherein the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is pramipexole or a pharmaceutically acceptable salt or solvate thereof in an amount per unit dosage form equivalent to 6.5 mg to 42 mg of pramipexole dihydrochloride monohydrate. **Claim 21** The ondansetron or a pharmaceutically acceptable salt or solvate thereof is ondansetron hydrochloride dihydrate in an amount equivalent to 2 mg to 32 mg of ondansetron base per unit dosage form, and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate in an amount per unit dosage form of 0.125 mg to 42 mg, the composition according to claim 17.

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