Pridopidine and its analogues for the treatment of neurodegenerative eye diseases

Abstract

According to the present disclosure, there is provided a pharmaceutical composition for treating a subject suffering from a neurodegenerative disease, the pharmaceutical composition comprising a predetermined amount of pridopidine and one of its analogs 1 to 8, and uses or applications thereof. Also provided according to the present disclosure is a method for treating a subject suffering from a neurodegenerative disease, the method comprising administering to the subject a pharmaceutical composition of the present disclosure in an amount effective to treat the subject.

Description

Technical Field

[0001] The present disclosure provides a composition for use in the treatment of neurodegenerative eye diseases and other neurodegenerative diseases, the composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of Compounds 1-8 (described herein) or a pharmaceutically acceptable salt thereof.

Background Art

[0002] (Pridopidine) Pridopidine (former name: ACR16, Huntexil (registered trademark)) is a highly pharmacologically active and highly selective sigma-1 receptor (S1R) agonist that is in clinical development as a therapeutic agent for neurodegenerative diseases such as Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). The chemical name of pridopidine is 4-(3-(methylsulfonyl)phenyl)-l-propylpiperidine, and the chemical substance registration number is CAS346688-38-8 (CSID:7971505, 2016). Also, the chemical substance registration number of pridopidine hydrochloride is 882737-42-0 (CSID:25948790, 2016). The synthesis processes of pridopidine and its pharmaceutically acceptable salts are disclosed in Patent Document 1 and Patent Document 2. Further, Patent Document 3 discloses pridopidine for treating Parkinson's disease, dyskinesia, dystonia, Tourette's disease, iatrogenic or non-iatrogenic psychosis or hallucinations, mood disorders or anxiety disorders, sleep disorders, autism spectrum disorder, ADHD, Huntington's disease, age-related cognitive impairment, and disorders associated with alcohol abuse or drug abuse.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

[0004] The present invention provides a method for treating, alleviating, or suppressing neurodegenerative eye disease or its symptoms in a subject, comprising the step of administering to the subject a composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 represented by the following formula or a pharmaceutically acceptable salt thereof.

[0005] [ka]

[0006] In other embodiments, the symptoms of neurodegenerative eye disease are damage or loss of optic nerve axons. In other embodiments, the symptoms of neurodegenerative eye disease are loss or death of retinal ganglion cells (RGCs). In other embodiments, the compositions of the Disclosure are effective in reducing or preventing loss or damage of optic nerve axons in a subject. In other embodiments, the compositions of the Disclosure are effective in reducing or preventing loss or death of retinal ganglion cells (RGCs) in a subject.

[0007] In other embodiments, optic nerve axon loss is reduced by at least 3%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In other embodiments, optic nerve axon loss is reduced by more than 50%, more than 60%, more than 70%, or more than 80%. In other embodiments, the compositions of the Disclosure are effective in protecting optic nerve axons from degeneration in a subject. In other embodiments, axonal degeneration is caused by increased intraocular pressure.

[0008] Furthermore, the present invention provides a method for preventing or reducing damage or loss of retinal ganglion cells in a subject, comprising the step of administering to the subject in an amount effective to prevent or reduce damage or loss of retinal ganglion cells, a composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or a pharmaceutically acceptable salt thereof.

[0009] Furthermore, the present invention provides a method for treating neurodegenerative eye disease in a subject, comprising the step of administering to the subject in an amount effective to provide a neuroprotective effect on retinal ganglion cells of a composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 represented by the following formula or a pharmaceutically acceptable salt thereof.

[0010] [ka]

[0011] Furthermore, the present invention provides a pharmaceutical composition for treating subjects suffering from neurodegenerative eye diseases, comprising a predetermined amount of pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof.

[0012] Furthermore, the present invention provides a pharmaceutical composition for use in combination therapy with a second pharmaceutical composition comprising a second agent for treating neurodegenerative eye diseases, the pharmaceutical composition comprising a predetermined amount of pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof.

[0013] Furthermore, the present invention provides a pharmaceutical composition for treating subjects suffering from neurodegenerative eye diseases as an add-on therapy, or for use in combination with a second agent for treating neurodegenerative eye diseases, comprising a predetermined amount of pridopidine or a pharmaceutically acceptable salt thereof, and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof.

[0014] Furthermore, the present invention provides a pharmaceutical composition in the form of a unit dose formulation useful for treating subjects suffering from neurodegenerative eye diseases, comprising a predetermined amount of pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, wherein the amount of pridopidine in the pharmaceutical composition is an effective amount for treating the subject when one or more unit dose formulations are administered to the subject. [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1 shows the synergistic effect of pridopidine and compound 4 on BDNF release from B104 cells. B104 neuroblastoma cells were cultured with the test compound for 5 days, and BDNF concentration was evaluated using in-situ ELISA. Figure 1(A): Shows the synergistic effect when 0.001 μM pridopidine and 0.001 μM compound 4 are used in combination. Pridopidine alone increased BDNF secretion by 13.5%. Compound 4 alone decreased BDNF secretion by 1.5%. When pridopidine and compound 4 were used in combination, BDNF secretion increased by 59.1%, and this effect was greater than the combined effect of administering both compounds individually. Figure 1(B): Shows the synergistic effect when 0.005 μM pridopidine and 0.001 μM compound 4 are used in combination. Pridopidine alone increased BDNF secretion by 26.0%. Compound 4 alone reduced BDNF secretion by 1.5%. Combining pridopidine with compound 4 increased BDNF secretion by 80.7%, an effect greater than the combined effect of administering each compound individually. [Figure 2]Figure 2 shows the synergistic effect of pridopidine and Compound 1 on BDNF release from B104 cells. B104 neuroblastoma cells were cultured with the test compounds for 5 days, and the BDNF concentration was evaluated using the in-situ ELISA method. Pridopidine alone at 0.01 μM increased BDNF secretion by 3.4%. Compound 1 alone at 1 μM increased BDNF secretion by 12.5%. When pridopidine and Compound 1 were used in combination, BDNF secretion increased by 53.1%, and this effect was greater than the sum of the effects when the two compounds were administered alone.

Mode for Carrying Out the Invention

[0016] The present invention provides a method for treating, delaying the progression of, reducing the exacerbation of, delaying the onset of, or delaying the progression of symptoms of a neurodegenerative disease or a neurodevelopmental disease in a subject, the method comprising administering to the subject a composition of the present disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of Compounds 1 to 8 represented by the following formula or a pharmaceutically acceptable salt thereof.

[0017]

Chemical formula

[0018] Neurodegenerative diseases or disorders are selected from the group consisting of Huntington's disease, prodromal / overt Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinson's disease with glucocerebrosidase (GBA) deficiency, dystonia, cognitive impairment, dyskinesia, mild cognitive impairment (MCI), Alzheimer's disease, age-related memory impairment, depression or anxiety, bacterial infection-induced depression, neurodegenerative eye diseases, optic neuropathy including glaucoma, age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), retinitis pigmentosa, microphthalmia, syndrome 12 (MCOPS12), mitochondrial diseases or dysfunctions (i.e., lysosomal storage disorders (LSD), leukodystrophy, leukodystrophy (VWM)), Wolfram's disease, and viral infections (COVID-19). Neurodevelopmental disorders or disorders are Rett syndrome or fragile X syndrome.

[0019] In some embodiments, the composition of the present disclosure used in the method of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1-8 or a pharmaceutically acceptable salt thereof, and the weight ratio of pridopidine or a pharmaceutically acceptable salt thereof to at least one of compounds 1-8 or a pharmaceutically acceptable salt thereof is in the range of 1:0.0001 to 1:0.1. In other embodiments, the weight ratio of pridopidine or a pharmaceutically acceptable salt thereof to at least one of compounds 1-8 or a pharmaceutically acceptable salt thereof is in the range of 1:0.0005 to 1:0.005. In other embodiments, the weight ratio of pridopidine or a pharmaceutically acceptable salt thereof to at least one of compounds 1-8 or a pharmaceutically acceptable salt thereof is in the range of 1:0.0005 to 1:0.0035. In other embodiments, the weight ratio of pridopidine or a pharmaceutically acceptable salt thereof to at least one of compounds 1-8 or a pharmaceutically acceptable salt thereof is in the range of 1:0.005 to 1:0.1. In other embodiments, the weight ratio of pridopidine or a pharmaceutically acceptable salt thereof to at least one of compounds 1-8 or a pharmaceutically acceptable salt thereof is in the range of 1:0.001 to 1:0.1. In other embodiments, the weight ratio of pridopidine or a pharmaceutically acceptable salt thereof to at least one of compounds 1-8 or a pharmaceutically acceptable salt thereof is in the range of 1:0.001 to 1:0.005.

[0020] In other embodiments, the composition of the Disclosure, comprising a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, as used in the method of the Disclosure, is administered in a daily dose of 0.5 to 315 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the Disclosure is an oral unit formulation administered in a daily dose of 0.5 to 315 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the oral unit formulation is administered in a daily dose of 1 to 10 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the oral unit formulation is administered in a daily dose of 10 to 22.5 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the oral unit formulation is administered in a daily dose of 22.5 to 315 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the oral unit formulation is administered in a daily dose of 10–315 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the oral unit formulation is administered in a daily dose of 0.5–50 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the oral unit formulation is administered in a daily dose of 45–250 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the oral unit formulation is administered in a daily dose of 45–135 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the oral unit formulation is administered in a daily dose of 90–315 mg of pridopidine or a pharmaceutically acceptable salt thereof.

[0021] In other embodiments, a method of the Disclosure for treating, slowing the progression of, mitigating the exacerbation of, delaying the onset of, or slowing the progression of a neurodegenerative or neurodevelopmental disorder in a subject includes the step of administering a composition of the Disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof to the subject. In other embodiments, the composition of the Disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 2 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition of the Disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 3 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition of the Disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition of the Disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 5 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition of the Disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 6 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition of the Disclosure comprises a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of compound 7 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition of the Disclosure comprises a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of compound 8 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition of the Disclosure comprises a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of compound 4 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition of the Disclosure comprises a primopidine base. In other embodiments, the composition of the Disclosure comprises a primopidine salt.

[0022] In some embodiments, the present invention provides a method for treating, slowing the progression of, mitigating the exacerbation of, delaying the onset of, or slowing the progression of a neurodegenerative or neurodevelopmental disorder in a subject, the method comprising administering to the subject a composition of the present disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof, and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and combinations thereof. Neurodegenerative diseases or disorders are selected from the group consisting of Huntington's disease, prodromal / overt Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinson's disease with glucocerebrosidase (GBA) deficiency, dystonia, cognitive impairment, dyskinesia, mild cognitive impairment (MCI), Alzheimer's disease, age-related memory impairment, depression or anxiety, bacterial infection-induced depression, neurodegenerative eye diseases, optic neuropathy including glaucoma, age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), retinitis pigmentosa, microphthalmia, syndrome 12 (MCOPS12), mitochondrial diseases or dysfunctions (i.e., lysosomal storage disorders (LSD), leukodystrophy, leukodystrophy (VWM)), Wolfram's disease, and viral infections (COVID-19). Neurodevelopmental disorders or disorders are Rett syndrome or fragile X syndrome. In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0023] In some embodiments, the present invention provides a method for treating, slowing the progression of, mitigating the exacerbation of, delaying the onset of, or slowing the progression of symptoms of a neurodegenerative or neurodevelopmental disorder in a subject, the method comprising administering to the subject a composition of the present disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof and Compound 1 or a pharmaceutically acceptable salt thereof. Neurodegenerative diseases or disorders are selected from the group consisting of Huntington's disease, prodromal / overt Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinson's disease with glucocerebrosidase (GBA) deficiency, dystonia, cognitive impairment, dyskinesia, mild cognitive impairment (MCI), Alzheimer's disease, age-related memory impairment, depression or anxiety, bacterial infection-induced depression, neurodegenerative eye diseases, optic neuropathy including glaucoma, age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), retinitis pigmentosa, microphthalmia, syndrome 12 (MCOPS12), mitochondrial diseases or dysfunctions (i.e., lysosomal storage disorders (LSD), leukodystrophy, leukodystrophy (VWM)), Wolfram's disease, and viral infections (COVID-19). Neurodevelopmental disorders or disorders are Rett syndrome or fragile X syndrome. In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0024] In some embodiments, the present invention provides a method for treating, slowing the progression of, mitigating the exacerbation of, delaying the onset of, or slowing the progression of symptoms of a neurodegenerative or neurodevelopmental disorder in a subject, the method comprising administering to the subject a composition of the present disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof, compound 1 or a pharmaceutically acceptable salt thereof, and compound 4 or a pharmaceutically acceptable salt thereof. Neurodegenerative diseases or disorders are selected from the group consisting of Huntington's disease, prodromal / overt Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinson's disease with glucocerebrosidase (GBA) deficiency, dystonia, cognitive impairment, dyskinesia, mild cognitive impairment (MCI), Alzheimer's disease, age-related memory impairment, depression or anxiety, bacterial infection-induced depression, neurodegenerative eye diseases, optic neuropathy including glaucoma, age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), retinitis pigmentosa, microphthalmia, syndrome 12 (MCOPS12), mitochondrial diseases or dysfunctions (i.e., lysosomal storage disorders (LSD), leukodystrophy, leukodystrophy (VWM)), Wolfram's disease, and viral infections (COVID-19). Neurodevelopmental disorders or disorders are Rett syndrome or fragile X syndrome. In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0025] In some embodiments, the present invention provides a method for treating, slowing the progression of, mitigating the exacerbation of, delaying the onset of, or slowing the progression of symptoms of a neurodegenerative or neurodevelopmental disorder in a subject, the method comprising administering to the subject a composition of the present disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. Neurodegenerative diseases or disorders are selected from the group consisting of Huntington's disease, prodromal / overt Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinson's disease with glucocerebrosidase (GBA) deficiency, dystonia, cognitive impairment, dyskinesia, mild cognitive impairment (MCI), Alzheimer's disease, age-related memory impairment, depression or anxiety, bacterial infection-induced depression, neurodegenerative eye diseases, optic neuropathy including glaucoma, age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), retinitis pigmentosa, microphthalmia, syndrome 12 (MCOPS12), mitochondrial diseases or dysfunctions (i.e., lysosomal storage disorders (LSD), leukodystrophy, leukodystrophy (VWM)), Wolfram's disease, and viral infections (COVID-19). Neurodevelopmental disorders or disorders are Rett syndrome or fragile X syndrome. In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0026] In another embodiment, the method of the present invention aims to delay the onset of symptoms in a patient with prodromal / manifest Huntington's disease having 36 or more CAG repeats in the huntingtin gene, and includes the step of administering a composition of the present disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and a combination thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof. In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0027] In other embodiments, the methods of the present invention are intended to treat or delay the progression of symptoms of prodromal / manifest Huntington's disease.

[0028] In other embodiments, the methods of the present invention maintain, reduce, or mitigate the increase in neurofilament light chains (NfLs) in biofluids (i.e., cerebrospinal fluid, blood, plasma). In other embodiments, the methods of the present invention maintain, reduce, or mitigate the increase in neurofilament light chains (NfLs) in biofluids (i.e., cerebrospinal fluid, blood, plasma) in patients with neurodegenerative diseases including Huntington's disease, ALS, and Parkinson's disease.

[0029] In other embodiments, the method of the present invention includes the step of administering a composition of the present disclosure, comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, for the purpose of treating Parkinson's disease, delaying its progression, mitigating its exacerbation, delaying its onset, or delaying the progression of its symptoms. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and a combination thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0030] In other embodiments, the method of the present invention includes the step of administering a composition of the present disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, for the purpose of treating, delaying the progression of, mitigating the exacerbation of, delaying the onset of, or delaying the progression of symptoms of Parkinson's disease associated with glucocerebrosidase (GBA) deficiency. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and a combination thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof. In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0031] In other embodiments, the method of the present invention includes the step of administering a composition of the present disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or a pharmaceutically acceptable salt thereof, to a subject for the treatment, delay of progression, reduction of exacerbation, delay of onset, or delay of progression of symptoms of Parkinson's disease, a disease associated with Parkinson's disease, or Parkinson's disease associated with glucocerebrosidase (GBA) deficiency. In other embodiments, symptoms include functional impairment and cognitive impairment. In certain embodiments, functional impairment is presented as a symptom selected from the group consisting of impairments according to the Unified Parkinson's Disease Rating Scale Part II (UPDRS Part II), including tremor, bradykinesia, rigidity, postural instability, and activities of daily living, and impairments according to the modified Hohen-Yahr classification of PD. In certain embodiments, functional impairment is presented as an impairment according to the Unified Parkinson's Disease Rating Scale Part II (UPDRS Part II), including activities of daily living. In certain embodiments, functional impairment of the subject is presented as an impairment according to the modified Hohen-Yahr classification.

[0032] In certain embodiments, cognitive decline is presented as a symptom selected from the group consisting of intellectual disability, thought disorders, depression, decreased motivation, decreased spontaneity, speech disorders, increased salivation, dysphagia, dysgraphia, and increased pain perception.

[0033] In other embodiments, the method of the present invention aims to treat dystonia, delay its progression, reduce its exacerbation, delay its onset, or delay the progression of its symptoms, and includes the step of administering a composition of the Disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof to a subject. In another embodiment, the dystonia is severe dystonia. In another embodiment, the symptoms of dystonia include involuntary limb movements or muscle contractions, twisted postures of the limbs or trunk, abnormal fixed postures of the limbs or trunk, equinovarus deformity, foot inversion, arm inversion, tremors of the hands, head, trunk or arms, leg dragging, torticollis, finger spasms, or dystonia of the trunk and / or limbs. In another embodiment, the composition of the Disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and combinations thereof. In another embodiment, the composition of the Disclosure comprises a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of Compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the Disclosure comprises a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of Compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the Disclosure comprises a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of Compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of Compound 4 or a pharmaceutically acceptable salt thereof. In yet another embodiment, the composition of the Disclosure comprises a primopidine base. In yet another embodiment, the composition of the Disclosure comprises a primopidine salt.

[0034] Severe dystonia can be determined by a score of 4 or higher on at least one body part of the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). The BFMDRS evaluates the severity and triggering factors for nine body parts (eyes, mouth, speech, swallowing, neck, trunk, right arm, right leg, left arm, left leg) on ​​a 5-point scale from 0 (no dystonia) to 4 (present dystonia at rest). A weighting coefficient of 0.5 is assigned to the dystonia scores for the eyes, mouth, and neck, while a weighting coefficient of 1.0 is assigned to the other six body parts. The score for each body part is obtained by multiplying the triggering factor by the severity factor and weighting factor, and then summing the scores for each body part. The maximum possible score is 120 points.

[0035] Severe dystonia can also be determined by a score of 4 or higher on at least one body part of the Unified Dystonia Rating Scale (UDRS). The UDRS assesses 14 body parts (eyes and upper face, lower face, jaw and tongue, larynx, neck, trunk, right shoulder / proximal arm, left shoulder / proximal arm, right distal arm / hand, left distal arm / hand, right proximal leg, left proximal leg, right distal leg / foot, left distal leg / foot) by evaluating the severity factor and duration coefficient for each part. The severity factor for each part is assessed on a 5-point scale from 0 (no dystonia) to 4 (severe dystonia). The duration factor is assessed on a 5-point scale from 0 (resting / activity) to 4 (submaximal / maximal). The total score is the sum of the scores for each domain (part), and the maximum possible score is 112.

[0036] In other embodiments, the method of the present invention includes the step of administering a composition of the present disclosure, comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, for the purpose of treating cognitive impairment, delaying its progression, mitigating its worsening, delaying its onset, or delaying the progression of its symptoms. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and a combination thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine base. In other embodiments, the compositions of the present disclosure include a pridopidine salt.

[0037] In certain embodiments, cognitive impairment is mild cognitive impairment. In certain embodiments, cognitive impairment includes memory loss. In certain embodiments, cognitive impairment includes age-related memory impairment.

[0038] Cognitive impairment refers to a impairment of a cognitive function selected from the group consisting of general cognitive function, sustained cognition, memory, language, executive function, and attention. In another embodiment, the cognitive function is memory. In one embodiment, memory is short-term memory. In another embodiment, memory is long-term memory. In another embodiment, memory is working memory. In one embodiment, the subject suffers from cognitive impairment. In another embodiment, the subject is prone to cognitive impairment. In one embodiment, cognitive impairment is memory impairment. In one embodiment, memory impairment is short-term memory impairment. In another embodiment, memory impairment is amnesia. In one embodiment, amnesia is caused by one or more of age-related memory impairment, mild cognitive impairment, dementia, and depression. In one embodiment, cognitive impairment is caused by or associated with a disease or disorder. In one embodiment, the disease or disorder is a disease or disorder related to NMDA receptors. In another embodiment, the disease or disorder is schizophrenia or autism. In another embodiment, the disease or disorder is epilepsy or anxiety disorder. In another embodiment, the disease or disorder is amyotrophic lateral sclerosis (ALS). In another embodiment, the disease or disorder is frontotemporal dementia (FTD). In another embodiment, the disease or disorder is mild cognitive impairment (MCI). In another embodiment, the disease or disorder is bipolar disorder. In another embodiment, the disease or disorder is Huntington's disease. In another embodiment, the disease or disorder is selected from the group consisting of major depressive disorder (MDD), Parkinson's disease, Alzheimer's disease, tardive dyskinesia, depression, sickle cell anemia, stroke, chronic pain syndrome, and intoxication. In another embodiment, the disease or disorder is selected from the group consisting of mild cognitive impairment, memory impairment, memory loss, memory impairment related to brain injury or post-stroke events, learning disability, and behavioral and cognitive problems related to brain tumors. In another embodiment, the disease or disorder is selected from the group consisting of dementia, Lewy body dementia, age-related cognitive decline, psychosis, attention deficit disorder (ADHD), bipolar disorder, brain injury, mood and affective disorders, Tourette syndrome, intellectual disability, progressive supranuclear palsy, Creutzfeldt-Jakob disease, corticobasal degeneration, vascular dementia, and Pick's disease.In another embodiment, the disease or disorder is selected from the group consisting of generalized anxiety disorder (GAD), social anxiety disorder (SAD), tardive dyskinesia, depression, sickle cell anemia, chronic pain syndrome, addiction, nicotine addiction, internet addiction, cocaine addiction, Tourette syndrome, intellectual disability, corticobasal degeneration, vascular dementia, Pick's disease, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, panic disorder (PD), trigeminal neuralgia, trigeminal musculoskeletal pain, phantom limb pain, irritable bowel syndrome, blepharospasm, complex regional pain syndrome, chronic low back pain, autism spectrum disorder (ASD), and infantile seizures (IS).

[0039] In other embodiments, the method of the present invention includes the step of administering a composition of the present disclosure, comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, for the purpose of treating dyskinesia, delaying its progression, mitigating its exacerbation, delaying its onset, or delaying the progression of its symptoms. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and a combination thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0040] Dyskinesia is a type of abnormal, involuntary movement of a part of the body, such as spasms, twisting, or writhing. There are several types of dyskinesia, classified as chorea, dystonia, myoclonus, tremor, and paroxysmal dizziness (late-onset). Examples of such movement disorders, though not limited to these, include Parkinson's disease, dizziness, chorea, dystonia, tremor, akathisia, athetosis, myoclonus, or tics. In some embodiments, the dyskinesia is L-DOPA-induced dyskinesia (LID). In some embodiments, the dyskinesia is Parkinson's disease (PD)-LID.

[0041] In other embodiments, the method of the present invention includes the step of administering a composition of the present disclosure, comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, for the purpose of treating Alzheimer's disease, delaying its progression, mitigating its exacerbation, delaying its onset, or delaying the progression of its symptoms. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and a combination thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0042] In other embodiments, the method of the present invention includes the step of administering a composition of the present disclosure, comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, for the purpose of treating, delaying the progression of, mitigating the worsening of, delaying the onset of, or delaying the progression of age-related memory impairment. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and a combination thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0043] In other embodiments, the method of the present invention includes the step of administering a composition of the present disclosure, comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, to a subject for the treatment, delay of progression, reduction of exacerbation, delay of onset, or delay of progression of neurodegenerative eye diseases, optic neuropathy including glaucoma, age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), retinitis pigmentosa, and related symptoms. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and a combination thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the Disclosure comprises a pharmaceutically acceptable salt thereof, compound 1 or a pharmaceutically acceptable salt thereof, and compound 4 or a pharmaceutically acceptable salt thereof. In yet another embodiment, the composition of the Disclosure comprises a pridopidine base. In yet another embodiment, the composition of the Disclosure comprises a pridopidine salt.

[0044] In other embodiments, the method of the present invention includes the step of administering a composition of the present disclosure, comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, to a subject for the treatment of Wolfram's disease, delaying its progression, mitigating exacerbations, delaying the onset, or delaying the progression of its symptoms. In other embodiments, symptoms of Wolfram's disease include urinary tract abnormalities, ataxia, loss of smell, loss of pharyngeal reflex, myoclonus, peripheral neuropathy, seizures, depression, impulsive and / or aggressive behavior, psychosis, gastrointestinal disorders, intellectual disability, irregular breathing, central apnea, central respiratory failure, hypogonadism in males, gastric and / or intestinal ulcers, and a tendency to bleed excessively from wounds. In yet another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and combinations thereof. In another embodiment, the composition of the Disclosure comprises a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of Compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the Disclosure comprises a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of Compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the Disclosure comprises a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of Compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of Compound 4 or a pharmaceutically acceptable salt thereof. In yet another embodiment, the composition of the Disclosure comprises a primopidine base. In yet another embodiment, the composition of the Disclosure comprises a primopidine salt.

[0045] In other embodiments, the method of the present invention includes the step of administering a composition of the present disclosure, comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, for the purpose of treating, delaying the progression of, reducing the exacerbation of, delaying the onset of, or delaying the progression of symptoms thereof for the purpose of treating bacterial infection-induced depression. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and a combination thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0046] In other embodiments, the method of the present invention includes the step of administering a composition of the present disclosure, comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, for the purpose of treating, delaying the progression of, reducing the exacerbation of, delaying the onset of, or delaying the progression of symptoms of symptomatic microphthalmia 12 (MCOPS 12). In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compound 1 or a pharmaceutically acceptable salt thereof, compound 4 or a pharmaceutically acceptable salt thereof, and a combination thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition of the present disclosure comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0047] In other embodiments, the present invention provides a method for treating, alleviating, or suppressing a neurodegenerative eye disease or its symptoms in a subject, comprising the step of administering a composition of the present disclosure to the subject, comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 represented by the following formula or a pharmaceutically acceptable salt thereof.

[0048] [ka]

[0049] In other embodiments, the compositions of the disclosure include a pridopidine base. In other embodiments, the compositions of the disclosure include a pridopidine salt.

[0050] In other embodiments, the symptoms of neurodegenerative eye disease are damage or loss of optic nerve axons. In other embodiments, the symptoms of neurodegenerative eye disease are loss or death of retinal ganglion cells (RGCs). In other embodiments, the compositions of the Disclosure are effective in reducing or preventing loss or damage of optic nerve axons in a subject. In other embodiments, the compositions of the Disclosure are effective in reducing or preventing loss or death of retinal ganglion cells (RGCs) in a subject.

[0051] In other embodiments, optic nerve axon loss is reduced by at least 3%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In other embodiments, optic nerve axon loss is reduced by more than 50%, more than 60%, more than 70%, or more than 80%. In other embodiments, the compositions of the Disclosure are effective in protecting optic nerve axons from degeneration in the subject. In other embodiments, axonal degeneration is caused by increased intraocular pressure.

[0052] In one embodiment, administration of the composition of the present disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof is effective in reducing or suppressing the symptoms of neurodegenerative eye disease in a subject.

[0053] In one embodiment, neurodegenerative eye diseases are selected from the group consisting of glaucoma, age-related macular degeneration, optic neuropathy, and retinitis pigmentosa. In another embodiment, neurodegenerative eye diseases refer to any disease affecting retinal ganglion cells, photoreceptors, other retinal nerve cells, and corneal nerves.

[0054] Optic neuropathy is a disease that affects retinal ganglion cells and their connections. Examples of optic neuropathy include glaucomatous optic neuropathy (also called glaucoma), inflammatory optic neuropathy (also called optic neuritis), ischemic optic neuropathy, toxic optic neuropathy, compressive optic neuropathy, infiltrative optic neuropathy, hereditary optic neuropathy, traumatic optic neuropathy, nutritional optic neuropathy, optic neuropathy due to increased intracranial pressure (also called palpebral hydrops optic neuropathy), optic disc drusen, autoimmune optic neuropathy, and other types of optic neuropathy. Each category of optic neuropathy has subcategories; for example, ischemic optic neuropathy includes non-arteritic anterior ischemic optic neuropathy, arteriotic anterior ischemic optic neuropathy, and posterior ischemic optic neuropathy.

[0055] In some embodiments, neurodegenerative eye disease is glaucoma, encompassing all clinical forms of glaucoma. For example, glaucoma includes open-angle glaucoma and closed-angle glaucoma, each with subcategories. For example, open-angle glaucoma has subcategories such as primary open-angle glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma, neovascular glaucoma, steroid-induced glaucoma, normal-tension glaucoma, and pressure-independent glaucoma.

[0056] Diseases affecting retinal photoreceptors and other cells other than retinal ganglion cells include age-related macular degeneration (AMD), including wet AMD and dry AMD; cystoid macular edema; central serous chorioretinopathy; macular packer or macular hole; diabetic and non-diabetic macular edema; epiretinal membrane; retinitis pigmentosa and all similar hereditary or non-hereditary retinal degenerations; retinal detachment; solar retinopathy; autoimmune retinopathy; retinal artery occlusion; retinal vein occlusion; diabetic retinopathy; infectious retinopathy; inflammation of the retina, including uveitis; myopic retinal degeneration; and lattice degeneration.

[0057] Diseases affecting the corneal nerve include infections such as herpesvirus, leprosy, Acanthamoeba, and fungi; toxic substances such as local anesthetics and preservatives; sensory nerve disorders such as trigeminal nerve disease or injury, and hereditary or acquired polyneuropathy; corneal diseases such as corneal dystrophy, keratoconus, and bullous keratopathy; autoimmune diseases such as Sjögren's syndrome; dry eye; and the effects of corneal surgeries such as laser in-situ keratotomy (LASIK) and corneal transplantation.

[0058] In one embodiment, the neurodegenerative eye disease is glaucoma. In another embodiment, the neurodegenerative eye disease is wet age-related macular degeneration (wet AMD) or dry age-related macular degeneration (dry AMD). In yet another embodiment, the neurodegenerative eye disease is Leber's hereditary optic neuropathy (LHON).

[0059] In one embodiment, the symptoms of neurodegenerative eye disease include damage or loss of retinal ganglion cells, or damage or loss of optic nerve axons.

[0060] In one embodiment, the method of the present disclosure includes reducing the loss or damage of retinal ganglion cells in a subject.

[0061] In one embodiment, the amounts of pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1-8 or a pharmaceutically acceptable salt thereof are effective in reducing or preventing retinal ganglion cell loss or damage in a subject. In another embodiment, retinal ganglion cell loss is reduced by at least 3%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In a further embodiment, retinal ganglion cell loss is reduced by more than 50%, more than 60%, more than 70%, or more than 80%.

[0062] In one embodiment, the treatment includes improving the survival rate of retinal ganglion cells in the patient by more than 50%, more than 60%, more than 70%, or more than 80%.

[0063] In another embodiment, the treatment includes reducing the loss of retinal ganglion cells in the patient by more than 50%, more than 60%, more than 70%, or more than 80%.

[0064] Furthermore, the present invention provides a method for preventing or reducing damage or loss of retinal ganglion cells in a subject, comprising the step of administering to the subject in an amount effective to prevent or reduce damage or loss of retinal ganglion cells, a pharmaceutical composition of the present disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or a pharmaceutically acceptable salt thereof. In one embodiment, the composition of the present disclosure is effective in improving the viability of retinal ganglion cells in a subject. In another embodiment, the composition of the present disclosure is effective in protecting retinal ganglion cells in a subject from cell death. In some embodiments, cell death is caused by an increase in intraocular pressure.

[0065] In one embodiment, the method of the present disclosure includes reducing loss or damage to optic nerve axons in a subject.

[0066] In one embodiment, a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or a pharmaceutically acceptable salt thereof is effective in reducing or preventing optic nerve axon loss or damage in a subject. In another embodiment, optic nerve axon loss is reduced by at least 3%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In a further embodiment, optic nerve axon loss is reduced by more than 50%, more than 60%, more than 70%, or more than 80%.

[0067] In one embodiment, the treatment includes improving the survival rate of the patient's optic nerve axons by more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, or more than 80%.

[0068] In another embodiment, the treatment includes reducing the patient's optic nerve axon loss by more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, or more than 80%.

[0069] Furthermore, the present invention provides a method for preventing or reducing damage or loss of optic nerve axons in a subject, comprising the step of administering to the subject in an amount effective to prevent or reduce damage or loss of optic nerve axons, a pharmaceutical composition of the present disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or a pharmaceutically acceptable salt thereof. In one embodiment, the composition of the present disclosure is effective in improving the viability of optic nerve axons in a subject. In another embodiment, the composition of the present disclosure is effective in protecting optic nerve axons in a subject from cell death. In some embodiments, cell death is caused by an increase in intraocular pressure.

[0070] In another embodiment, the treatment includes slowing the progression of neurodegenerative disease of the eye in the subject. In some embodiments, the treatment includes slowing the progression of visual field loss leading to blindness in a patient with glaucoma. In some embodiments, the treatment includes preventing blindness in a patient with glaucoma.

[0071] In one embodiment, pridopidine is pridopidine hydrochloride.

[0072] In the methods and uses of this disclosure, the route of administration may be, for example, oral. The route of administration can also be classified according to whether the effect is local (e.g., in topical administration) or systemic (e.g., in enteral or parenteral administration). As used herein, “topical administration” means administering the compound or composition directly to the site where its effect is desired, excluding systemic administration in particular. As used herein, “topical administration” of a compound or composition means applying the compound or composition to a body surface such as the skin or a mucous membrane such as the eye. As used herein, “ocular administration” means applying the compound or composition to the target eye, the skin around the eye (periorbital skin), or the mucous membrane around the eye, particularly the conjunctiva of the target, i.e., topical administration. Examples of ocular administration include direct topical administration to the eye, topical application to the eyelid, and injection into the eye or part of the eyelid. In addition, as used herein, “ocular pharmaceutical composition” means a pharmaceutical composition formulated for ocular administration. A predetermined amount of pridopidine and the pharmaceutical composition of the present invention may be administered orally, topically, systemically, topically, or orally. In other embodiments, the composition of the present disclosure may be administered orally, topically, intraocularly, periocularly, or orally. In other embodiments, the composition of the present disclosure may be administered by instillation into the conjunctiva.

[0073] In one embodiment, a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or a pharmaceutically acceptable salt thereof is administered systemically. In some embodiments, the pharmaceutical compositions of the present disclosure are administered orally. In another embodiment, the pharmaceutical compositions of the present disclosure are administered in the form of an aerosol, an inhalable powder, an injection, a liquid, a gel, a cream, a solid, a capsule, or a tablet. In yet another embodiment, the compositions of the present disclosure are administered orally, topically, intraocularly, intravitreally, periocularly, or ocularly. In yet another embodiment, the compositions of the present disclosure are administered by eye drops into the conjunctiva.

[0074] In one embodiment, the pharmaceutical compositions of this disclosure are administered by topical administration to the eye. In another embodiment, pridopidine and at least one of compounds 1 to 8 or their pharmaceutically acceptable salts are administered by topical administration. In further embodiments, pridopidine is administered by intraocular, periorbital, or ocular administration. In some embodiments, pridopidine is administered (applied) in the form of a liquid, gel, cream, or contact lens.

[0075] In another embodiment, the pharmaceutical composition of the present disclosure is administered directly (applied) to the eye of a subject, for example, as eye drops, an intraocular depot injection, an eye gel, a tablet inserted into the conjunctiva, or a lens loaded with pridopidine. In one embodiment, pridopidine hydrochloride is administered to the eye of a subject.

[0076] In one embodiment, the pharmaceutical composition of the present disclosure is formulated as an ophthalmic solution suitable for administration by eye instillation. The ophthalmic solution may be in the form of a liquid or a gel, preferably in the form of a liquid. When the pharmaceutical composition of the present disclosure is administered topically to the eye in the form of a liquid or a gel, a smaller amount of pridopidine can produce the same clinical effect as when pridopidine is administered systemically.

[0077] In one embodiment, the amount of pridopidine administered systemically is 22.5–315 mg / day, 90–315 mg / day, 90–250 mg / day, or 90–180 mg / day. In another embodiment, the dose of pridopidine is approximately 22.5 mg / day, approximately 45 mg / day, approximately 67.5 mg / day, approximately 90 mg / day, approximately 100 mg / day, approximately 112.5 mg / day, approximately 125 mg / day, approximately 135 mg / day, approximately 150 mg / day, approximately 180 mg / day, approximately 200 mg / day, approximately 225 mg / day, approximately 250 mg / day, or approximately 315 mg / day. In yet another embodiment, the composition of the present disclosure comprising pridopidine or a pharmaceutically acceptable salt thereof is administered in a daily dose containing an amount of pridopidine ranging from 22.5 to 315 mg / day. In other embodiments, the compositions of the present disclosure, comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or a pharmaceutically acceptable salt thereof, are administered in a daily dose containing 22.5 to 315 mg / day of pridopidine.

[0078] In one embodiment, the amount of pridopidine administered systemically in a single dose is approximately 22.5 mg, 45 mg, 67.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 135 mg, 150 mg, 180 mg, 200 mg, 250 mg, or 315 mg.

[0079] In another embodiment, the pharmaceutical composition of the present disclosure is administered directly to the eye of the subject. In some embodiments, the pharmaceutical composition of the present disclosure is formulated for direct administration to the eye, for example, topical administration to the eye, for example, as eye drops, and pridopidine is prepared in a dose range of 0.1 to 50 mg or 0.2 to 20 mg.

[0080] In one embodiment, the amount of pridopidine administered locally is 0.1 to 50 mg / day, or 0.2 mg / day. In another embodiment, the amount of pridopidine administered locally in a single dose is 0.1 to 50 mg, or 0.2 to 20 mg.

[0081] In one embodiment, the pharmaceutical composition of this disclosure is administered periodically.

[0082] In one embodiment, the pharmaceutical composition of this disclosure is administered daily.

[0083] In another embodiment, the pharmaceutical composition of the Disclosure is administered more than once a day or less than once a day. In one embodiment, the pharmaceutical composition of the Disclosure is administered more than once a day, for example, twice or three times a day. In another embodiment, the pharmaceutical composition of the Disclosure is administered less than once a day, for example, every other day or once a week.

[0084] In one embodiment, the periodic administration of the pharmaceutical composition of the Disclosure is continued for at least 3 days, 30 days or more, 42 days or more, 8 weeks or more, at least 12 weeks, at least 24 weeks, 24 weeks or more, or 6 months or more. In some embodiments, for example, in the treatment of a subject suffering from glaucoma, the treatment is a chronic treatment and the pharmaceutical composition of the Disclosure is administered periodically for 12 months or more, 18 months or more, or 24 months or more.

[0085] In one embodiment, the subject is a human patient.

[0086] In one embodiment, the method of the present disclosure further comprises administering a second agent for treating a neurodegenerative eye disease. In another embodiment, the second agent is a p-adrenergic antagonist, an adrenergic agonist, a parasympathetic agonist, a prostaglandin analog, or a carbonic anhydrase inhibitor.

[0087] In another embodiment, the second agent lowers elevated intraocular pressure in the subject. In a further embodiment, the second agent is a prostaglandin agonist, a beta-blocker, a carbonic anhydrase inhibitor, an alpha-agonist, or any combination thereof. In an additional embodiment, the second agent is latanoprost, bimatoprost, travoprost eye drops, unoprostone eye drops, tafluprost, betaxolol eye drops, carteolol, timolol, levobunolol, metipranolol, dorzolamide, brinzolamide, acetazolamide, metazolamide, brimonidine, apraclonidine, or any combination thereof.

[0088] In one embodiment, a subject is administered a multi-drug mixture containing the pharmaceutical composition of the present disclosure and a second drug.

[0089] In one embodiment, the amounts of pridopidine and the second drug are prepared to be administered simultaneously, concurrently, or in combination.

[0090] Furthermore, the present invention provides a pharmaceutical composition for treating subjects suffering from neurodegenerative eye diseases, comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof.

[0091] In one embodiment, the pharmaceutical composition of the present disclosure further comprises a predetermined amount of a second agent for treating a neurodegenerative eye disease.

[0092] In one embodiment, a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof, at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, and a second drug is prepared to be administered simultaneously, concurrently, or in combination.

[0093] Furthermore, the present invention provides a pharmaceutical composition for use in combination therapy with a pharmaceutical composition comprising a second agent for treating neurodegenerative eye diseases, the pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof.

[0094] Furthermore, the present invention provides a pharmaceutical composition for treating subjects suffering from neurodegenerative eye diseases as an add-on therapy, or for use in combination with a second agent for treating neurodegenerative eye diseases, comprising a predetermined amount of pridopidine or a pharmaceutically acceptable salt thereof, and at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof.

[0095] In one embodiment, the amount of pridopidine in the pharmaceutical composition of the Disclosure is about 22.5 mg, about 45 mg, about 67.5 mg, about 90 mg, about 100 mg, about 112.5 mg, about 125 mg, about 135 mg, about 150 mg, about 180 mg, about 200 mg, about 250 mg, or about 315 mg.

[0096] In one embodiment, the amount of pridopidine in the pharmaceutical composition of this disclosure is 0.1 to 50 mg, or 0.2 to 20 mg.

[0097] In one embodiment, the dose of pridopidine in the pharmaceutical composition of the Disclosure is measured as the amount of pridopidine per unit body weight of the subject. In another embodiment, the dose of pridopidine is 1 to 100 mg / kg. In yet another embodiment, the dose of pridopidine is 1 to 10 mg / kg, 20 to 50 mg / kg, or 50 to 100 mg / kg. In yet another embodiment, the dose of pridopidine is 3 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg. The present invention also provides a pharmaceutical composition in a unit dosage form useful for treating a subject suffering from a neurodegenerative eye disease, comprising a predetermined amount of pridopidine or a pharmaceutically acceptable salt thereof, wherein the amount of pridopidine in the composition is an effective amount for treating the subject when one or more unit dosage forms of the pharmaceutical composition are administered to the subject.

[0098] Furthermore, the present invention provides an ophthalmic pharmaceutical composition comprising a predetermined amount of pridopidine or a pharmaceutically acceptable salt thereof, at least one of compounds 1 to 8 or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient suitable for administration to the eye.

[0099] In one embodiment, the ophthalmic pharmaceutical composition of the present disclosure further comprises a second agent for treating neurodegenerative eye diseases. In one embodiment, the second agent for treating neurodegenerative eye diseases is an antiglaucoma agent.

[0100] In another embodiment, the amount of pridopidine in the ophthalmic pharmaceutical composition of this disclosure is 0.1 to 50 mg, or 0.2 to 20 mg.

[0101] In one embodiment, the ophthalmic pharmaceutical composition of the Disclosure is in liquid form. In some embodiments, the concentration of pridopidine in the ophthalmic pharmaceutical composition of the Disclosure is 0.0001 to 10.0 w / v%, 0.001 to 5 w / v%, 0.01 to 1 w / v%, or 0.1 to 10 w / v%.

[0102] Furthermore, the present invention provides an ophthalmic pharmaceutical composition for use in the treatment of neurodegenerative eye diseases in the subject.

[0103] The present invention further provides an eye drop containing the pharmaceutical composition of the present disclosure. The present invention further provides a container containing the pharmaceutical composition of the present disclosure and the eye drop.

[0104] Furthermore, the present invention provides eye drops or a container for eye drops for use in the method of the present invention.

[0105] Furthermore, the present invention provides pridopidine or a pharmaceutically acceptable salt thereof, and at least one of compounds 1 to 8 or a pharmaceutically acceptable salt thereof, for use in the treatment of subjects suffering from neurodegenerative eye diseases.

[0106] term

[0107] When used in this specification, unless otherwise specified, the following terms shall have the definitions set forth below.

[0108] As used herein, “pridopidine” means a pridopidine base or a pharmaceutically acceptable salt thereof or a derivative thereof, such as deuterium-enriched pridopidine or a salt thereof.

[0109] "~salt" refers to a salt of the compound modified by producing an acidic or basic salt of the compound. In this regard, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid-addition or base-addition salt of the compound of the present invention. For example, one method of producing such a salt is to treat the compound of the present invention with an inorganic base.

[0110] As used herein, “neurodegenerative eye disease” refers to diseases involving degeneration of the sensory cells of the eyeball and / or optic nerve, particularly retinal cells and / or retinal axons. Sensory cells include retinal ganglion cells, optic axons, retinal pigment epithelial cells, cones, rods, and all other nerve cells or glial cells of the retina. Examples of neurodegenerative eye diseases include glaucoma, age-related macular degeneration (AMD), including wet AMD and dry AMD, all variants of retinitis pigmentosa, and optic neuropathy, but not limited to ischemic optic neuropathy (ION), Leber's hereditary optic neuropathy (LHON), and retinopathy (e.g., Stargardt disease). Examples of neurodegenerative eye diseases include diseases affecting the nerve cells and their connections in the eye, such as diseases affecting retinal ganglion cells, photoreceptor cells, and other retinal nerve cells, as well as corneal nerves.

[0111] Optic neuropathy is a disease that affects retinal ganglion cells and their connections. Examples of optic neuropathy include glaucomatous optic neuropathy (also called glaucoma), inflammatory optic neuropathy (also called optic neuritis), ischemic optic neuropathy, toxic optic neuropathy, compressive optic neuropathy, infiltrative optic neuropathy, hereditary optic neuropathy, traumatic optic neuropathy, nutritional optic neuropathy, optic neuropathy due to increased intracranial pressure (also called palpebral hydrops optic neuropathy), optic disc drusen, autoimmune optic neuropathy, and other types of optic neuropathy. Each category of optic neuropathy has subcategories; for example, ischemic optic neuropathy includes non-arteritic anterior ischemic optic neuropathy, arteriotic anterior ischemic optic neuropathy, and posterior ischemic optic neuropathy.

[0112] In some embodiments, neurodegenerative eye disease is glaucoma and includes all clinical forms of glaucoma. For example, glaucoma includes open-angle glaucoma and closed-angle glaucoma, each with subcategories. For example, open-angle glaucoma has subcategories such as primary open-angle glaucoma, pigmentary glaucoma, pseudo-exfoliation glaucoma, neovascular glaucoma, steroid-induced glaucoma, normal-tension glaucoma, and pressure-independent glaucoma. In some embodiments, neurodegenerative eye disease is glaucoma and includes all clinical forms of glaucoma, such as primary glaucoma and secondary glaucoma. Examples of primary glaucoma include primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), primary closed-angle glaucoma (PACG), acute closed-angle glaucoma (AACG), and closed-angle glaucoma (ACG). Examples of secondary glaucoma include pseudoexfoliation glaucoma, pigmentary glaucoma, neovascular glaucoma, steroid-induced glaucoma, and treatment-resistant glaucoma.

[0113] Diseases affecting retinal photoreceptors and other cells other than retinal ganglion cells include age-related macular degeneration (AMD), including wet AMD and dry AMD; cystoid macular edema; central serous chorioretinopathy; macular packer or macular hole; diabetic and non-diabetic macular edema; epiretinal membrane; retinitis pigmentosa and all variants of similar hereditary or non-hereditary retinal degenerations; retinal detachment; solar retinopathy; autoimmune retinopathy; retinal artery occlusion; retinal vein occlusion; diabetic retinopathy; infectious retinopathy; inflammation of the retina, including uveitis; myopic retinal degeneration; and lattice degeneration. In one embodiment, the disease is symptomatic microphthalmia (MCOPS12).

[0114] Diseases affecting the corneal nerve include infections such as herpesvirus, leprosy, Acanthamoeba, and fungi; toxic substances such as local anesthetics and preservatives; sensory nerve disorders such as trigeminal nerve disease or injury, and hereditary or acquired polyneuropathy; corneal diseases such as corneal dystrophy, keratoconus, and bullous keratopathy; autoimmune diseases such as Sjögren's syndrome; dry eye; and the effects of corneal surgeries such as laser in-situ keratotomy (LASIK) and corneal transplantation.

[0115] As used herein, “amount” or “dose” of pridopidine measured in milligrams refers to the amount of pridopidine contained in the preparation, regardless of the form of the preparation. For example, “a dose of 90 mg of pridopidine” means that the amount of pridopidine contained in the preparation is 90 mg, regardless of the form of the preparation. Therefore, if it is in the form of a salt, such as pridopidine hydrochloride, the weight of the salt form required to provide a dose of 90 mg of pridopidine will be greater than 90 mg due to the presence of additional salt ions.

[0116] As used herein, "unit dose" and "unit dosage form" mean a single drug administration entity.

[0117] As used herein, “approximately” in the context of a number or numerical range means ±10% of the stated or claimed number or numerical range.

[0118] As used herein, “effective” when referring to the amount of pridopidine means an amount of pridopidine sufficient to produce the desired therapeutic response. Effectiveness can be measured, for example, by a decrease in the number of retinal ganglion cells or by loss or damage of optic nerve axons.

[0119] As used herein, “administration to a subject” or “administration to a (human) patient” means the administration, dosing, or application of a drug, medicine, or therapeutic agent to a subject / patient for the purpose of alleviating, curing, or reducing symptoms associated with a condition such as a pathological state. Administration may be periodic. As used herein, “periodic administration” means repeated administration divided into predetermined periods. The interval between administrations is preferably constant each time. Periodic administration may include, for example, administration once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, three times weekly, four times weekly, etc.

[0120] As used herein, “pharmaceutically acceptable excipients suitable for ocular administration” includes any excipients known or expected to be suitable for direct ocular administration.

[0121] Excipients (or additives) commonly used in the formulation of eye drops can be used with pridopidine. Excipients may include preservatives. Examples of preservatives include quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride; cationic compounds such as chlorhexidine gluconate; p-hydroxybenzoic acids such as methyl p-hydroxybenzoate and propyl p-hydroxybenzoate; alcohol compounds such as chlorobutanol and benzyl alcohol; sodium dehydroacetate; thimerosal; and sorbic acid (U.S. Patents 6, 114, and 319). Formulations suitable for eye drop administration may include buffers. Examples of buffers include acetates such as sodium acetate; phosphates such as sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate; aminocaproic acid; amino acid salts such as sodium glutamate; boric acid and its salts; citric acid and its salts (U.S. Patents 6, 114, and 319). Furthermore, formulations suitable for ophthalmic administration may contain excipients such as stabilizers, antioxidants, pH adjusters, chelating agents, and thickeners (U.S. Patent Nos. 6, 114, 319). Examples of antioxidants include ascorbic acid and its salts, sodium thiosulfate, sodium bisulfite, tocopherol, sodium thiosulfate, sodium bisulfite, pyruvic acid and its salts (U.S. Patent Nos. 6, 114, 319). Examples of chelating agents include sodium edetate, citric acid and its salts (U.S. Patent Nos. 6, 114, 319). Examples of pH adjusters include hydrochloric acid, phosphoric acid, acetic acid, sodium hydroxide, sodium bicarbonate, potassium hydroxide, sodium carbonate, sulfuric acid, and aqueous ammonia (U.S. Patent Nos. 6, 114, 319). The pH of formulations suitable for ophthalmic administration may be any pH within an ophthalmologically acceptable range, for example, in the range of pH 5.0 to pH 8.0. When administering pridopidine as eye drops, it is preferable to prepare the formulation so that the concentration of pridopidine is between 0.0001% and 10.0% w / v%.

[0122] Pharmaceutically acceptable salts

[0123] The active compounds for use in accordance with the present invention may be provided in any form suitable for the intended dosage. Suitable forms include pharmaceutically (i.e., physiologically) acceptable salts of the compounds of the Disclosure, and predrug or prodrug forms of the compounds of the Disclosure. Examples of pharmaceutically acceptable addition salts, but not limited to, are addition salts of non-toxic inorganic or organic acids, such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, and toluene-p-sulfonate. These salts can be formed by methods well known in the art.

[0124] In other embodiments, the pharmaceutical composition used in the method of the present invention may include salts of pridopidine. Examples of pridopidine salts include hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, and toluene-p-sulfonate.

[0125] In other embodiments, the method of the present invention uses a pharmaceutical composition comprising at least one of the salts of compounds 1 to 8, wherein the salts of compounds 1 to 8 include hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, or toluene-p-sulfonate.

[0126] In other embodiments, the method of the present invention uses a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1 to 8 or a pharmaceutically acceptable salt thereof, wherein the weight ratio of pridopidine to at least one of compounds 1 to 8 is in the range of 1:0.0001 to 1:0.1. In other embodiments, the weight ratio of pridopidine to at least one of compounds 1 to 8 is in the range of 1:0.005 to 1:0.1. In other embodiments, the weight ratio of pridopidine to at least one of compounds 1 to 8 is in the range of 1:0.001 to 1:0.005.

[0127] In other embodiments, the concentration of compound 1, 2, 3, 4, 5, 6, 7, or 8 or their pharmaceutically acceptable salts in the pharmaceutical composition is in the range of 0.001 to 10% by weight. In other embodiments, the concentration of compound 1, 2, 3, 4, 5, 6, 7, or 8 or their pharmaceutically acceptable salts in the pharmaceutical composition is in the range of 0.001 to 0.05% by weight. In other embodiments, the concentration of compound 1, 2, 3, 4, 5, 6, 7, or 8 or their pharmaceutically acceptable salts in the pharmaceutical composition is in the range of 0.05 to 0.35% by weight. In other embodiments, the concentration of compound 1, 2, 3, 4, 5, 6, 7, or 8 or their pharmaceutically acceptable salts in the pharmaceutical composition is in the range of 0.001 to 0.5% by weight. In other embodiments, the concentration of compound 1, 2, 3, 4, 5, 6, 7, or 8 or their pharmaceutically acceptable salts in the pharmaceutical composition is in the range of 0.001 to 0.15% by weight. In other embodiments, the concentration of compound 1, 2, 3, 4, 5, 6, 7, or 8 or their pharmaceutically acceptable salts in the pharmaceutical composition is in the range of 0.01 to 0.15% by weight. In other embodiments, the concentration of compound 1, 2, 3, 4, 5, 6, 7, or 8 or their pharmaceutically acceptable salts in the pharmaceutical composition is in the range of 0.01 to 0.5% by weight. In other embodiments, the concentration of compound 1, 2, 3, 4, 5, 6, 7, or 8 or their pharmaceutically acceptable salts in the pharmaceutical composition is in the range of 0.01 to 1% by weight.

[0128] The active compound for use in accordance with the present invention may be administered in the form of the raw material compound, but it is preferable that the active compound or a pharmaceutically acceptable salt thereof be included in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other common pharmaceutical adjuvants. In one embodiment, the present invention provides a pharmaceutical composition comprising an active compound or a pharmaceutically acceptable salt or derivative thereof, one or more pharmaceutically acceptable carriers, and optionally other therapeutic and / or prophylactic components known and used in the art. The carrier must be “acceptable” in the sense that it is compatible with the other components of the pharmaceutical composition and is not harmful to the subject to whom the pharmaceutical composition of this disclosure is administered.

[0129] In other embodiments, the compositions of the Disclosure are administered orally, topically, intraocularly, intravitreally, periocularly, or orally. In other embodiments, the compositions of the Disclosure are administered by eye drops into the conjunctiva.

[0130] In other embodiments, the compositions of the Disclosure may be administered topically (e.g., by topical administration) or systemically (e.g., by enteral or parenteral administration). As used herein, "topical administration" means administering the composition directly to the site where its effect is desired, and excludes systemic administration in particular. • When used in this specification, "topical administration" refers to the administration of the composition to a body surface such as the skin or to a mucous membrane such as the eye. As used herein, "ocular administration" refers to the administration of the composition to the eye, the skin around the eye (periorbital skin), or the mucous membrane around the eye, particularly the conjunctiva of the subject, i.e., local administration. Examples of ocular administration include direct local administration to the eye, local application to the eyelid, and injection into the eye or part of the eyelid.

[0131] The compositions of this disclosure are administered orally, topically, intraocularly, periorbitally, or orally. In other embodiments, they are administered to the cornea, subconjunctiva, sub-Tenon's capsule, intracavitary, intraretinal, subretinal, subeyelid, or posterior chamber.

[0132] In other embodiments, the compositions of the present disclosure are administered by instillation into the conjunctiva.

[0133] The pharmaceutical compositions of this disclosure may be administered by any convenient route suitable for the desired treatment. Preferred routes of administration include, in particular, oral administration in the form of tablets, capsules, multiparticles, sugar-coated preparations, powders, or liquids, and, in particular, parenteral administration by skin, subcutaneous, intramuscular, or intravenous injection.

[0134] The pharmaceutical compositions used in the method of the present invention may be oral unit formulations formulated as tablets, capsules, pills, powders, liquid solutions, or liquid suspensions.

[0135] In other embodiments, the compositions of the present disclosure are formulated as eye drops, eye solutions, eye suspensions, eye emulsions, eye ointments, and eye sprays.

[0136] In other embodiments, the pharmaceutical compositions of this disclosure may be in the form of ophthalmic compositions for topical application to the eye of interest. As used herein, the term “ophthalmic composition” is understood to mean any composition specifically formulated for direct and topical administration to the eye of a patient. The compositions of this disclosure may be formulated for topical administration to the eye or injection into the eye (i.e., intravitreal or intraocular injection). The ophthalmic compositions may be provided as any formulation that enables topical administration to the eye and allows the therapeutic compound to function in accordance with this disclosure. The ophthalmic compositions may be provided in the form of, but are not limited to, solutions, drops, mists / sprays, bandages and pressure-sensitive adhesives, ointments, lotions, creams, gels, lyophilized / spray-dried forms, etc. In a particular non-limiting embodiment, the ophthalmic composition may be provided in the form of a topical application such as an eye drop formulation, etc. In addition, the ophthalmic compositions of this disclosure may be designed to provide delayed release, controlled release, and / or sustained release using formulation techniques well known in the art.

[0137] The active compound for use in accordance with the present invention may be administered in the form of the starting compound, but it is preferable that the active compound or a pharmaceutically acceptable salt thereof be included in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other general pharmaceutical adjuvants.

[0138] In one embodiment, the present invention provides a pharmaceutical composition comprising an active compound or a pharmaceutically acceptable salt or derivative thereof, one or more pharmaceutically acceptable carriers, and optionally other therapeutic and / or prophylactic components known and used in the art. The carriers must be “acceptable” in the sense that they are compatible with the other components of the pharmaceutical composition and are not harmful to the subject to whom the pharmaceutical composition of this disclosure is administered.

[0139] General techniques and compositions for producing useful dosage forms in the present invention are described in the following references (the entire contents of these references are incorporated herein by reference). "Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979)"; "Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981)"; "Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976)"; "Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985);Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992);Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995);Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., JG Hardy, SSDavis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). .

[0140] As used herein, “treatment” or “to treat” includes, for example, inducing the suppression, regression, or cessation of a disorder and / or disease, such as depression, or alleviating, reducing, suppressing, inhibiting, reducing the severity, eliminating or substantially eliminating, or improving the symptoms of a disease or disorder. Treatment further includes providing neuroprotective effects on ocular cells, such as retinal ganglion cells or optic nerve axons of the subject. The “neuroprotective effects” of pridopidine are disclosed herein. Neuroprotective effects include (a) protection from damage or cell death of nerve cells, such as vascular ganglion cells (RGCs) or optic nerve axons, or (b) improvement of the function of nerve cells, such as vascular ganglion cells (RGCs) or optic nerve axons. As used herein, “neuroprotective effects” means suppressing, preventing, attenuating, and / or reversing the progression of neurodegeneration. As used herein, “neurodegeneration” means the progression of loss of nerve cells, such as vascular ganglion cells (RGCs) or optic nerve axons, due to damage or cell death.

[0141] As used herein, “inhibition” of disease progression or disease complications in the subject means prevention or reduction of disease progression and / or disease complications in the subject.

[0142] The “symptoms” associated with glaucoma include, but are not limited to, any clinical or laboratory findings related to glaucoma that the subject can feel or observe.

[0143] As used herein, the term "suffering from glaucoma" means that the subject has been diagnosed with glaucoma.

[0144] When used herein, the term "baseline" refers to the subject (patient) before administration of pridopidine in the treatment described herein.

[0145] A "pharmaceutically acceptable carrier" refers to a carrier or excipient suitable for use in humans and / or animals that does not cause excessive side effects (such as toxicity, irritation, or allergic reactions) commensurate with a reasonable benefit / risk ratio. A pharmaceutically acceptable carrier may be a pharmaceutically acceptable solvent, suspension, or vehicle for delivering the compound of the present invention to the target.

[0146] If a parameter range is provided, it should be understood that all integers within that range, and even one-tenths thereof, are also provided by the present invention. For example, "0.1 to 40.0 mg" includes 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, ... up to a maximum of 40.0 mg.

[0147] As used herein, “compound drug” refers to a drug containing two active ingredients. Generally, these two drugs are very difficult to separate by means readily available to the patient. Non-limiting examples include tablets, pills, or solutions containing the two drugs.

[0148] Where comparative terms such as "the loss of retinal ganglion cells (or optic nerve axons) in the subjects (patients) was reduced by at least 10%" are used in this application, the comparison is made against subjects with similar diseases, for example, control subjects in a prior relevant clinical trial, and not against healthy subjects. For example, the loss of retinal ganglion cells (or optic nerve axons) can be compared to the average loss of retinal ganglion cells (or optic nerve axons) in subjects with similar diseases who do not receive treatment with pridopidine. Thus, the comparative value can be determined using the placebo group of the clinical trial as a baseline.

[0149] The combination of two active compounds according to the present invention can be formulated for simultaneous, individual, or sequential administration using pharmaceutically acceptable carriers, additives, adjuvants, or excipients, as described herein at least. Therefore, the combination of two active compounds is • Administered simultaneously as the same drug, or The two drugs are administered simultaneously, sequentially, or individually. As used herein, "simultaneous administration" or "combined administration" means administering two drugs in close proximity in time so that the individual therapeutic effects of each drug overlap.

[0150] As used herein, “add-on” or “add-on therapy” means administering a second treatment regimen containing one or more additional drugs to a patient who is already receiving a first treatment regimen containing one or more drugs. Therefore, not all drugs used in those therapies are administered simultaneously. For example, adding pridopidine therapy to a glaucoma patient who is already receiving treatment with eye drops to lower intraocular pressure.

[0151] With respect to the embodiments described above, each embodiment disclosed herein is considered applicable to each other embodiment disclosed herein. For example, the elements enumerated in the embodiments of the method of the present invention can be used in the embodiments of the pharmaceutical composition, packaging, and use described herein, and vice versa.

[0152] The present invention will be better understood by referring to the "Experimental Details" section below. However, it will be readily apparent to those skilled in the art that the specific experiments described in detail are merely illustrative examples of the present invention, which are more fully described in the claims.

[0153] Experiment details

[0154] Example 1: Synergistic effect of pridopidine and compound 1, or synergistic effect of pridopidine and compound 4.

[0155] Both compound 1 and compound 4 show a synergistic effect with pridopidine on the secretion of brain-derived neurotrophic factor (BDNF) from B104 neuroblastoma cells. As shown in Table 1, compound 1 and compound 4 selectively bind to the sigma-1 receptor (S1R) (Ki = 0.37 μM for compound 1 and Ki = 2.9 μM for compound 4), but do not selectively bind to the sigma-2 receptor (S2R) (Ki > 100 μM for both compound 1 and compound 4).

[0156] [Table 1]

[0157] Thus, both compound 1 and compound 4 showed high affinity for the sigma-1 receptor (S1R), but showed no affinity for the sigma-2 receptor (S2R) (Ki>100).

[0158] Decreased levels of brain-derived neurotrophic factor (BDNF) play a crucial role in the pathogenesis of neurodegenerative diseases. BDNF levels are reduced in neurodegenerative diseases and neurodevelopmental disorders such as Huntington's disease (HD), Parkinson's disease, Alzheimer's disease (Zuccato and Cattaneo 2009), and Rett syndrome (Katz 2014).

[0159] In-situ ELISA assays showed that pridopidine demonstrated a dose-dependent increase in BDNF secretion in rat neuroblastoma cells. Since pharmacological inhibition of the sigma-1 receptor (S1R) abolished the effect of pridopidine, this effect is thought to be mediated by S1R activation (Geva, Birnberg, et al. 2016).

[0160] When the synergistic effect of compound 1 or compound 4 with pridopidine was evaluated, an unexpected synergistic effect was observed. This effect was observed in an in-situ ELISA assay of BDNF (Geva, Kusko, et al. 2016).

[0161] Therefore, the synergistic effect on BDNF release shown below is directly related to the therapeutic effect of pridopidine with compound 1 or compound 4.

[0162] The following data surprisingly and unexpectedly demonstrate that the combined use of pridopidine with compound 4 or compound 1 shows a synergistic effect on BDNF release.

[0163] Synergistic effect of compound 4 and pridopidine on BDNF release

[0164] Pridopidine alone increased BDNF release by 13.5% at a concentration of 0.001 μM and by 26% at a concentration of 0.005 μM compared to untreated control cells. Compound 4 alone at a concentration of 0.001 μM had no effect on BDNF release compared to untreated control cells (-1.5%). However, the combination of pridopidine and compound 4 resulted in an unexpected synergistic effect on BDNF release.

[0165] When 0.001 μM pridopidine was used in combination with 0.001 μM compound 4, BDNF release increased by 59.1% compared to untreated control cells (Figure 1(A)).

[0166] When 0.005 μM pridopidine was used in combination with 0.001 μM compound 4, BDNF release increased by 80.7% compared to untreated control cells (Figure 1(B)).

[0167] The combined effect of pridopidine and compound 4 was greater than the sum of the individual effects of each compound. This indicates that the combined use of pridopidine and compound 4 produces a remarkable synergistic effect on BDNF secretion. The results are shown as a percentage change compared to the untreated control.

[0168] Synergistic effect of compound 1 and pridopidine on BDNF release

[0169] Pridopidine alone at a concentration of 0.01 μM increased BDNF release by 3.4% compared to untreated control cells. Compound 1 alone at a concentration of 1 μM increased BDNF release by 12.5% ​​compared to the control. On the other hand, a synergistic effect on BDNF release was observed when pridopidine and compound 1 were used in combination (+53.1%).

[0170] When pridopidine (0.01 μM) was used in combination with compound 1 (1 μM), BDNF release increased by 53.1% compared to untreated control cells (Figure 2).

[0171] Similar to the combined use of compound 4 and pridopidine, the combined effect of pridopidine and compound 1 was greater than the sum of the individual effects of each compound. This indicates that the combined use of pridopidine and compound 1 produces a surprising and unexpected synergistic effect on BDNF secretion.

[0172] Thus, the inventors of this application have revealed that compounds 1 and 4 have selective binding affinity to S1R, and that they exhibit a surprising and unexpected synergistic effect with pridopidine on BDNF release.

[0173] References cited in Example 1 "Cheng, Yung-Chi, and William H. Prusoff. 1973. "Relationship between the Inhibition Constant (KI) and the Concentration of Inhibitor Which Causes 50 per Cent Inhibition (I50) of an Enzymatic Reaction." Biochemical Pharmacology. https: / / doi.org / 10.1016 / 0006-2952(73)90196-2." 「Geva, Michal, Tal Birnberg, Brian Weiner, Andrew Lysaght, Yoonjeong Cha, Avia Merenlender -Wagner, Aric Orbach, et al. 2016. "Pridopidine Activates Neuroprotective Pathways Impaired in Huntington Disease." Human Molecular Genetics 25 (18): 3975-87. https: / / doi.org / 10.1093 / hmg / ddw238.」 「Johnston, Tom H., Michal Geva, Lilach Steiner, Aric Orbach, Spyros Papapetropoulos, Juha-Matti Savola, Ian J. Reynolds, et al. 2019. "Pridopidine, a Clinic-Ready Compound, Reduces 3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Parkinsonian Macaques." Movement Disorders, December. https: / / doi.org / 10.1002 / mds.27565.」 「Katz, DM. 2014. "Brain-Derived Neurotrophic Factor and Rett Syndrome." Handbook of Experimental Pharmacology 220: 481-95. https: / / doi.org / 10.1007 / 978-3-642-45106-5_18.」 「Zuccato, Chiara, and Elena Cattaneo. 2009. "Brain-Derived Neurotrophic Factor in Neurodegenerative Diseases." Nature Reviews Neurology 5 (6): 311-22. https: / / doi.org / 10.1038 / nrneurol.2009.54.」

Claims

1. A pharmaceutical composition for treating, alleviating, or suppressing neurodegenerative eye diseases or their symptoms that lack genetic mitochondrial dysfunction in a subject, A pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof, and at least one of compound 1 or 4 represented by the following formula or a pharmaceutically acceptable salt thereof. 【Chemistry 1】

2. A pharmaceutical composition according to claim 1, The composition is a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition according to claim 1, The composition is a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition according to claim 1, The composition is a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof, compound 1 or a pharmaceutically acceptable salt thereof, and compound 4 or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition according to any one of claims 1 to 4, The aforementioned neurodegenerative eye disease is selected from the group consisting of glaucoma, age-related macular degeneration, optic neuropathy, symptomatic microphthalmia 12 (MCOPS 12), and retinitis pigmentosa, and is used in the pharmaceutical composition.

6. A pharmaceutical composition according to claim 5, The aforementioned age-related macular degeneration is either wet age-related macular degeneration (wet AMD) or dry age-related macular degeneration (dry AMD), in this pharmaceutical composition.

7. A pharmaceutical composition according to any one of claims 1 to 4, The aforementioned neurodegenerative eye disease is symptomatic microphthalmia 12 (MCOPS12), and the pharmaceutical composition is as described above.

8. A pharmaceutical composition according to claim 1, A pharmaceutical composition wherein the symptoms of the aforementioned neurodegenerative eye disease are damage or loss of retinal ganglion cells.

9. A pharmaceutical composition according to claim 1, A pharmaceutical composition that is effective in reducing or preventing the loss or damage of retinal ganglion cells in the subject.

10. A pharmaceutical composition according to claim 9, A pharmaceutical composition that reduces the loss of retinal ganglion cells by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%.

11. A pharmaceutical composition according to claim 9 or 10, A pharmaceutical composition that reduces the loss of retinal ganglion cells by more than 50%, more than 60%, more than 70%, or more than 80%.

12. A pharmaceutical composition according to claim 1, The composition is a pharmaceutical composition that is effective in improving the survival rate of retinal ganglion cells in the subject.

13. A pharmaceutical composition according to claim 1, A pharmaceutical composition in which the weight ratio of pridopidine to at least one of compounds 1 and 4 is in the range of 1:0.0001 to 1:0.

1.

14. A pharmaceutical composition according to claim 13, A pharmaceutical composition in which the weight ratio of pridopidine to at least one of compounds 1 and 4 is in the range of 1:0.0005 to 1:0.

005.

15. A pharmaceutical composition according to claim 1, The composition is configured in a form comprising a unit dose of the pridopidine or a pharmaceutically acceptable salt thereof, wherein the amount of the pridopidine in the unit dose is 22.5 mg to 315 mg.

16. A pharmaceutical composition according to claim 15, The composition is a pharmaceutical composition administered once, twice, or three times a day.

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