Compositions and method for treating retinal degeneration

Abstract

The present invention describes pharmaceutical combinations of a 5HT3-antagonist, an NK1-antagonist and / or fluoxetine with pramipexole for the treatment of retinal degeneration, including Age-related Macular Degeneration. The present invention also describes methods for treatment of retinal degeneration, including Age-related Macular Degeneration by administration of the pharmaceutical combinations of the invention.

Description

COMPOSITIONS AND METHOD FOR TREATING RETINAL DEGENERATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Patent Application Serial No. 63 / 658,194, filed June 10, 2024, and United States Provisional Patent Application Serial No. 63 / 658,223, filed June 10, 2024, the disclosures of which are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION

[0002] Retinal degeneration includes a group of eye diseases in which light-sensitive cells in the retina progressively degenerate, leading to vision loss. These diseases can be genetic, caused by injury, or related to the aging process or other health conditions. Common examples include age-related macular degeneration (AMD), retinitis pigmentosa (RP), diabetic retinopathy, and Stargardt disease, a rare form of juvenile macular disease.

[0003] Age-related macular degeneration (AMD) is a chronic disease, it is the leading cause of visual loss and irreversible blindness in people over 50 years of age. It affects about 200 million people worldwide (Ambati et al, 2021) and about 18 million people in the US (CDC, 2022). AMD is characterized by slowly progressive loss of central vision.

[0004] Two types of AMD have been described:

[0005] Dry AMD 70% of cases; no treatments until Jan 2023; one NDA was recently approved, but the approved drug has safety issues;

[0006] Wet AMD, treated by monthly intraocular injections of monoclonal anti-VEGF. Recently Vabysmo in quarterly intra-ocular injections was approved by the FDA

[0007] The hallmark of early AMD is the formation of Drusen, small yellow or white spots on the retina that contain high concentrations of lipofuscin (Wolfe, 2003), that accumulate at themacula, leading to slowly progressive retinal degeneration. Mild to moderate vision loss is observed at the early stages of the disease.

[0008] Typical symptoms of AMD include blurry, fuzzy vision; difficulty recognizing familiar faces; loss of central vision, which is necessary for driving, reading, recognizing faces, and performing close-up work.

[0009] Major risk factors for AMD are advanced age; exposure to environmental factors, notably to light.

[0010] Safe and effective pharmacotherapy is highly desirable for treatment of retinal degeneration including dry and wet AMD and geographic atrophy.SUMMARY OF THE INVENTION

[0011] In embodiments, the present invention relates to a combination of two drugs. One drug, pramipexole, carries efficacy in treating AMD but has dose-limiting adverse effects that prevent safely reaching efficacious doses in humans, the other drug, a 5HT3 -antagonist or an NK1 -antagonist antagonizes the dose limiting adverse effects without antagonizing efficacy, thus enabling the safe use of high efficacious doses of pramipexole. In some aspects, the invention relates to a triple drug combination including pramipexole and both a 5HT3- antagonists and an NK1 -antagonist.

[0012] Pramipexole (Mirapex) is a dopamine receptor agonist with high affinity and selectivity forD3 dopaminergic receptors. It is indicated for the treatment of PD in doses up to 4.5 mg / day.

[0013] In several rodent models of AMD, pramipexole has been shown to slow the progression of light induced retinal degeneration in a dose-dependent manner (Shibagaki et al). In humans, pramipexole was not effective at doses that were tolerated. This difference between rodents and humans may be explained by the difference of tolerated plasma concentrations of pramipexole in rodents and in humans. Compared to humans, rodents have been shown to tolerate much higher plasma concentrations of pramipexole.

[0014] In embodiments, the present intention also relates to a pharmaceutical combination of pramipexole and fluoxetine and its use for the treatment of AMD.

[0015] Fluoxetine, l-methylamino-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propane, is a selective serotonin reuptake inhibitor (SSRI) antidepressant. It is currently used in the treatment of major depressive disorder, obsessive-compulsive disorder (OCD), bulimia nervosa, panic disorder, and premenstrual dysphoric disorder. When taken by mouth at recommended maintenance IR-doses (20 mg to 80 mg daily in 1 to 2 divided doses), or ER- dose (90 mg onceweekly) by patients with these disorders, fluoxetine typically evinces a high degree of efficacy.

[0016] The mechanism by which fluoxetine benefits patients with psycho-affective disorders is generally considered to be linked to the drug's ability to augment CNS serotonin-mediated transmission. In addition, however, large fluoxetine doses in rodents have been shown to induce a significant increase in extracellular concentrations of norepinephrine and dopamine after acute systemic administration (Bymaster et al. 2002).

[0017] Fluoxetine augments levels of neurotrophic factors such as glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) and, in addition, the effects of fluoxetine in in vivo transgenic models of alpha-synucleinopathy have received careful investigative attention.

[0018] It has also been extensively reported to exhibit neuroprotective activity in various cellular and animal models of neurodegenerative disease (Ubhi K et al. 2012).

[0019] For example, a laboratory study examined the effect of fluoxetine in the MBPl-ha-syntg mice, a model of MSA (Shults, et al. 2005). Fluoxetine can protect against 6-OHDA (6- hydroxydopamine) (Suzuki, et al. 2010) and MPTP (l-methyl-4-phenyl-l, 2,3,6- tetrahydropyridine) (Chung, et al. 201 l)-induced damage in toxin-induced models of PD. Fluoxetine is not indicated for the treatment of any ocular disease or disorder. Safe and effective treatment options are needed for patients with ocular disorder. This disclosure addresses this and other needs.

[0020] In one aspect, the present invention relates to increasing the therapeutic window for pramipexole, for the treatment of retinal degeneration to safely enable the full efficacy of pramipexole. In particular, the present invention relates to a combination of pramipexole with a 5HT3 -antagonist or an NK1 -antagonist to increase the therapeutic window for pramipexole.

[0021] 5HT3 -antagonists and NK1 -antagonists by reducing or even abrogating the doselimiting GI adverse effects of high doses of pramipexole may enable the full potential of pramipexole for the treatment of retinal degeneration.

[0022] By using a 5HT3 -antagonist or an NK1 -antagonist, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, it is possible to safely treat a patient suffering from AMD by maintaining a therapeutically effective pramipexole daily dose with minimal adverse effects.

[0023] The combination of said 5HT3 -antagonist or said NK1 -antagonist with pramipexole or a pharmaceutically acceptable salt or solvate thereof enables the full anti-retinal degeneration efficacy of pramipexole.

[0024] For example, combining pramipexole dihydrochloride monohydrate with a 5HT3- antagonist or an NK1- antagonist allows the administration of a therapeutically effective dose of pramipexole dihydrochloride monohydrate that, in many patients, increases the dose of pramipexole dihydrochloride monohydrate thus achieving sufficient efficacy in the treatment of a patient suffering from retinal neurodegeneration.

[0025] More particularly, in patients suffering from retinal neurodegeneration, doses of pramipexole equivalent to a range of from 5 mg to 45 mg per dose, or from 5 mg to 45 mg / day, normally from 5 mg to 20 mg / day, of pramipexole dihydrochloride monohydrate, in combination with a 5HT3 -antagonist, may offer significant efficacy.

[0026] Advantageously, in combination with a 5HT3 -antagonist or an NK1 -antagonist, pramipexole daily doses equivalent to from more than 4.5 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg or from 6.5 mg to 45 mg, normally from more than 6 mg to 20 mg or from 6.5 to 20 mg of pramipexole dihydrochloride monohydrate may provide safe treatment for patients suffering from retinal degeneration such as AMD.

[0027] Hitherto, notwithstanding the aforementioned literature reporting the possibility of pramipexole’ s efficacy in rodent models of AMD, no one suspected that retinal degeneration could be safely cured by using a combination of pramipexole and a 5HT3- or NK1 -antagonist and substantially without the inherent pramipexole adverse effects.

[0028] Thus, in one aspect the present invention provides a pharmaceutical combination comprising: (a) a 5HT3 -antagonist or an NK1 -antagonist; and (b) pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an effective daily dose, for use for the treatment of AMD and other diseases involving retinal degeneration.

[0029] According to this aspect, the present invention provides the use of (or a method using) a 5HT3 -antagonist or an NK1 -antagonist for enabling the full anti -retinal degeneration efficacy of pramipexole in the treatment of AMD and other diseases involving retinal degeneration.

[0030] According to this aspect, the invention provides a 5HT3 -antagonist or an NK1- antagonist, for use in the treatment of retinal neurodegeneration, in combination with an effective daily dose of pramipexole.

[0031] According to this aspect, the invention also provides a method for treating a patient suffering from retinal degeneration, which comprises treating said patient with a 5HT3- antagonist or an NK1 -antagonist in combination with an effective daily dose of pramipexole.

[0032] According to this aspect, the method (or use) provides a safe administration of a 5HT3- antagonist or an NK1 -antagonist in combination with pramipexole daily doses (in pramipexoledihydrochloride monohydrate) of from 0.375 mg to 45 mg. For each patient, after the initial titration starting at a daily dose of 0.375 mg, said daily dose is gradually increased to a dose regiment of from 3 mg to 45 mg, preferably from more than 4.5 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg or from 6.5 mg to 45 mg, normally from more than 4.5 mg to 20 mg, from 5 mg to 20 mg, from more than 6 mg to 20 mg, or from 6.5 mg to 20 mg. In embodiments, the daily dose of pramipexole (in pramipexole dihydrochloride monohydrate) is from 0.375 mg to 6 mg. In embodiments, the daily dose of pramipexole (in pramipexole dihydrochloride monohydrate) is from 0.375 mg to 4.5 mg.

[0033] In particular, the invention provides a method (or use) of said 5HT3 -antagonist or NK1- antagonist for treating a patient suffering from retinal degeneration, notably AMD, which comprises treating said patient with said 5HT3 -antagonist or NK1 -antagonist, in combination with a pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from more than 4.5 mg to 45 mg, preferably from 5 mg to 45 mg, from more than 6 mg to 45 mg or from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.

[0034] Normally, as set forth above, said pramipexole daily dose, depending on the degree of gravity of the illness and the age and condition of the patient, will be equivalent to from 5 mg to 20 mg from more than 6 mg to 20 mg, or from 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate.

[0035] According to another aspect, the invention provides the use of said 5HT3 -antagonist or NK1 -antagonist for the preparation or manufacture of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said 5HT3 -antagonist or said NK1 -antagonist, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., admixture with a pharmaceutical carrier or vehicle, for preventing or curing the AEs of pramipexole or of a pharmaceutically acceptable salt and / or solvate thereof in the treatment of retinal degeneration, and also, principally, for administering said pramipexole to a patient suffering from retinal degeneration.

[0036] In particular, according to this aspect, the invention provides the use of a 5HT3- antagonist or an NK1 -antagonist for the preparation or manufacture of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said 5HT3 -antagonist or said NK1 -antagonist, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle, for the treatment of retinal degeneration in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.

[0037] Preferably, according to this aspect, the invention provides the use of a 5HT3 -antagonist or an NK1 -antagonist for the manufacture of a medicament for the safe treatment of retinal degeneration, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose (in pramipexole dihydrochloride monohydrate) that can significantly and safely provide a therapeutically effective dose of pramipexole dihydrochloride monohydrate for the symptomatic treatment of an eye diseases. As described above, said daily dose is from 0.375 mg to 45 mg, in particular from more than 4.5 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg or from 6.5 mg to 45 mg, normally from 5 mg to 20 mg, from more than 6 mg to 20 mg or from 6.5 mg to 20 mg.

[0038] According to an embodiment, for said method (or use), said 5HT3 -antagonist or said NK1 -antagonist, and said pramipexole or pharmaceutically acceptable salt or solvate thereof are each formulated in a pharmaceutical composition (fixed-dose combination), e.g., admixture with a pharmaceutical carrier or vehicle and separately administered, concurrently or sequentially, to the patient in need of treatment with said combination, in particular to a patient suffering from retinal degeneration, and more particularly of AMD. Said compositions may be in dosage unit form.

[0039] According to another embodiment of said use or said method, said 5HT3 -antagonist or NK1 -antagonist and said pramipexole or pharmaceutically acceptable salt or solvate thereof are co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle, to be administered to the patient suffering from retinal degeneration such as AMD, in need of said treatment. Normally, said compositions are in dosage unit form.

[0040] A 5HT3 -antagonist or an NK1 -antagonist indicated for the prevention of post-operative nausea and vomiting or of chemotherapy-induced nausea and vomiting may preferably be used in combination with a dose of pramipexole. The use of this combination may significantly improve the condition of patients suffering from retinal degeneration by concurrently mitigating or even eliminating the adverse effects of pramipexole, otherwise intolerable when using said pramipexole alone.

[0041] According to an aspect of the present invention, said 5HT3 -antagonists or NK1- antagonists are those shown to be effective in or approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of the chemotherapy-induced nausea and vomiting. In fact, surprisingly, 5HT3- and NK1 -antagonists, known to block nausea, vomiting, and diarrhea induced by chemotherapeutic drugs, have been shown, in particularwhen administered at high doses, to also block the gastro-intestinal adverse effects of pramipexole.

[0042] This finding is surprising because, notwithstanding the gravity of the illnesses and the fact that both said 5HT3-antagonists or NK1 -antagonists and pramipexole were in use for more than a decade, each in its own indication, to date no one thought that, by combining an effective dose of said 5HT3 -antagonist or said NK1 -antagonist with an effective dose of pramipexole, it would be possible to safely improve the conditions of patients suffering from retinal degeneration, by also allowing an increase of the pramipexole therapeutic dose, in particular the dose of pramipexole dihydrochloride monohydrate.

[0043] According to another embodiment, the invention provides a pharmaceutical fixed-dose combination consisting of a pharmaceutical composition comprising an effective dose / unit form of a 5HT3 -antagonist or an NK1 -antagonist, as Component (a) and an effective dose / unit form of pramipexole, as Component (b). The pharmaceutical combination may contain a pharmaceutical carrier or vehicle.

[0044] In said combination, Component (a) is present in said composition in an amount per unit form of from 1 pg to 300 mg; and Component (b) is present in said composition in an amount per unit form equivalent to from 0.125 mg to 45 mg, normally from 0.125 mg to 20 mg of pramipexole dihydrochloride monohydrate.

[0045] The dose per unit form of pramipexole or pharmaceutically acceptable salt or solvate thereof, in pramipexole dihydrochloride monohydrate, may be in a range selected from the group consisting of from 0.125 to 6 mg, from 0.125 to 0.375 mg, from 1.5 mg to 20 mg, from 1.625 mg to 20 mg, from 3 mg to 20 mg, from 5 mg to 20 mg, from more than 6 mg to 20 mg and from 6.5 mg to 20 mg.

[0046] In another aspect, the present invention provides a combination of pramipexole and an antidepressant, such as fluoxetine, the use of said combination for the treatment of AMD, and methods for treatment of AMD with the combination of pramipexole and fluoxetine.

[0047] Preferably, the method for treating a patient suffering from AMD comprises administering to said patient in need of said treatment, an effective daily dose of fluoxetine hydrochloride that is at least as high as the dose approved for the treatment of depression, and an effective daily dose of pramipexole dihydrochloride monohydrate.

[0048] According to an embodiment, fluoxetine or a pharmaceutically acceptable salt or solvate thereof and the pramipexol or a pharmaceutically acceptable salt or solvate thereof are each formulated (e.g., admixture) in a pharmaceutical composition with a pharmaceuticalcarrier and concurrently or sequentially administered to a patient in need of said treatment.

[0049] According to another embodiment, fluoxetine or a pharmaceutically acceptable salt or solvate thereof and pramipexole or a pharmaceutically acceptable salt or solvate thereof coformulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or as separate dosage forms that are combined, to be administered to the patient in need of said treatment.

[0050] According to an advantageous embodiment, in the method (or use) for the treatment of AMD, fluoxetine or a pharmaceutically acceptable salt or solvate thereof is co-formulated in a pharmaceutical composition (fixed-dose combination) e.g., admixture with a pharmaceutical carrier or vehicle. This composition is administered to a patient in need of said treatment at a daily dose that is equivalent to from 5 mg to 90 mg of fluoxetine base, in combination with a pramipexole or pharmaceutically acceptable salt or solvate thereof.

[0051] In this embodiments, said pramipexole is also formulated in a pharmaceutical composition in with a pharmaceutical carrier or vehicle and is administered to said patient in need of said treatment at a daily dose that is equivalent to from 1.5 mg to 3000 mg of pramipexole dihydrochloride monohydrate, said daily dose including an (S)-enantiomer daily dose equivalent to from 1.5 to 20 mg, from 1.5 mg to 15 mg, from 1.5 mg to 10 mg, from 1.5 mg to 7.5 mg, or from 1.5 mg to 6 mg of pramipexole dihydrochloride monohydrate.

[0052] In said method (or use), said fluoxetine and pramipexole combination is administered to said patient in a fixed-dose combination wherein said fluoxetine and pramipexole are combined with a pharmaceutical carrier or vehicle.

[0053] Preferably, fluoxetine is used as fluoxetine hydrochloride and the pramipexole is used as pramipexole dihydrochloride monohydrate.

[0054] According to another aspect, the present invention provides a pharmaceutical combination comprising pramipexole and fluoxetine and an NK1 -antagonist and / or a 5HT3- antagonists. In said pharmaceutical combination, each drug may be present a doses discussed. The drugs may be formulated separately or together in a fixed dose combination. In another aspect, the present invention provides a method for treating AMD by administering to a patient in need thereof this drug combination. In another aspect, the present invention provides a use of this drug combination for treating of AMD in a patent in need thereof or for manufacturing a medication for the treatment of AMD in said patient.DETAILED DESCRIPTIONDefinitions

[0055] “AE(s)”: Adverse Effect(s).

[0056] “AMD” Age related Macular Degeneration

[0057] “CGI”: Clinical Global Impression.

[0058] “CNS”: Central Nervous System.

[0059] “IR”: Immediate Release.

[0060] “ER”: Extended Release.

[0061] “ GI”: Gastro-Intestinal.

[0062] “NIMH”: National Institute of Mental Health.

[0063] “ 5HT3 -antagonist”: an antagonist of the serotonin receptor subtype-3, in the literature also referred to as a 5-HT3 receptor antagonist or a 5-HT3 receptor inhibitor.

[0064] “Effective daily dose of 5HT3 -antagonist”: as used herein, refers to a daily dose of said 5HT3 -antagonist of from 1 pg to 300 mg.

[0065] “Effective dose / unit form of a 5HT3-antagonist” or “effective dose per unit form of a 5HT3 -antagonist”: an amount of said 5HT3 -antagonist per unit form in the range of from 1 pg to 300 mg.

[0066] “NK1 -antagonist”: Neurokinin-1 receptor antagonist.

[0067] “Fluoxetine”: l-methylamino-3-phenyl-3-[4-(trifluoromethyl)phenoxy] propane, and has the structure below:

[0068] The term fluoxetine (INN) refers to the fluoxetine free base and salts and solvates thereof, in particular its hydrochloride salt.

[0069] " Effective daily dose of fluoxetine" : a daily dose of fluoxetine free base or fluoxetine hydrochloride salt that that is sufficient to treat a symptom of eye disease.

[0070] The terms “treat,” “treatment,” and “treating” in the context of the administration of a therapy to a subject refers to the reduction or amelioration of the severity of a one or more symptoms of an eye disease or disorder.

[0071] “Pramipexole”: the (S)-6-propylamino-4,5,6,7-tetrahydro-l,3-benzothiazole-2-amine,and has the structure below:

[0072] The term pramipexole refers to the free base and its pharmaceutically acceptable salts and solvates, unless otherwise specified.

[0073] “Effective daily dose of pramipexole” or “therapeutically effective dose of pramipexole”: a daily dose of pramipexole free base or pramipexole dihydrochloride monohydrate that is sufficient to treat a symptom of eye disease.

[0074] “ Salts or solvates thereof’ or “salts and solvates thereof’, with reference to any 5HT3- antagonist or to pramipexole: this expression indicates that any salt of said pramipexole or said 5HT3 -antagonist may be solvated with a solvent, normally water.

[0075] All references to pramipexole, 5-HT3 antagonists, NK1 -antagonists described herein also encompass all of their pharmaceutically acceptable solvates, hydrates, salts, and deuterated forms. For example, the methods described herein administers pramipexole or an equivalent dose of its pharmaceutically acceptable salt thereof.

[0076] As used herein, “equivalent dose” of refers to an amount of a pharmaceutically acceptable salt, free base, or deuterated form of a compound (e.g., pramipexole) that contains the same number of moles as the reference compound.Combination of Pramipexole and 5HT3-antagonists and / or NK1 -antagonists

[0077] The present invention relates to a pharmaceutical combination comprising a 5HT3- antagonist and / or an NK1 -antagonist, preferably shown effective or indicated for the prevention of post-operative nausea and vomiting or for the prevention and treatment of chemotherapy-induced nausea and vomiting, for use for the treatment of retinal degeneration in combination with pramipexole.

[0078] The present invention relates to the use of a pharmaceutical combination comprising said 5HT3 -antagonist and / or said NK1 -antagonist and pramipexole for the preparation of a medicament for treatment of retinal degeneration comprising an effective dose per unit form of pramipexole.

[0079] The invention also relates to a method for treating AMD by administering to a patient in need thereof a pharmaceutical combination comprising a 5HT3 -antagonist and / or an NK1-antagonist and pramipexole.

[0080] In said combination, the effective dose of pramipexole may be higher, and even much higher, than a total daily dose of 4.5 mg.

[0081] More particularly, the invention concerns, according to its aspects, a method for the treatment of retinal degeneration in a patient in need of said treatment, which comprises administering to said patient a 5HT3-antagonist or an NK1 -antagonist in combination with a therapeutically effective pramipexole daily dose; a 5HT3 -antagonist and / or an NK1 -antagonist for use for the treatment of retinal degeneration in a patient in need of said treatment, in combination with a therapeutically effective daily dose of pramipexole; and the use of a 5HT3- antagonist or an NK1 -antagonist for the preparation or manufacture of a medicament for the treatment of retinal degeneration in a patient in need of said treatment, in combination with a therapeutically effective daily dose of pramipexole.5HT3 -antagonists

[0082] Any of the 5HT3 -antagonists, especially those shown to be effective or indicated for the prevention of post-operative nausea and vomiting or of the chemotherapy-induced nausea and vomiting, may be used in combination with a dose of pramipexole.

[0083] The long-term use of this combination may improve the condition of a patient suffering from retinal degeneration, by concurrently mitigating or even eliminating the adverse effects induced by said pramipexole.

[0084] A 5HT3 -antagonist may be selected from: 5-methyl-2-[(4-methyl-lH-imidazol-5- yl)methyl]-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one (alosetron) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride, disclosed in US 5,360,800; (±)-6-chloro,3,4-dihydro-4-methyl-3-oxo-N-(quinuclidinyl)-2Z7-l,4-benzoxazine-8- carboxamide (azasetron) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride, disclosed in US 4,892,872; [(15,5A)-8-methyl-8-azabicyclo[3.2.1]octan-3- yl] 3,5-dichlorobenzoate (bemesetron, CAS: 40796-97-2); (10A)-10-[(2-methyl-U7-imidazol- l-yl)methyl]-5,6,9,10-tetrahydro-4H-pyrido(3,2,l: / A:)carbazol-l 1-one (cilansetron) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate, disclosed in US 4,939,136; (3A)-10-oxo-8-azatricyclo[5.3.1.03’8]undec-5-yl 1H- indole-3 -carboxylate (dolasetron) and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, disclosed in US 4,906755; (+)-(A)-8,9- dihydro-10-methyl-7-[(5-methylimidazol-4-yl)methyl]pyrido[l,2-a]indol-6(7J7)-one(fabesetron) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride or maleate, disclosed in US 5,141,945; l-methyl-A-((U?,3r,55)-9-methyl-9- azabicyclo[3.3. l]nonan-3-yl)-U / -indazole-3 -carboxamide (granisetron)and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride, disclosed in US 4,886,808; 2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-oxo-lZZ-benzimidazole-l- carboxamide (itasetron)and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride, disclosed in US 5,223,511; l-phenylmethyl-2-(l-piperazinyl)-UT- benzimidazole (lerisetron) and pharmaceutically acceptable salts and solvates thereof, specially its hydrochloride, disclosed in US 5,256,665 and, in a transdermal preparation, in US 6,136,807; 6-fluoro-5-methyl-2-[(5-methyl-U7-imidazol-4-yl)methyl]-2,3,4,5-tetrahydro-U / - pyrido[4,3-b]indol-l-one (lurosetron, CAS 128486-54-4) and pharmaceutically acceptable salts and solvates thereof, especially its mesylate (GR 87445 N); (±) l,2,3,9-tetrahydro-9- methyl-3-[(2-methyl- I T / -imidazol- l -yl)methyl]-47 / -carbazol-4-one (ondansetron) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride dihydrate, disclosed in US 4,695578; (3a5)-2-[(5)-l-azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro- I -oxo- l 7 / -benz[t / c]isoqui noline (palonosetron) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride, disclosed in US 5,202,333; 1- methylindol-3-yl)- [(5A)-4,5,6,7-tetrahydro-3J / -benzimidazol-5-yl]methanone (ramosetron) and pharmaceutically acceptable salts and solvates thereof, especially its fumarate, disclosed in US 5,344,927; e fo-A-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethyl-indole- 1-carboxamide (3,3-dimethyl-N- l a7 / ,5a7 / -tropan-3a-yl- l -indolinecarboxamide, ricasetron, CAS 117086-68-7) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; (3-e fo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester of U / -indole-3 -carboxylic acid (3 -tropanylindole-3 -carboxylate, tropisetron) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride, disclosed in US 4,789,673; and 5-chloro-2,2- dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-l-benzofuran-7-carboxamide (zatosetron) and pharmaceutically acceptable salts and solvates thereof, especially its maleate, disclosed in US 5,563,148.

[0085] The disclosures of all the US patents cited above is incorporated herein in their entirety by reference. Advantageously, said 5HT3 -antagonist may be selected from azasetron and pharmaceutically salts and solvates thereof, dolasetron and pharmaceutically acceptable salts and solvates thereof, granisetron and pharmaceutically salts and solvates thereof, ondansetron and pharmaceutically salts and solvates thereof, palonosetron and pharmaceutically salts andsolvates thereof, ramosetron, and pharmaceutically salts and solvates thereof and tropisetron and pharmaceutically salts and solvates thereof.

[0086] Illustrative examples of salts of said 5HT3 -antagonists and of said pramipexole include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, carbonic acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid and the like. The solvation agent is generally water.

[0087] Antagonists of the 5HT3 receptor available for the prevention or treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting are particularly useful according to the present invention. In particular, azasetron hydrochloride, commercially available in 10 mg tablet, and in 10 mg vials for intravenous injection; dolasetron monomethanesulfonate monohydrate (also referred to as dolasetron mesylate), commercially available in 200 mg maximal dose tablet, and in 12.5 mg / 0.625 ml vial; granisetron hydrochloride, commercially available in 2.24 mg maximal dose tablet; ondansetron hydrochloride dihydrate, commercially available in 10 mg maximal dose tablet and in a 2 mg / ml (in ondansetron base) solution available as a 20 ml multidose vial; palonosetron hydrochloride, commercially available in 0.28 mg / 5 mL injection and 0.56 mg capsule and in 0.075 mg / 1.5 ml or 0.25 mg / 5 ml (in palonosetron base) vials; ramosetron, commercially available in 0.15 mg / ml injection and in 0.1 mg oral tablet; and tropisetron hydrochloride, commercially available in 5.64 mg capsules, in 2.256 mg / 2 ml vials for intravenous injection, and in 5.64-mg vials for intravenous or subcutaneous injection; are particularly advantageous 5HT3-antagonists.

[0088] According to the present invention, the 5HT3 -antagonist is used in a pharmaceutical composition comprising, as an active ingredient, said 5HT3 -antagonist in an amount per unit form of from 1 pg to 300 mg, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., admixture with a pharmaceutical carrier or vehicle, and is administered, in combination with a pramipexole daily dose equivalent to from 0.375 mg to 45 mg, normally from more than 4.5 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg or from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate, to a patient suffering from retinal degeneration.

[0089] Thus, for example, an oral pharmaceutical composition according to the presentinvention to be administered in combination with pramipexole may comprise a 5HT3- antagonist selected from the group consisting of azasetron and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 5 mg to 10 mg of azasetron hydrochloride, to be administered at a daily dose equivalent to from 15 mg to 40 mg of azasetron hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 25 mg to 200 mg of dolasetron mesylate, to be administered at a daily dose equivalent to from 75 mg to 200 mg of dolasetron mesylate; granisetron and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 0.5 mg to 2 mg granisetron base, to be administered at a daily dose equivalent to from 1.5 mg to 8 mg of granisetron base; ondansetron and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 0.5 mg to 16 mg, normally from 2 mg to 8 mg of ondansetron base, to be administered at a daily dose equivalent to from 6 mg to 64 mg, normally from 6 mg to 32 mg of ondansetron base; palonosetron and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 0.25 mg to 0.5 mg of palonosetron base, to be administered at a daily dose equivalent to from 0.75 mg to 2 mg of palonosetron base; ramosetron and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 0.05 mg to 0.2 mg of ramosetron hydrochloride, to be administered at a daily dose equivalent to from 0.05 mg to 0.2 mg of ramosetron hydrochloride; and tropisetron and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 2.5 mg to 5 mg of tropisetron base, to be administered at a daily dose equivalent to from 7.5 mg to 20 mg of tropisetron base.

[0090] Preferably, said 5HT3 -antagonist is selected from the group consisting of azasetron hydrochloride, in an amount per unit form equivalent to from 5 mg to 10 mg to be administered at a daily dose equivalent to from 15 mg to 40 mg of azasetron hydrochloride; dolasetron mesylate, in an amount per unit form equivalent to from 25 mg to 200 mg of dolasetron mesylate, to be administered at a daily dose equivalent to from 75 mg to 200 mg; granisetron hydrochloride, in an amount per unit form equivalent to from 0.5 mg to 2 mg granisetron base, to be administered at a daily dose equivalent to from 1.5 mg to 16 mg, normally of from 2 mg to 8 mg; ondansetron hydrochloride dihydrate, in an amount equivalent to from 0.5 mg to 32 mg, normally from 2 mg to 32 mg, from 2 mg to 16 mg or from 2 mg to 8 mg ondansetron base, to be administered at a daily dose equivalent to from 6 mg to 64 mg, normally from 6 to 32 mg of ondansetron base; palonosetron hydrochloride, in an amount equivalent to from 0.25mg to 0.5 mg palonosetron base, to be administered at a daily dose equivalent to from 0.75 to 2 mg of palonosetron base; ramosetron hydrochloride, in an amount per unit form of from 0.05 mg to 02 mg, to be administered at a daily dose of from 0.05 mg to 0.2 mg; and tropisetron hydrochloride, in an amount equivalent to from 2.5 mg to 5 mg tropisetron base, to be administered at a daily dose equivalent to from 7.5 to 20 mg of tropisetron base.

[0091] This composition is to be administered to a patient suffering from retinal degeneration, in combination with a pharmaceutical composition in dosage unit form comprising pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form in a range equivalent to from 0.125 to 45 mg, preferably from more than 4.5 mg to 45 mg, from more than 6 mg to 45 mg or from 6.5 mg to 45 mg, normally from 3 mg to 20 mg, preferably from more than 5 mg to 20 mg, from more than 6 mg to 20 mg or from 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate.NK1 -antagonists

[0092] Any NK1 -antagonist, especially those shown to be effective or indicated for the prevention of post-operative nausea and vomiting or of the chemotherapy-induced nausea and vomiting, may be used in combination with a dose of pramipexole.

[0093] The long-term use of this combination may improve the condition of a patient suffering from retinal degeneration, by concurrently mitigating or even eliminating the adverse effects induced by said pramipexole.

[0094] An NK1 -antagonist may be selected from: 5-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-l,2-dihydro- 3H-l,2,4-triazol-3-one (aprepitant); described in US 5,719,147, in a liquid oral formulation, in US 2017 / 0035774, and in an injectable emulsion in a single-dose vial for intravenous use containing 130 mg aprepitant in 18 ml of emulsion (Cinvanti®), described in US 9,808,465 (the contents of each of which are incorporated herein in their entirety by reference); [3-{[(2R,3S)-2-[(lR)-l-[3,5-bis(trifhroromethyl)phenyl] ethoxy]-3-(4- fhrorophenyl)morpholin-4-yl]methyl } -5-oxo-2H- 1 ,2,4-triazol- 1 -yl]phosphonic acid(fosaprepitant), disclosed, for example as meglumine salt in US 5,691,336 and as di(cyclohexylamine) salt in US 2016 / 0355533, the contents of each of which are incorporated herein in their entirety by reference; (2S,4S)-4-(4-Acetyl-l-piperazinyl)-N-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methyl-l- piperidinecarboxamide (casopitant) described in US 7,294,630, the contents of which areincorporated herein in its entirety by reference; (2S)-l-[(3aS,4S,7aS)-4-hydroxy-4-(2- methoxyphenyl)-7,7-diphenyl-l,3,3a,5,6,7a-hexahydroisoindol-2-yl]-2-(2- methoxyphenyl)propan-l-one (INN: dapitant); (2S,3S)-N-(5-tert-Butyl-2-methoxybenzyl)-2- (diphenylmethyl)-l-azabicyclo[2.2.2]octan-3-amine (maropitant), disclosed in U.S. 5,807,867, W02005 / 082416 and EP 3173071 the contents of each of which are incorporated herein in their entirety by reference; (2S,3S)-2-Diphenylmethyl-3-[(5-isopropyl-2- methoxybenzyl)amino]quinuclidine (INN: ezlopitant), disclosed by Evangelista S (2001). "Ezlopitant. Pfizer"; Current Opinion in Investigational Drugs: 2 (10): 1441-3; reviewed in Drugs: the Investigational Drugs Journal 6 (8 ): 758-72, the contents of each of which are incorporated herein in their entirety by reference; (2S)-N-{2-[3,5-bis(trifluoromethyl) phenyl]ethyl}-2-[4-(cyclopropylmethyl)piperazin-l-yl]-N-methyl-2-phenylacetamide (INN: figopitant) N-[(2R)-l-[Acetyl-[(2-methoxyphenyl)methyl]amino]-3-(lH-indol-3-yl)propan-2- yl]-2-(4-piperidin-l-ylpiperidin-l-yl)acetamide (INN: lanepitant); 2-[3,5- bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-l- piperazinyl)-3-pyridinyl]propanamide (netupitant), described in US 6,297,375, US 6,593,472, US 6,719,996, and, in an oral composition, comprising 300 mg of netupitant and palonosetron hydrochloride in an amount equivalent to 0.5 mg of palonosetron base, herein below referred to as “netupitant-300 / palonosetron-0.5”, in US 8,951,969, the contents of each of which are incorporated herein in their entirety by reference; (2R,4S)-4-[(8aS)-6-oxo-l,3,4,7,8,8a- hexahydropyrrolo[l,2-a]pyrazin-2-yl]-N-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4- fluoro-2-methylphenyl)-N-methylpiperidine-l -carboxamide (INN: orvepitant), disclosed in US 2005 / 0176715 and, as crystalline maleate, in US 2011 / 0166150, the contents of each of which are incorporated herein in their entirety by reference; (5S,8S)-8-({(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy}methyl)-8-phenyl-l,7-diazaspiro[4.5]decan-2-one (rolapitant), described in US 7,049,320 and, for an injectable form thereof, in US 9,101,615, the contents of each of which are incorporated herein in their entirety by reference; 3- ((3aR,4R,5S,7aS)-5-[(lR)-l- [3,5-bis(trifluoromethylphenyl] ethoxy] -4-(4-fluorophenyl)- l,3,3a,4,5,6,7,7a-octahydroisoindol-2-ylcyclopent-2-en-l-one (serlopitant) described in US 7,544,815 and US 7,217,731, the contents of each of which are incorporated herein in their entirety by reference; 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-l- carboxylic acid [1-(R)- (3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide (INN: vestipitant), described in WO 2001 / 25219 and, in intravenous formulation having a reduced tendency to cause hemolysis, in WO 2012 / 175434, the contents of each of which are incorporated herein in their entirety byreference; and (2S,3S)-N-[(2-methoxy-5-[5-(trifluoromethyl)tetrazol-l-yl]phenylmethyl]-2- phenylpiperi din-3 -amine (INN: vofopitant), disclosed by Gardner CJ et al. Regul Pept. 1996 Aug 27;65(l):45-53, the contents of which are incorporated herein in their entirety by reference.

[0095] Any NK1 -antagonist, especially those shown to be effective or indicated for the prevention of post-operative nausea and vomiting or of the chemotherapy-induced nausea and vomiting, may be used in combination with a dose of pramipexole.

[0096] Illustrative examples of pharmaceutically acceptable salts of basic advantageous NK1- antagonists include acid addition salts with mineral acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, phosphoric acid and the like and acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, gluconic acid, aspartic acid, glutamic acid, and the like.

[0097] Illustrative examples of pharmaceutically acceptable salts of acidic NK1 -antagonists, such as fosaprepitant, include salts with inorganic bases such as alkaline metal or alkaline-earth metal salts, and salts with organic bases such as dicyclohexylamine salts, N-methyl-D- glucamine (meglumine) salts, and salts with amino acids, as described in US 5,691,336, the contents of which are incorporated herein in their entirety by reference.

[0098] An advantageous NK1 -antagonist to be used in combination with pramipexol may be selected from aprepitant and pharmaceutically acceptable salts and solvates thereof, fosaprepitant and pharmaceutically acceptable salts and solvates thereof, casopitant and pharmaceutically acceptable salts and solvates thereof, maropitant and pharmaceutically acceptable salts and solvates thereof, eziopitant and pharmaceutically acceptable salts and solvates thereof, lanepitant and pharmaceutically acceptable salts and solvates thereof, netupitant and pharmaceutically acceptable salts and solvates thereof, orvapitant and pharmaceutically acceptable salts and solvates thereof, rolapitant and pharmaceutically acceptable salts and solvates thereof, serlopitant and pharmaceutically acceptable salts and solvates thereof, vestipitant and pharmaceutically acceptable salts and solvates thereof, vofopitant and pharmaceutically acceptable salts and solvates thereof, andnetupitant- 300 / palonosetron-0.5.

[0099] Aprepitant, fosaprepitant meglumine, fosaprepitant di(cyclohexylamine), rolapitant, rolapitant hydrochloride and netupitant-300 / palonosetron-0.5 are particularly advantageousNKl-antagonists.

[0100] Antagonists of the NK1 receptor that are approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting are particularly useful according to the present invention. Aprepitant, commercially available (Emend®) in capsules containing 40 mg, 80 mg, or 125 mg aprepitant; fosaprepitant meglumine, commercially available (Emend® Injection), in vials containing 115 mg or 150 mg fosaprepitant; rolapitant, available (Varubi®) in 90-mg tablets; and netupitant-300 / palonostron- 0.5, available (Akynzeo®) in a fixed-dose combination in capsules containing 300 mg of netupitant and 0.5 mg of the NK1 -antagonist palonosetron (as hydrochloride); are preferred NKl-antagonists.

[0101] In the aforementioned method, use and combination, including fixed-dose combinations, said NKl-antagonst may be present in an amount per unit form and may be administered at a daily dose of 1 pg to 600 mg, normally from 1 mg to 600 mg, or from 1 mg to 300 mg.

[0102] More particularly, in said combination, said NK1 -antagonist is selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; rolapitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 15 mg to 270 mg of rolapitant, netupitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 300 mg to 600 mg; and netupitant- 300 / palonosetron-0.5.

[0103] For its administration to a patient suffering from a retinal degeneration in combination with pramipexol, each of the above NKl-antagonists is formulated in a pharmaceutical composition in dosage unit form comprising, as an active ingredient, said NK1 -antagonist, coformulated in a pharmaceutical composition (fixed-dose combination), e.g., admixture with a pharmaceutical carrier or vehicle.

[0104] In particular, said NK1- antagonist active ingredient of said pharmaceutical composition is selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; rolapitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 15 mg to270 mg of rolapitant; netupitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 300 mg to 600 mg; and netupitant- 300 / palonosetron-0.5.

[0105] Advantageously, said NK1 -antagonist is aprepitant, in an amount per unit form of from 10 mg to 250 mg; fosaprepitant meglumine, in an amount per unit form equivalent to from 10 mg to 250 mg of aprepitant; or rolapitant, in an amount per unit form of from 15 mg to 270 mg or from 30 mg to 270 mg.

[0106] As set forth above, by using an NK1 -antagonist in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, it may be possible to treat a patient suffering from a retinal degeneration by maintaining a therapeutically effective daily dose of pramipexole or pharmaceutically acceptable salt or solvate thereof with minimal adverse effects.

[0107] Thus, in order to assure a sure, safe and concurrent administration of said NK1- antagonist and said pramipexol, the present invention provides a fixed-dose combination consisting of a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said NK1 -antagonist and an effective amount per unit form of said pramipexol, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., admixture with a pharmaceutical carrier or vehicle.Pramipexole

[0108] In the combination of the present invention, the beneficial action of the 5HT3- antagonist or NK1 -antagonists, counteracting the adverse effects of pramipexole in patients suffering from retinal degeneration and more particularly AMD, allows for the safe administration of pramipexole daily doses otherwise not tolerable in most of said patients for administering about 0.375 mg to about 4.5 mg per day of pramipexole dihydrochloride monohydrate.

[0109] In addition, a 5HT3 -antagonist or NK1 -antagonists, especially selected among those shown effective or approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of the chemotherapy-induced nausea and vomiting, renders it possible to safely treat said patients with daily doses of pramipexole or pharmaceutically acceptable salt thereof equivalent to from more than 4.5 mg to 45 mg, from more than 6 mg to 45 mg or from 6.5 mg to 45 mg of pramipexole dihydrochloride dihydrate.

[0110] Pharmaceutically acceptable salts of pramipexole are those with inorganic or organicacids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, acetic acid, propionic acid, stearic acid, glycolic acid, oxalic acid, succinic acid, lactic acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, 2- hydroxy ethanesulfonic (isethionic) acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid, 4- amino-benzenesulfonic (sulfanilic) acid, 2,6-naphthalenedisulfonic acid, 1,5- naphthalenedisulfonic acid, and pamoic (embonic) acid. The solvation solvent is normally water.[OHl] For its administration in combination with the 5 HT3 -antagonist or NK1 -antagonists, pramipexole or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition in dosage unit form comprising an effective dose per unit form of said pramipexole or pharmaceutically acceptable salt thereof, as an active ingredient, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., admixture with a pharmaceutical carrier or vehicle. Said active ingredient is formulated according to known technologies for any administration route.

[0112] In the case of pramipexole dihydrochloride monohydrate, commercially available, stable pharmaceutical compositions comprising pramipexole dihydrochloride monohydrate, disclosed in WO 2012 / 0140604 and in WO 2008 / 122638; and sustained release compositions comprising pramipexole dihydrochloride monohydrate, disclosed in US 8,399,016; may be useful for the use in combination with a 5HT3 -antagonist or an NK1 -antagonist for the treatment of retinal degeneration. The contents of these documents are incorporated herein in their entirety by reference.

[0113] In pharmaceutical compositions with a 5HT3 -antagonist or an NK1 -antagonist, the dose per unit form of pramipexole or pharmaceutically acceptable salt or solvate thereof is equivalent to a range selected from the group consisting of from 0.125 mg to 45 mg, from 3 mg to 45 mg, from more than 4.5 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg and from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate. Normally, said dose per unit form is equivalent to a range selected from the group consisting of from 0.125 mg to 20 mg, from 1.6 mg to 20 mg, from 3 mg to 20 mg, from more than 4.5 mg to 20 mg, from 5 mg to 20 mg, from more than 6 mg to 20 mg and from 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate.

[0114] The dose of pramipexole or pharmaceutically acceptable salt or solvate thereof per IR-unit form will preferably be equivalent to a range selected from the group consisting of from 0.125 mg to 22.5 mg, from 3 mg to 22.5 mg, from more than 4.5 mg to 22.5 mg, from more than 6 mg to 22.5 mg and from 6.5 mg to 22.5 mg, normally in a range selected from the group consisting of from 0.125 mg to 10 mg, from 1.5 mg to 10 mg, from 1.625 mg to 10 mg, from 3 mg to 10 mg, from more than 4.5 mg to 10 mg, from 5 mg to 10 mg, from more than 6 mg to 10 mg, and from 6.5 mg to 10 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with the 5HT3 -antagonist or an NK1 -antagonist).

[0115] The dose per unit form of pramipexole or pharmaceutically acceptable salt or solvate thereof in an ER formulation, including slow-release compositions and transdermal therapeutic systems such as transdermal patches, will range from an amount per unit form that is equivalent to a range selected from the group consisting of from 0.375 mg to 45 mg, from 1.5 mg to 45 mg, from 3 mg to 45 mg, from more than 4.5 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg and from 6.5 mg to 45 mg, of pramipexole dihydrochloride monohydrate, normally equivalent to a range selected from the group consisting of from 0.375 mg to 45 mg, from 1.5 to 20 mg, from 3 mg to 20 mg, from more than 4.5 mg to 20 mg, from 5 mg to 20 mg, from more than 6 mg to 20 mg, and from 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate, depending on the tolerability (in combination with said 5HT3 -antagonist or NK1 -antagonist).

[0116] The pramipexole doses per unit form provided herein include low doses that can be used especially in the case of the initial titration of the pramipexole daily dose or in the less frequent case of the use in the treatment of pediatric patients with retinal degeneration.

[0117] In embodiments of the present invention, the pramipexol is preferably selected from the group consisting of: pramipexole and pharmaceutically acceptable salts and solvates thereof, in particular its dihydrochloride monohydrate (US AN: pramipexole hydrochloride), in a dose per unit form equivalent to from 0.125 mg to 45 mg, preferably from 0.125 mg to 40 - 42 mg of pramipexole dihydrochloride monohydrate; (R,S)-pramipexole (the racemate) and pharmaceutically acceptable salts an solvates thereof, in a dose per unit form equivalent to from 0.25 mg to 90 mg of pramipexole dihydrochloride monohydrate (thus, obviously, including a dose per unit form equivalent to from 0.125 mg to 45 mg, preferably from 0.125 mg to 40 - 42 mg of pramipexole dihydrochloride monohydrate, and a dose per unit form equivalent to from 0.125 mg to 45 mg, preferably from 0.125 mg to 40 mg of pramipexole dihydrochloride monohydrate), and preferably, from 0.25 mg to 90 mg, preferably from 0.25 mg to 80-84 mg of pramipexole dihydrochloride monohydrate (thus, obviously, including a dose per unit formequivalent to from 0.125 mg to 40 - 42 mg of pramipexole dihydrochloride monohydrate, and a dose per unit form of (R)-enantiomer equivalent to from 0.125 mg to 40 - 42 mg of pramipexole dihydrochloride monohydrate); and an (R) / (S)-mixture in a pharmaceutical composition in dosage unit form comprising pramipexol, at a dose per unit form equivalent to from 50 mg to 3000 mg, preferably to from 150 mg to 3000 mg, of pramipexole dihydrochloride monohydrate, said amount per unit form including a (S)-enantiomer amount equivalent to from 0.125 mg to 45 mg, preferably from 0.125 mg to 45 mg of pramipexole dihydrate monohydrate (thus, obviously, said amount per unit form being constituted by an amount of (S)-enantiomer equivalent to from 0.125 mg to 45 mg, preferably from 0.125 mg to 40 -42 mg of pramipexole dihydrochloride monohydrate and by a (R)-enantiomer amount per unit form equivalent to from 50 mg, preferably from 150 mg, to 3000 mg (minus from 0.125 mg to 45 mg, normally from 0.125 to 40 - 42 mg) of pramipexole dihydrochloride monohydrate), and preferably, from 0.125 mg to 40 - 42 mg of pramipexole dihydrochloride monohydrate (thus, obviously, said amount per unit form being constituted by an amount of (S)-enantiomer equivalent to from 0.125 mg to 45 mg, preferably from 0.125 mg to 40 - 42 mg of pramipexole dihydrochloride monohydrate and by a (R)-enantiomer amount per unit form equivalent to from 50 mg, preferably from 150 mg, to 3000 mg (minus from 0.125 mg to 45 mg, preferably from 0.125 to 40 - 42 mg) of pramipexole dihydrochloride monohydrate).

[0118] An effective daily dose of pramipexole or of (S)-enantiomer is a dose equivalent to at least the pramipexole dihydrochloride monohydrate daily approved dose of from 0.375 mg to 4.5 mg. However, it is hereby specified that, according to the present invention, the combination of a 5HT3 -antagonist or an NK1 -antagonist with said pramipexole or (S)- enantiomer allows the administration of pramipexole dihydrochloride monohydrate without any adverse effect..Pharmaceutical combination of pramipexole and a 5 HT 3 -antagonist and / or an NK1- antagonist for treating retinal degeneration

[0119] In one aspect, the present invention provides a pharmaceutical combination comprising:(a) a 5HT3 -antagonist or an NK1 -antagonist, and(b) said pramipexole or a pharmaceutically acceptable salt or solvate thereof, at an effective daily dose, for use for the treatment of retinal degeneration.

[0120] In another aspect, the present invention includes a method for safely slowing or even reversing disease progression of patients suffering from a retinal degeneration and treated with pramipexol, by concurrently and chronically administering to said patients a 5HT3- or an NK1-antagonist.

[0121] More particularly, the invention provides a method for treating a retinal degeneration in a patient, which comprises administering to said patient in need of said treatment an effective daily dose of a NK1 -antagonist and / or a 5HT3 -antagonist in combination with an effective daily dose of pramipexol.

[0122] Embodiments of the present invention include: a 5HT3 -antagonist or an NK1 -antagonist, for use for the treatment of retinal degeneration in a patient in need of said treatment in combination with an effective daily dose of pramipexole or of a pharmaceutically acceptable salt thereof; and a method for treating a patient suffering from retinal degeneration, which comprises administering to a patient in need of said treatment a 5HT3 -antagonist or an NK1 -antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt thereof.

[0123] Said 5HT3 -antagonist or an NK1 -antagonist may be administered at a daily dose of from 1 pg to 300 mg, in combination with a pramipexole effective daily dose, including a daily dose for use during the titration period, equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate.

[0124] In embodiments, pramipexole may be used at the lowest doses (from 0.375 mg to less than 3 mg or to less than 4.5 mg daily), in combination with a 5HT3-antagonist or an NK1- antagonist. An advantage provided by the present invention is an increase in the safe titration threshold dose, due to the concomitant administration of said 5HT3-antagonis or NK1- antagonist.

[0125] In addition, according to the present invention, the concomitant administration of a 5HT3 -antagonist or an NK1 -antagonist allows for the administration of pramipexole daily doses of pramipexole dihydrochloride monohydrate about 0.375 mg to about 4.5 mg daily dose.

[0126] A 5HT3 -antagonist or an NK1 -antagonist indicated for the prevention of post-operative nausea and vomiting or of chemotherapy-induced nausea and vomiting may be used in combination with pramipexole according to the present invention.

[0127] In carrying out the method (or according to the use) of the present invention, the daily dose of these 5HT3 -antagonists or NK1 -antagonists may be at least as high as that preventing or treating nausea and vomiting in pediatric or adult patients undergoing a surgical operation or cancer chemotherapy according to the current protocols for said treatment or prevention.

[0128] Normally, in the method (or use) for the treatment of retinal degeneration according tothe present invention, pramipexole or pharmaceutically acceptable salt or solvate thereof, normally in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle, is administered to a patient in need of said treatment at a daily dose that is equivalent to from 0.375 mg to 45 mg, from 1.5 mg to 45 mg, from 3 mg to 45 mg, from 5 mg to 45 mg , from more than 6 mg to 45 mg and from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate, in some cases from 1.5 mg to 20 mg, advantageously from 3 mg to 20 mg, preferably from 5 mg to 20 mg of pramipexole dihydrochloride monohydrate. In said method (or use) pramipexole is administered to said patient in combination with a 5HT3 -antagonist or an NK1 -antagonist.

[0129] According to a particular embodiment, in said method (or use), said pramipexole or pharmaceutically acceptable salt thereof is pramipexole dihydrochloride monohydrate, that is orally administered to said patient at a daily dose of from 1.5 mg to 20 mg, advantageously from 3 mg to 20 mg, normally from 5 mg to 20 mg. According to this embodiment, in said method (or use) said pramipexole or pharmaceutically acceptable salt thereof is administered to said patient in combination with said 5HT3-or NK1 -antagonist, administered by any administration route.

[0130] Preferably, in the method (or use) for treating retinal degeneration in a patient according to the present invention, said 5HT3 -antagonist, in said combination, is selected from the group consisting of ondansetron or a pharmaceutically acceptable salt thereof, administered at a daily dose equivalent to from 2 mg to 32 mg of ondansetron base, and dolasetron and pharmaceutically acceptable salts thereof, administered at a daily dose equivalent to from 75 mg to 200 mg of dolasetron mesylate; and said NK1 -antagonist in said combination, is selected from the group consisting aprepitant, said pramipexole or pharmaceutically acceptable salt thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg, in particular from 1.5 mg to 45 mg, from 3 mg to 45 mg, from 5 mg to 45 mg , from more than 6 mg to 45 mg and from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.

[0131] Normally, in said method (or use), said 5HT3 -antagonist is ondansetron or a pharmaceutically acceptable salt thereof, at an effective daily dose and said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt thereof, at an effective daily dose.

[0132] Normally, in said method (or use), said 5HT3 -antagonist is ondansetron or a pharmaceutically acceptable salt thereof, at an effective daily dose (in ondansetron) of from 4 mg to 32 mg, administered in combination with said pramipexole or a pharmaceutically acceptable salt or solvate thereof, at an effective daily dose (in pramipexole dihydrochloridemonohydrate) of from 1.5 mg to 20 mg, advantageously from 3 mg to 20 mg, preferably from 5 mg to 20 mg.

[0133] In some embodiments of the invention, for their administration for the treatment of retinal degeneration, said pramipexole or pharmaceutically acceptable salt or solvate thereof and said 5HT3 -antagonist or NK1 -antagonist are each formulated in a pharmaceutical composition with a pharmaceutical carrier or vehicle (e.g., in admixture). In particular, in said combination, said 5HT3-antagonist is formulated in a pharmaceutical composition in dosage unit form comprising, as an active ingredient, an effective amount per unit form of said 5HT3- antagonist with a pharmaceutical carrier or vehicle (e.g., in admixture); and, said NK1- antagonist is formulated in a pharmaceutical composition in dosage unit form comprising, as an active ingredient, an effective amount per unit form of said NK1 -antagonist with a pharmaceutical carrier or vehicle, and, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is also co-formulated (e.g., in admixture) in a pharmaceutical composition in dosage unit form comprising, as an active ingredient, an effective amount of said pramipexole or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutical carrier or vehicle.

[0134] More particularly, in said combination 5HT3 -antagonist is formulated in a pharmaceutical composition in dosage unit form comprising said 5HT3 -antagonist in an amount per unit form of from 0.1 mg to 300 mg, with a pharmaceutical carrier or vehicle said (e.g., in admixture); and said NK1 -antagonist is formulated (e.g., in admixture) in a pharmaceutical composition in dosage unit form comprising said NK1 -antagonist in an amount per unit form of from 5 mg to 300 mg, with a pharmaceutical carrier or vehicle; and said pramipexole or pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition in dosage unit form comprising said pramipexole or pharmaceutically acceptable saltthereofin an amount per unit form equivalent to from 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate, with a pharmaceutical carrier or vehicle (e.g., in admixture).

[0135] Preferably, in said combination said 5HT3 -antagonist in said composition is selected from the group consisting of ondansetron and pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from 2 mg to 32 mg of ondansetron base, and dolasetron and pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from from 25 mg to 200 mg of dolasetron mesylate.

[0136] Preferably, in said combination said NK1 -antagonist in said composition is selected from the group consisting of aprepitant and pharmaceutically acceptable salt or solvate thereof,in an amount per unit form equivalent to from 5 mg to 200 mg.

[0137] Pramipexole is preferably present, in said composition, in an amount per unit form equivalent to from 5 mg to 45 mg or from 6.5 mg to 45 mg, normally from 5 mg to 20 mg or from 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate.

[0138] The pharmaceutical compositions thus obtained are concurrently or sequentially administered to a patient suffering from retinal degeneration.

[0139] Said pramipexole or pharmaceutically acceptable salt or solvate thereof and said 5HT3- antagonist or said NK1 -antagonist may also be co-formulated together in a fixed-dose combination (e.g., in admixture) consisting of a pharmaceutical composition comprising said pramipexole or pharmaceutically acceptable salt or solvate thereof and said 5HT3-or NK1- antagonist, with a pharmaceutical carrier or vehicle (e.g., in admixture).

[0140] Normally, in the method (or use) of the present invention, said combination is a fixed- dose combination consisting of a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said 5HT3 -antagonist or NK1 -antagonist, and an effective amount per unit form of said pramipexole or a pharmaceutically acceptable salt thereof, with a pharmaceutical carrier or vehicle (e.g., in admixture).

[0141] The fixed-dose combinations assure the safe, concurrent administration of pramipexole or pharmaceutically acceptable salt or solvate thereof and of the 5HT3- or NK1 -antagonist.

[0142] As set forth above, when using a 5HT3-or an NK1 -antagonist indicated for the prevention or treatment of postoperative nausea and vomiting or for the prevention of the chemotherapy-induced nausea and vomiting, the amount per unit form of said antagonist is at least as high as the pediatric or adult dose approved for this indication. However, it may be up to 6 times said dose.

[0143] In the above fixed-dose combinations, the pramipexole dose / unit form, in pramipexole dihydrochloride monohydrate, is in a range selected from the group consisting of from 0.125 mg to 45 mg, from 3 mg to 45 mg, from more than 4.5 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg and from 6.5 mg to 45 mg. Normally said range is selected from the group consisting of from 0.125 mg to 20 mg, from 3 mg to 20 mg, from more than 4.5 mg to 20 mg, from 5 mg to 20 mg, from more than 6 mg to 20 mg, and from 6.5 mg to 20 mg; and the dose / unit form of the 5HT3 -antagonist ranges from 1 pg to 300 mg, and the dose / unit form of the NK1 -antagonist ranges from 1 mg to 300 mg.

[0144] If the 5HT3 -antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof, its dose / unit form (in ondansetron) is from 2 mg to 32 mg, normally from 4 mg to 32mg, or from 8 mg to 32 mg.

[0145] If the 5HT3 -antagonist is dolasetron or a pharmaceutically acceptable salt or solvate thereof, its dose / unit form (in dolasetron mesylate) is from 1.5 mg to 200 mg.

[0146] If the NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof, the dose / ER-unit form (in aprepitant will range from 50 to 150mg.

[0147] If said pramipexole or pharmaceutically acceptable salt thereof is pramipexole dihydrochloride monohydrate, the dose-range per oral IR-unit form, depending on safety and tolerability (in combination with the 5HT3-or the NH1 antagonist) is selected from the group consisting 0.125 mg to 22.5 mg, from 1.5 mg to 22.5 mg, from 3 mg to 22.5 mg, from more than 4.5 mg to 22.5 mg, from 5 mg to 22.5 mg, from more than 6 mg to 22.5 mg, and from 6.5 mg to 22.5 mg, normally from 1.5 mg to 10 mg, from 3 mg to 10 mg, from more than 4.5 mg to 10 mg, from 5 mg to 10 mg, from more than 6 mg to 10 mg, and from 6.5 mg to 10 mg. If the 5HT3 -antagonist is ondansetron hydrochloride dihydrate, the ondansetron dose per oral IR unit form, in combination with pramipexole dihydrochloride monohydrate, will be equivalent to from 2 mg to 16 mg, normally from 4 mg to 16 mg of ondansetron base. If the NK1- antagonist is aprepitant hydrochloride dihydrate, the NK1 -antagonist dose per oral IR unit form, in combination with pramipexole dihydrochloride monohydrate, will be equivalent to from 80 mg to 150 mg, normally from 80 mg to 100 mg of ondansetron base.

[0148] The dose / unit form of pramipexole or pharmaceutically acceptable salt thereof, in pramipexole dihydrochloride monohydrate, in an ER formulation, including slow-release compositions and transdermal therapeutic systems such as transdermal patches, will be in a range selected from the group consisting of from 1.5 mg to 45 mg, from 3 mg to 45 mg, from more than 4.5 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg, and from 6.5 mg to 45 mg, normally from 1.5 mg to 20 mg, from 3 mg to 20 mg, from more than 4.5 mg to 20 mg, from 5 mg to 20 mg, from more than 6 mg to 20 mg, and from 6.5 mg to 20 mg, depending on the tolerability (in combination with the 5HT3 -antagonist).Use of 5HT3-antagonists and / or NK1 -antagonists for the preparation of a medicament

[0149] Another aspect of the present invention provides the use of a 5HT3 -antagonist or an NK1 -antagonist for the preparation of a medicament containing a pharmaceutical composition comprising, as an active ingredient, said 5HT3 -antagonist or said NK1 -antagonist, with a pharmaceutical carrier or vehicle, (e.g., in admixture) for the treatment of retinal degeneration, in combination with an effective daily dose of pramipexole or a pharmaceutically acceptablesalt or solvate thereof.

[0150] In embodiments, the invention provides the use of said 5HT3- or NK1 -antagonist for the preparation of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said 5HT3 -antagonist, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle, for the treatment of retinal degeneration in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, also in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.

[0151] In embodiments, the invention provides the use of said 5HT3- or NK1 -antagonist for the preparation of a medicament consisting of a pharmaceutical composition in dosage unit form comprising an effective dose per unit form of said 5HT3- or NK1 -antagonist, coformulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier, for the treatment of retinal degeneration in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof in doses, in pramipexole dihydrochloride monohydrate, at least about 0.375 mg to about 4.5 mg per day.

[0152] In particular, a 5HT3 -antagonist or an NK1 -antagonist is formulated in a pharmaceutical composition comprising said 5HT3 -antagonist or an NK1 -antagonist in an amount per unit form of from 1 pg to 300 mg, from 0.1 mg to 300 mg or from 1 mg to 300 mg, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle.

[0153] A preferred 5HT3 -antagonist in said pharmaceutical composition, for its indication for the treatment of retinal degeneration in combination with said pramipexole, is selected from the group consisting of azasetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount / unit form equivalent to from 5 mg to 10 mg of azasetron hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular its mesylate monohydrate, in an amount / unit form equivalent to from 20 mg to 200 mg of dolasetron mesylate; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount / unit form equivalent to from 0.5 mg to 2 mg granisetron base; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride dihydrate, in an amount / unit form equivalent to from 2 mg to 32 mg, normally from 2 mg to 16 mg of ondansetron base; palonosetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount / unit form equivalent to from 0.1 mg to 2 mg, normally from 0.25 mg to 0.5 mg palonosetron base;ramosetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount / unit form equivalent to from 2.5 pg to 100 pg of ramosetron hydrochloride; and tropisetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount / unit form equivalent to from 2.5 mg to 5 mg tropisetron base.

[0154] A preferred NK1 -antagonist in said pharmaceutical composition, for its indication for the treatment of retinal degeneration in combination with said pramipexole, is selected from the group consisting of aprepitant, in an amount per unit form of from 10 mg to 250 mg; fosaprepitant dimeglumine, in an amount per unit form of from 10 mg to 150 mg, rolapitant, in an amount per unit form of from 30 mg to 270 mg and netupitant, in an amount per unit form of from 100 mg to 600 mg. If said NK1- antagonist is netupitant, in an amount per unit form of from 100 mg to 600 mg, the above pharmaceutical composition Component (a) may also comprise, as a second active ingredient, palonosetron or a pharmaceutically acceptable salt thereof, in an amount per unit form equivalent to from 0.1 mg to 0.5 mg of palonosetron base.

[0155] These pharmaceutical compositions, used in combination each other, for the first time allow the use of pramipexole high doses for a substantial and efficacious treatment of a patient suffering from retinal degeneration. In fact, a pharmaceutical composition as described according to this aspect of the invention allows for the safe treatment of a patient suffering from retinal degeneration in combination with a pramipexole daily dose of from 0.375 mg to 45 mg, especially from more than 4.5 mg to 45 mg, normally from 5 mg to 45 mg, from more than 6 mg to 45 mg or from 6.5 mg to 45 mg, thus slowing and even resolving the progression of the retinal degeneration of said patients. In certain cases, said pramipexole daily dose is from more than 4.5 mg to 20 mg, from 5 mg to 20 mg, from more than 6 mg to 20 mg or from 6.5 mg to 20 mg.

[0156] In the treatment of retinal degeneration, a 5HT3 -antagonist or an NK1 -antagonist and pramipexole are used in combination and the two active components may be co-administered simultaneously or sequentially, or in a fixed dose combination including a pharmaceutical composition comprising the 5HT3 -antagonist or an NK1 -antagonist and pramipexol, together co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutically acceptable carrier or vehicle.

[0157] The 5HT3 -antagonist or an NK1 -antagonist and pramipexole can be administered separately or together in any conventional oral or parenteral dosage unit form such as capsule, tablet, powder, cachet, suspension, solution, eye drop, or transdermal device.

[0158] In the case of separate (concurrent or sequential) administration of said 5HT3- or NK1- antagonist, in an effective amount per unit form, and of said pramipexole, in an effective amount per unit form, each of them can be packaged in a kit comprising said 5HT3- or NK1- antagonist, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle, in a dual chamber capsule or packaged in a container (one for each product); and said pramipexole, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle, in another, separate container.

[0159] In the case of a concurrent administration, said 5HT3- or NK1 -antagonist and said pramipexole may be formulated together in a fixed-dose combination consisting of a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said 5HT3- or NK1 -antagonist and an effective amount per unit form of said pramipexole or a pharmaceutically acceptable salt thereof, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle.

[0160] In embodiments, the invention provides the use of a 5HT3- or an NK1 -antagonist for the preparation of a medicament for the treatment of retinal degeneration, said medicament being a fixed-dose combination consisting of a pharmaceutical composition comprising, as an active ingredient, said 5HT3- or NK1 -antagonist and, as a second active ingredient, pramipexole or a pharmaceutically acceptable salt or solvate thereof, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle.

[0161] In embodiments, said fixed-dose combination consists of a pharmaceutical composition comprising:(c) said 5HT3- or NK1 -antagonist; and(d) pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form (in pramipexole dihydrochloride monohydrate) at least as high as an amount per unit comprising a therapeutically effective dose, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle, for use for the treatment of retinal degeneration.

[0162] Advantageously, in embodiments of this aspect of the invention, said fixed-dose combination consists of a pharmaceutical composition in dosage unit form comprising:(e) said 5HT3- or NK1 -antagonist, in an amount / unit form at least at least as high as an amount / unit form approved for the prevention of chemotherapy-induced nauseaand vomiting; and(f) pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount / unit form (in pramipexole dihydrochloride monohydrate) at least as high as an amount / unit form providing a therapeutically effective dose, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle, for the treatment of retinal degeneration.

[0163] In general, in the above pharmaceutical composition said 5HT3 -antagonist is present in an amount of from 1 pg to 300 mg, or said NK1 -antagonist is present in an amount of from 5 mg to 300 mg, and said pramipexole is present in an amount of from 0.125 mg to 45 mg.

[0164] If the 5HT3- or the NK1 -antagonist is selected from among those indicated for the prevention or treatment of postoperative nausea and vomiting or for the prevention of the chemotherapy-induced nausea and vomiting, said 5HT3 -antagonist is present in said composition in an amount / unit form at least at least as high as an amount / unit form shown to be effective in or approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of the chemotherapy-induced nausea and vomiting, and up to 6 times said dose.

[0165] In fixed-dose combinations, the pramipexole dose / unit form, in pramipexole dihydrochloride monohydrate, normally ranges from 0.125 mg to 20 mg, advantageously from 3 mg to 20 mg, preferably from 5 mg to 20 mg, from more than 6 mg to 20 mg or from 6.5 mg to 20 mg; and the dose / unit form of the 5HT3 -antagonist ranges from 1 pg to 300 mg.

[0166] -If the 5HT3 -antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof, its dose / unit form (in ondansetron) is from 2 mg to 32 mg, normally from 4 mg to 32 mg.

[0167] If the 5HT3 -antagonist is dolasetron or a pharmaceutically acceptable salt or solvate thereof, its dose / unit form (in dolasetron mesylate) is from 1.5 mg to 200 mg.

[0168] If the NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof, its dose / unit form (in aprepitant ) is from 50 mg to 120 mg, normally from 80 mg to 100 mg.

[0169] An advantageous fixed-dose combination consists of a pharmaceutically composition in dosage unit form comprising of: as component (a), a 5HT3 -antagonist selected from the group consisting of alosetron or a pharmaceutically acceptable salt or solvate thereof, in particular its hydrochloride, in an amount / unit dose (in alosetron) of from 0.25 mg to 2 mg; azasetron or a pharmaceutically acceptable salt or solvate thereof, in particular itshydrochloride, in an amount / unit dose of from 5 mg to 10 mg; dolasetron or a pharmaceutically acceptable salt or solvate thereof, in particular its mesylate monohydrate, in an amount / unit dose (in dolasetron mesylate) of from 25 mg to 200 mg; granisetron or a pharmaceutically acceptable salt or solvate thereof, in particular its hydrochloride, in an amount / unit dose equivalent to from 0.5 mg to 2 mg granisetron base; ondansetron or a pharmaceutically acceptable salt or solvate thereof, in particular its hydrochloride dihydrate, in an amount / unit dose equivalent to from 2 mg to 32 mg of ondansetron base; palonosetron or a pharmaceutically acceptable salt or solvate thereof, in particular its hydrochloride, in an amount / unit dose equivalent to from 0.25 mg to 0.5 mg palonosetron base; ramosetron or a pharmaceutically acceptable salt or solvate thereof, in particular its hydrochloride, in an amount / unit dose of from 50 pg to 40 mg; and tropisetron or a pharmaceutically acceptable salt or solvate thereof, in particular its hydrochloride, in an amount / unit dose equivalent to from 2.5 mg to 5 mg tropisetron base; or an NK1 -antagonist selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; rolapitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 15 mg to 270 mg of rolapitant; netupitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 300 mg to 600 mg; and netupitant-300 / palonosetron-0.5; and as component (b), pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount equivalent to from 0.125 mg to 45 mg, preferably from 5 mg to 45 mg, from more than 6 mg to 45 mg, or from 6.5 mg to 45 mg, and normally equivalent to a range selected from the group consisting of from 0.125 mg to 20 mg, from 3 mg to 20 mg, from more than 4.5 mg to 20 mg, from 5 mg to 20 mg, from more than 6 mg to 20 mg and from 6.5 mg to 20 mg, of pramipexole dihydrochloride monohydrate, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle.

[0170] According to an embodiment, said advantageous composition comprises, as active ingredients, (g) a 5HT3 -antagonist selected from the group consisting of ondansetron or a salt or solvate thereof, in an amount (in ondansetron base) of from 2 mg to 32 mg; and dolasetron, in an amount (in dolasetron mesylate) from 25 mg to 200 mg; or an NK1 -antagonist such as aprepitant; (h) pramipexole or a pharmaceutically acceptable salt thereof, in an amount (in pramipexole dihydrochloride monohydrate) of from 0.125 mg to 45 mg, co-formulated in apharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle.

[0171] Said advantageous composition preferably comprises, as Component (b) pramipexole or a pharmaceutically acceptable salt thereof, in an amount (in pramipexole dihydrochloride monohydrate) selected from the group consisting of from 3 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg, and from 6.5 mg to 45 mg.

[0172] A 5HT3-antagonist / pramipexole fixed-dose combination, normally for use in the treatment of retinal degeneration, consists of a pharmaceutical composition comprising a 5HT3 -antagonist selected from the group consisting of ondansetron or a pharmaceutically acceptable salt or solvate thereof, in an amount corresponding to from 2 mg to 32 mg of ondansetron base, as Component (a); and pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount that is equivalent to from 0.125 mg to 20 mg, advantageously from 3 mg to 20 mg, preferably from 5 mg to 20 mg, from more than 6 mg to 20 mg or from 6.5 mg to 20 mg, of pramipexole dihydrochloride monohydrate, as Component (b), coformulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle.

[0173] Herein, the pramipexole doses / unit forms include low doses that can be used especially in the case of the titration of the pramipexole daily dose or in the less frequent case of use in the treatment of pediatric patients with retinal degeneration.Pharmaceutical Compositions with 5HT3-antagonists

[0174] In the pharmaceutical compositions of the present invention for oral, subcutaneous, intravenous, transdermal or topical administration, the active ingredients are preferably administered in the form of dosage units, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with the pharmaceutical carriers or vehicles.

[0175] The pharmaceutical compositions may be formulated in oral forms such as tablets or gelatin capsules wherein the 5HT3-antagonist or pramipexole or both the active ingredients are co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a carrier or vehicle that may include a diluent, such as cellulose, dextrose, lactose, mannitol, sorbitol or sucrose; a lubricant, such as, acid, calcium or magnesium stearate, polyethylene glycol, silica, or talc; and if needed, a binder such as magnesium aluminum silicate, gelatin, methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone.

[0176] Said oral forms may be tablets coated with sucrose or with various polymers; or,alternatively, the tablets can be manufactured by using carriers such as acrylic and methacrylic acid polymers and copolymers; cellulose derivatives such as hydroxypropylethylcellulose; or other appropriate materials, to have a prolonged or delayed activity by progressively releasing a predetermined quantity of 5HT3 -antagonist or of pramipexole (or of a pharmaceutically acceptable salt or solvate thereof), or of both the active ingredients. The oral formulations can also be in form of capsules allowing the extended release the pramipexole (or pharmaceutically acceptable salt or solvate thereof), or of 5HT3 -antagonist, or of both the active ingredients.

[0177] The pharmaceutical compositions may also be formulated in TTS, such as a patch formulation wherein the active ingredient or the mixture of the active ingredients may comprise adjuvants such as D-sorbitol, gelatin, kaolin, methyl paraben, polysorbate 80, propylene glycol, propyl paraben, povidone, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water. A patch formulation may also contain skin permeability enhancer such as lactate esters (e.g., lauryl lactate), triacetin or diethylene glycol monoethyl ether.

[0178] In the above pharmaceutical compositions, the preferred pramipexole or pharmaceutically acceptable salt or solvate thereof active ingredient is pramipexole base or its dihydrochloride monohydrate and the preferred 5HT3 -antagonist active ingredient is ondansetron base or its hydrochloride dihydrate, or dolasetron base or its mesylate monohydrate.

[0179] For the intended use in the treatment of retinal degeneration in combination with pramipexole, the 5HT3 -antagonist is formulated in a pharmaceutical composition, wherein said 5HT3 -antagonist is co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle.

[0180] In embodiments, the pharmaceutical composition is administered into an eye via any one of ocular administration routes known in the art.

[0181] The dosage, i.e. the amount of active ingredient in a single dose to be administered to the patient, can vary widely depending on the age, weight, and the health condition of the patient. This dosage, in a pharmaceutical composition in dosage unit form as illustrated herein above, includes the administration of a single dose from 1 pg to 300 mg according to the potency of each 5HT3-antagonist and the age of the patient, and a single dose of pramipexole or a pharmaceutically acceptable salt thereof that is equivalent to from 0.125 mg to 45 mg, normally from 0.125 mg to 20 mg, advantageously from 3 mg to 20 mg, preferably from 5 mg to 20 mg or from 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate, according tothe age of the patient, from one to three times a day by intravenous, subcutaneous, oral, or transcutaneous administration, according to the strength of the doses of the each of the active ingredients. If the 5HT3 -antagonist is ondansetron hydrochloride dihydrate, said dosage (single dose) ranges from 4 mg to 16 mg (in ondansetron base): and, if the pramipexole or a pharmaceutically acceptable salt thereof is pramipexole dihydrochloride monohydrate, said dosage (single dose) ranges from 0.125 mg to 45 mg, from 3 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg or from 6.5 mg to 45 mg, normally from 0.125 mg to 20 mg, advantageously from 3 mg to 20 mg, preferably from 5 mg to 20 mg or from 6.5 mg to 20 mg. Ondansetron may also be administered via a transdermal drug delivery system (TDDS). "Transdermal drug delivery system" provides transdermal delivery using transdermal drug formulations and transdermal patches incorporating such transdermal drug formulations. For example, the transdermal drug delivery system may include a composition in form of a patch, a cream, a gel, a lotion or a paste comprising a 5HT3 -antagonist (such as ondansetron). Examples of transdermal formulations may include, but are not limited, to those as described in US 6,562,368, a transdermal gel formulation as described in US 7,029,694; US 7, 179,483; US 8,241,662 and US 2009 / 0018190, a transdermal or transmucosal pharmaceutical formulation, that can be utilized for topical or transdermal application, such that solutions, creams, lotions, sprays, ointment, gels, aerosols and patch drug deliveries as described in WO 2005 / 039531, US2007 / 022379, US 2010 / 0216880, US 2014 / 0037713 and US 8,652,491, a transdermal absorption preparation as described in WO2013 / 061969 and US 2014 / 0271796, the disclosures of which are herein incorporated by reference in their entirety. The transdermal patches may also include, but are not limited to, a patch pump having an in-dwelling rigid catheter with flexible features and / or a flexible catheter attachment as described in US 9,782,536, a selectively activatable patch pump as described in US 9,724,462, a patch pump attached to a wireless communication system as described in US 9,623,173, a conformable patch pump as described in US 9,616,171, an infusion pump as described in US 8,915,879, a portable infusion drug delivery as described in US 8,480,649, a micropump as described in US 8,282,366, and a patch pump as described in US 7,828,771; the disclosures of which are herein incorporated by reference in their entirety. Other transdermal patches may include, but are not limited to, a patch in which oxybutynin is incorporated in an adhesive agent layer composition comprising the acrylic-based polymer as the adhesive base agent, and the acrylic-based polymer is a copolymer of polymethyl methacrylate with a polyacrylate as described in US 8,802,134, a patch consisting of a support layer and of an adhesive agent layer arranged on theat least one surface of the support layer as described in US 8,877,235, a patch using a monoglyceride or a mixture of monoglycerides of fatty acids as skin permeation-enhancer as described in US 5,441,740 and US 5,500,222, a patch for using a monoglyceride or a mixture of monoglycerides plus a lactate ester as skin permeation-enhancer as described in US 5,686,097; US 5,747,065; US 5,750,137 and US 5,900,250, a patch with a non-rate controlling tie layer on the skin-proximal surface of the reservoir, not affecting the drug release as described in US 5,614,211 and US 5,635,203, a patch using triacetin as permeation enhancer as described in US 5,212,199, US 5,227,169, US 5,601,839 and US 5,834,010, a patch with a matrix mass in the form of a layer which is self-adhesive, and in which the matrix mass consists of ammonium-group-containing (meth)acrylate copolymers as described in US 6,555,129, a transdermal patch as described in US 6,743,441; 7,081,249; US 7,081,250; US 7,081,251; US 7,081,252 and US 7,087,241; the disclosures of which are herein incorporated by reference in their entirety. Preferably, the transdermal drug delivery system is a patch, a patch pump, an infusion pump, or a micropump.

[0182] The pharmaceutical compositions of the present invention are formulated with the classic excipients suitable for different ways of administration. Particularly advantageous are the formulations in the form of tablets, multi-score tablets, coated tables, orally disintegrating tablets, extended release tablets, hard or soft capsules, extended-release capsules, patches for transdermal administration, liquid oral solutions, syrups or suspensions in a predetermined unit form, and vials for the intravenous or subcutaneous administration.

[0183] Thus, for example, a pharmaceutical composition according to the present invention to be chronically administered in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit dose (in pramipexole dihydrochloride monohydrate) of from 0.125 mg to 45 mg, from 3 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg or from 6.5 mg to 45 mg, normally from 0.125 mg to 20 mg, advantageously from 3 mg to 20 mg, preferably from 5 mg to 20 mg or from 6.5 mg to 20 mg, to be administered at a daily dose of from 1.5 mg to 45 mg, advantageously from 3 mg to 45 mg, preferably from 5 mg to 45 mg or from 6.5 mg to 45 mg, normally from 1.5 mg to 20 mg, advantageously from 3 mg to 20 mg, preferably from 5 mg to 20 mg or from 6.5 mg to 20 mg, may comprise alosetron hydrochloride, in an amount / unit dose (in alosetron) of from 0.25 mg to 2 mg to be administered at a daily dose of from 0.25 mg to 3 mg; azasetron hydrochloride, in an amount / unit dose of from 5 mg to 10 mg to be administered at a daily dose of from 15 mg to 20 mg; dolasetron mesylate monohydrate, in an amount / unit dose (in dolasetronmesylate) of from 25 mg to 200 mg to be administered at a daily dose of from 75 mg to 200 mg; granisetron hydrochloride, in an amount / unit dose equivalent to from 0.5 mg to 2 mg granisetron base, to be administered at a daily dose of from 1.5 mg to 8 mg; ondansetron hydrochloride dihydrate, in an amount / unit dose equivalent to from 2 mg to 8 mg ondansetron base, to be administered at a daily dose of from 6 mg to 32 mg; palonosetron hydrochloride, in an amount / unit dose equivalent to from 0.25 mg to 0.5 mg palonosetron base, to be administered at a daily dose of from 0.75 to 2 mg; ramosetron hydrochloride, in an amount / unit dose of from 50 pg to 20 mg to be administered at a daily dose of from 75 pg to 40 mg; or tropisetron hydrochloride, in an amount / unit dose equivalent to from 2.5 mg to 5 mg tropisetron base, to be administered at a daily dose of from 7.5 to 20 mg.

[0184] In the case of pediatric or obese patients, the 5HT3 -antagonist daily dose may be decided on the basis of the body weight. Thus, for example, azasetron hydrochloride may be administered at a daily dose of 0.4-0.5 mg / kg, dolasetron mesylate may be administered at a daily dose of 9-9.5 mg / kg, granisetron hydrochloride may be administered at a daily dose of 0.09-0.11 mg / kg, ondansetron hydrochloride dihydrate may be administered at a daily dose of 0.45-0.55 mg / kg, palonosetron hydrochloride may be administered at a daily dose of 0.03 mg / kg and tropisetron hydrochloride may be administered at a daily dose of 0.5-0.6 mg / kg.Pharmaceutical Compositions with NKl-antagonists

[0185] For their administration for the treatment of AMD, the NKl-antagonist and pramipexole or a pharmaceutically acceptable salt or solvate thereof may each be co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle.

[0186] In the pharmaceutical compositions of the present invention for oral, subcutaneous, intravenous, transdermal or topical administration, the active ingredients are preferably administered in the form of dosage units, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with the classic pharmaceutical carriers or vehicles, as set forth above.

[0187] The pharmaceutical compositions thus obtained are concurrently or sequentially administered to a patient suffering from a depressive disorder, including MDD.

[0188] Said NKl-antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof may also be formulated together in a fixed-dose combination consisting of a pharmaceutical composition comprising said pramipexole or a pharmaceutically acceptablesalt or solvate thereof, and said NKl-antagonist, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle.

[0189] The dosage, i.e. the amount of active ingredient in a single dose (amount per unit form) to be administered to the patient, can vary widely depending on the age, weight, and the health condition of the patient.

[0190] This dosage includes the administration of a NKl-antagonist dose from 1 pg to 600 mg, normally from 1 mg to 600 mg or from 1 mg to 300 mg, according to the potency of said NKl- antagonist and the age of the patient.

[0191] In general, the dose of pramipexole or pharmaceutically acceptable salt or solvate thereof is in an amount per IR-unit form, in pramipexole dihydrochloride monohydrate, of from 0.125 mg to 22.5 mg, from more than 1.5 mg to 22.5 mg, from 3 mg to 22.5 mg, from 5 mg to 22.5 mg, from 6.5 mg to 22.5 mg or from 7.5 mg to 22.5 mg, depending on safety and tolerability (in combination with the NK1- antagonist) and including doses per IR-unit form to be used in the titration period.

[0192] In general, the dose of pramipexole or pharmaceutically acceptable salt or solvate thereof, per ER-unit form, is an amount-range, in pramipexole dihydrochloride monohydrate, of from 0.125 mg to 45 mg, from more than 4.5 mg to 45 mg, from more than 6 mg to 45 mg, from 10 mg to 45 mg, from 13 mg to 45 mg or from 15 mg to 45 mg, depending on safety and tolerability (in combination with the NK1 -antagonist).

[0193] Normally, the dose of pramipexole or pharmaceutically acceptable salt or solvate thereof per IR-unit form will be in an amount-range, in pramipexole dihydrochloride monohydrate, of from 0.125 mg to 10.5 mg, from 1.6 mg to 10.5 mg, from 3 mg to 10.5 mg, from 5 mg to 10.5 mg, from 6.5 mg to 10.5 mg or from 7.5 mg to 10.5 mg depending on safety and tolerability (in combination with the NKl-antagonist).

[0194] The dose per unit form of pramipexole or pharmaceutically acceptable salt or solvate thereof in an ER formulation, including slow-release compositions and transdermal therapeutic systems such as transdermal patches, will normally in a range that is equivalent to from 0.375 mg to 21 mg, from more than 4.5 mg to 21 mg, from more than 6 mg to 21 mg, from 10 mg to 21 mg, from 13 mg to 21 mg or from 15 g to 21 mg of pramipexole dihydrochloride monohydrate, depending on the tolerability (in combination with said NKl-antagonist).

[0195] As set forth above, the pramipexole doses / unit forms include low doses that can be used especially in the case of the titration of the pramipexole daily dose or in the less frequent case of use in the treatment of pediatric depressed patients.

[0196] The pharmaceutical compositions of the present invention are in unit form formulated with the classic excipients suitable for different ways of administration, as described above. Said unit forms are manufactured according to conventional technologies allowing, for example, the formulation of the NKl-antagonist in an IR- form and of pramipexole dihydrochloride monohydrate in ER-form in the same unit- form. Particularly advantageous are the formulations in the form of tablets, multi- score tablets, multi-layer tablets, coated tables, orally disintegrating tablets, extended release tablets, hard or soft capsules, multicompartment capsules, extended-release capsules, patches for transdermal administration, liquid oral solutions, syrups or suspensions in a predetermined unit form, and vials for the intravenous, intravitreal, intracameral, or subcutaneous administration.

[0197] The pharmaceutical compositions may be formulated in oral unit forms such as tablets or gelatin capsules wherein pramipexole or a pharmaceutically acceptable salt or solvate thereof or the NKl-antagonist or both the active ingredients are co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a carrier or vehicle that may include a diluent, such as cellulose, dextrose, lactose, mannitol, sorbitol or sucrose; a lubricant, such as, acid, calcium or magnesium stearate, polyethylene glycol, silica, or talc; and if needed, a binder such as magnesium aluminum silicate, gelatin, methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone.

[0198] Said oral forms may be tablets coated with sucrose or with various polymers; or, alternatively, the tablets can be manufactured by using carriers such as acrylic and methacrylic acid polymers and copolymers; cellulose derivatives such as hydroxypropylethylcellulose; or other appropriate materials, to have a prolonged or delayed activity by progressively releasing a predetermined quantity of pramipexole (or pharmaceutically acceptable salt or solvate thereof), or of NKl-antagonist, or of both the active ingredients. The oral formulations can also be in form of capsules allowing the extended release the pramipexole (or pharmaceutically acceptable salt or solvate thereof), or of NKl-antagonist, or of both the active ingredients.

[0199] As mentioned above, said oral unit forms may also be tablets or capsules wherein one of the active ingredient is in an IR-formulation and the other one is in an ER-formulation. For example said unit form comprises aprepitant or rolapitant in an IR-formulation and pramipexole dihydrochloride monohydrate in an ER-formulation, each at the amount per unit form as described above.

[0200] The pharmaceutical compositions may also be formulated in TTS, such as a patch formulation wherein the active ingredient or the mixture of the active ingredients may compriseadjuvants such as D-sorbitol, gelatin, kaolin, methyl paraben, polysorbate 80, propylene glycol, propyl paraben, povidone, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water. A patch formulation may also contain skin permeability enhancer such as lactate esters (e.g., lauryl lactate), triacetin or diethylene glycol monoethyl ether.

[0201] Accordingly, for example, pramipexole, preferably as a free base, may be formulated in a TTS, transdermally delivering a pramipexole effective dose, as described in "The pramipexole Component (b)" section, normally throughout the day; and, preferably, with a NKl-antagonist as described below, aprepitant be may formulated in an oral IR-form fosaprepitant meglumine may be formulated in a vial for injection, rolapitant may be formulated in an oral IR-unit form, each at a dose per unit form as described in "The NKl- antagonist Component (a)" section. In the case of pediatric or obese patients, the NKl- antagonist daily dose may be decided on the basis of the body weight. Thus, for example, aprepitant may be administered at a daily dose of from 0.67 to 2 mg / kg.Combination of Pramipexole and Fluoxetine and Uses Thereof

[0202] The present invention also relates to a pharmaceutical combination comprising fluoxetine for use for the treatment of retinal degeneration in combination with pramipexole.

[0203] The present invention relates to the use of a pharmaceutical combination comprising fluoxetine and pramipexole for the preparation of a medicament for treatment of retinal degeneration, including AMD, comprising an effective dose per unit form of pramipexole.

[0204] The invention also relates to a method for treating retinal degeneration by administering to a patient in need thereof a pharmaceutical combination comprising fluoxetine and pramipexole.

[0205] The present invention is based on the idea that fluoxetine may synergistically and substantially improve the ability of safe and tolerable doses of pramipexol to treat retinal degeneration, and thus benefit patients with retinal degeneration to a previously unrealized degree.

[0206] This is unexpected since the ability of fluoxetine to augment the biomarker response to pramipexole to a degree that confers clinical patient benefit has never before been described, suggested or even anticipated in view of the lack of a rational basis and differences in the drugs’ pharmacologic properties including their mechanisms of action.

[0207] Thus, according to one aspect, the present invention provides a method for treating apatient suffering from retinal degeneration, including AMD, which comprises administering to a patient in need of said treatment an effective yet tolerable daily dose of fluoxetine or a pharmaceutically acceptable salt or solvate thereof in combination with an effective daily dose of a pramipexol or a pharmaceutically acceptable salt thereof.

[0208] Unless otherwise specified, the term fluoxetine (INN) designates the fluoxetine free base and salts and solvates thereof, in particular its hydrochloride salt.

[0209] Illustrative examples of these salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid and the like or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, carbonic acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid and the like. The solvation agent is generally water.

[0210] In the method (or use) for the treatment of retinal degeneration, including AMD, fluoxetine or a pharmaceutically acceptable salt or solvate thereof is co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle. This composition is administered to a patient in need of said treatment at a daily dose that is equivalent to from 5 mg to 90 mg of fluoxetine base, in combination with pramipexole or pharmaceutically acceptable salt or solvate thereof. Said pramipexole is also co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle and is administered to said patient in need of said treatment at a daily dose that is equivalent to from 1.5 mg to 3000 mg of pramipexole dihydrochloride monohydrate, said daily dose including an (S)-enantiomer daily dose equivalent to from 1.5 to 20 mg, from 1.5 mg to 15 mg, from 1.5 mg to 10 mg, from 1.5 mg to 7.5 mg, or from 1.5 mg to 6 mg of pramipexole dihydrochloride monohydrate.

[0211] In said pharmaceutical composition, pramipexole or pharmaceutically acceptable salt or solvate thereof is selected from the group consisting of pramipexole or a pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 0.125 mg to 20 mg of pramipexole dihydrochloride monohydrate; pramipexole (the racemate) or pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 0.25 mg to 40 mg of pramipexole dihydrochloride monohydrate; and a (R) / (S)-mixture. comprising pramipexole, in an amount per unit form equivalent to from 50 mg to 3000 mg of pramipexole dihydrochloride monohydrate, said amount per unit formincluding a (S)-enantiomer amount equivalent to from 0.125 mg to 20 mg of pramipexole dihydrochloride monohydrate and (R)-enantiomer, in an amount equivalent to from 50 mg to 3000 mg (minus from 0.125 mg to 20 mg) of pramipexole dihydrochloride monohydrate.

[0212] Normally, in the pharmaceutical composition to be administered in combination with the above illustrated fluoxetine pharmaceutical composition, the pramipexole is preferably selected from the group consisting of (S)-pramipexole (INN: pramipexole) and pharmaceutically acceptable salts and solvates thereof, in particular its dihydrochloride monohydrate (US AN: pramipexole hydrochloride), in a dose per unit form equivalent to from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, or from 0.125 mg to 6 mg of pramipexole dihydrochloride monohydrate;(R,S)- pramipexole (the racemate) and pharmaceutically acceptable salts an solvates thereof, in a dose per unit form equivalent to from 0.25 mg to 40 mg, from 0.25 mg to 30 mg, from 0.25 mg to 20 mg, from 0.25 mg to 15 mg, or from 0.25 mg to 12 mg of pramipexole dihydrochloride monohydrate (thus, obviously, including a dose per unit form of (S)-enantiomer equivalent to from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, or from 0.125 mg to 6 mg of pramipexole dihydrochloride monohydrate, and a dose per unit form of (R)-enantiomer equivalent to from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, or from 0.125 mg to 6 mg of pramipexole dihydrochloride monohydrate); and - (R) / (S)-mixture. i.e. a pharmaceutical composition in dosage unit form comprising pramipexole, at a dose per unit form equivalent to from 50 mg to 3000 mg, preferably to from 150 mg to 3000 mg, of pramipexole dihydrochloride monohydrate, said amount per unit form including a (S)- enantiomer amount equivalent to from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, or from 0.125 mg to 6 mg of pramipexole dihydrate monohydrate, thus, obviously, said amount per unit form being constituted by an amount of (S)-enantiomer equivalent to from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, or from 0.125 mg to 6 mg of pramipexole dihydrochloride monohydrate and by a (R)-enantiomer amount per unit form equivalent to from 50 mg (or 150 mg) to 3000 mg (minus from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, or from 0.125 to 6 mg) of pramipexole dihydrochloride monohydrate).

[0213] The dose of the pramipexole, per IR-unit form, will range from 0.125 mg to 1500 mg, said dose including a (S)-isomer amount per IR-form equivalent to from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, from 0.125 mg to 5 mg, from 0.125 mg to 3.75 mg, or from 0.125 to3 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with fluoxetine, in the above dose / unit form).

[0214] The dose of the pramipexole, per ER-unit form, will range from 0.375 mg to 3000 mg, said dose including a (S)-isomer amount per ER-form equivalent to from 0.375 mg to 20 mg, from 0.375 mg to 15 mg, from 0.375 mg to 10 mg, from 0.375 mg to 7.5 mg, or from 0.375 to 6 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with fluoxetine, in the above dose / unit form).

[0215] The dose of pramipexole or pharmaceutically acceptable salt thereof, per IR-unit form, will be equivalent to from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, from 0.125 mg to 5 mg, from 0.125 mg to 3.75 mg, or from 0.125 mg to 3 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with fluoxetine, in the above dose / unit form).

[0216] The dose of pramipexole or pharmaceutically acceptable salt thereof, per ER-unit form, will be equivalent to from 0.375 mg to 20 mg, from 0.375 mg to 15 mg, from 0.375 mg to 10 mg, from 0.375 mg to 7.5 mg, or from 0.375 mg to 6 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with fluoxetine, in the above dose / unit form).

[0217] According to this aspect, the invention provides a pharmaceutical combination comprising:(g) fluoxetine, at a dose that is at least as high as a dose approved for the treatment of depression, and(h) a pramipexole or a pharmaceutically acceptable salt or solvate thereof, for use for the treatment of a retinal degeneration, including AMD.

[0218] According to an embodiment of this aspect, the invention provides fluoxetine, in a pharmaceutical composition comprising, as an active ingredient, fluoxetine or a pharmaceutically acceptable salt or solvate thereof, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle, for use for the treatment of a retinal degeneration, including AMD, in combination with pramipexole, also in a co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle.

[0219] According to this embodiment, said fluoxetine, or a pharmaceutically acceptable salt or solvate thereof, is present in said composition in an amount / unit form, in fluoxetine, at least as high as a dose / unit form approved for the treatment of depression, co-formulated in apharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier, for use for the treatment of retinal degeneration, including AMD, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof in doses, in pramipexole dihydrochloride monohydrate, approved for the relief of the symptoms of PD.

[0220] According to another aspect, the invention provides the use of fluoxetine for the preparation of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said fluoxetine, or a pharmaceutically acceptable salt or solvate thereof, coformulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle, for the treatment of retinal degeneration, including AMD, in combination with pramipexole or of a pharmaceutically acceptable salt and / or solvate thereof, preferably with pramipexole or a pharmaceutically acceptable salt thereof.

[0221] According to another aspect, the invention provides the use of fluoxetine for the preparation of a medicament for the treatment of retinal degeneration, including AMD, in a patient in need of said treatment, said medicament consisting of a pharmaceutical composition in dosage unit form comprising, as an active ingredient said fluoxetine and, as a second active ingredient, pramipexole, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle, .

[0222] In particular, the invention provides a pharmaceutical fixed-dose combination consisting of a pharmaceutical composition in dosage unit form comprising fluoxetine or a pharmaceutically acceptable salt or solvate thereof, as Component (a) and a pramipexole or a pharmaceutically acceptable salt or solvate thereof, preferably with pramipexole or a pharmaceutically acceptable salt thereof, as Component (b), co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle

[0223] According to an embodiment of this aspect, the invention provides a fixed-dose combination consisting of a pharmaceutical composition comprising(i)fluoxetine hydrochloride, in an amount / unit form (in fluoxetine base) at least at least as high as the amount / unit form, in fluoxetine base, approved for the treatment of depression; and(j)pramipexole dihydrochloride monohydrate, in an amount / unit form at least at least as high as an amount / unit form 0.375 mg to 4.5 mg, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle,

[0224] for use for the treatment of retinal degeneration, including AMD,.

[0225] Moreover, according to an embodiment of this aspect, the invention provides the use of(k) fluoxetine hydrochloride, in an amount / unit form (in fluoxetine base) at least at least as high as the amount / unit form, in fluoxetine base, approved for the treatment of depression; and(l) pramipexole dihydrochloride monohydrate, in an amount / unit form at least at least as high as an amount / unit form 0.375 mg to 4.5 mg, for the preparation of a medicament consisting of a pharmaceutical composition comprising said fluoxetine and said pramipexole dihydrochloride monohydrate, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle, for the treatment of retinal degeneration, including AMD,.

[0226] In the above compositions according to this aspect, fluoxetine or a pharmaceutically acceptable salt thereof Component (a) is present in an amount equivalent to from 2 mg to 90 mg of fluoxetine hydrochloride and said pramipexole or a pharmaceutically acceptable salt and / or solvate thereof is present in an amount equivalent to of from 0.125 mg to 3000 mg of pramipexole dihydrochloride monohydrate, said amount including an S-enantiomer amount equivalent to from 0.125 mg to 20 mg of pramipexole dihydrochloride monohydrate. Preferably, in the above compositions, said pramipexole is pramipexole or a pharmaceutically acceptable salt thereof, in an amount equivalent to from 0.125 mg to 20 mg of pramipexole dihydrochloride monohydrate.

[0227] The dose of fluoxetine, or of a pharmaceutically acceptable salt or solvate thereof, per IR-unit form, will be in an amount that is equivalent to from 2 mg to 40 mg or from 5 mg to 40 mg of fluoxetine base, depending on safety and tolerability (in combination with pramipexole). Preferably, said fluoxetine pharmaceutically acceptable salt is fluoxetine hydrochloride in the above IR-dose / unit form.

[0228] The dose / unit form of fluoxetine, or of a pharmaceutically acceptable salt or solvate thereof, in an ER-formulation, including slow-release compositions and transdermal therapeutic systems such as transdermal patches, will be in an amount (in fluoxetine) of from 20 mg to 90 mg, depending on safety and tolerability (in combination with a pramipexole).

[0229] In particular, according to an embodiment of this aspect, the invention, provides a fixed- dose combination consisting of a pharmaceutical composition which comprises (a) fluoxetine, in an amount per unit form of from 2 mg to 90 mg; and (b) a pramipexole selected from thegroup consisting of (S)-pramipexole or a pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 0.125 mg to 20 mg of pramipexole dihydrochloride monohydrate;(R,S)-6pramipexole (the racemate) and pharmaceutically acceptable salts an solvates thereof, in an amount per unit form equivalent to from 0.25 mg to 40 mg of pramipexole dihydrochloride monohydrate; and a (R) / (S)-mixture comprising pramipexole, in an amount per unit form equivalent to from 50 mg to 3000 mg, said amount per unit form including a (S)-enantiomer amount equivalent to from 0.125 mg to 20 mgof pramipexole dihydrochloride monohydrate and (R)-enantiomer, in an amount equivalent to from 50 mg to 3000 mg (minus from 0.125 mg to 20 mg) of pramipexole dihydrochloride monohydrate; co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle.

[0230] In the pharmaceutical composition to be administered in combination with the above illustrated fluoxetine pharmaceutical composition, for example in the fixed-dose combination according this aspect of the invention, the pramipexole is preferably selected from the group consisting of(S)-pramipexole (INN: pramipexole) and pharmaceutically acceptable salts and solvates thereof, in particular its dihydrochloride monohydrate (US AN: pramipexole hydrochloride), in a dose per unit form equivalent to from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, or from 0.125 mg to 6 mg of pramipexole dihydrochloride monohydrate;(R,S)-pramipexole (the racemate) and pharmaceutically acceptable salts an solvates thereof, in a dose per unit form equivalent to from 0.25 mg to 40 mg, from 0.25 mg to 30 mg, from 0.25 mg to 20 mg, from 0.25 mg to 15 mg, or from 0.25 mg to 12 mg of pramipexole dihydrochloride monohydrate (thus, obviously, including a dose per unit form of (S)-enantiomer equivalent to from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, or from 0.125 mg to 6 mg of pramipexole dihydrochloride monohydrate, and a dose per unit form of (R)-enantiomer equivalent to from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, or from 0.125 mg to 6 mg of pramipexole dihydrochloride monohydrate); and(R) / (S)-mixture comprising pramipexole, at a dose per unit form equivalent to from 50 mg to 3000 mg, preferably to from 150 mg to 3000 mg, of pramipexole dihydrochloride monohydrate, said amount per unit form including a (S)-enantiomer amount equivalent to from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5mg, or from 0.125 mg to 6 mg of pramipexole dihydrochloride monohydrate, thus, obviously, said amount per unit form being constituted by an amount of (S)-enantiomer equivalent to from 0.125 mg to 20 mg of pramipexole dihydrochloride monohydrate and by a (R)-enantiomer amount per unit form equivalent to from 50 mg (or 150 mg) to 3000 mg (minus from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, or from 0.125 to 6 mg) of pramipexole dihydrochloride monohydrate.

[0231] The dose of the pramipexole, per IR-unit form, will range from 0.125 mg to 1500 mg, said dose including a (S)-enantiomer amount per IR-form equivalent to from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, from 0.125 mg to 5 mg, from 0.125 mg to 3.75 mg, or from 0.125 to 3 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with fluoxetine, in the above dose / unit form).

[0232] The dose of pramipexole or pharmaceutically acceptable salt thereof, per IR-unit form, will be equivalent to from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, from 0.125 mg to 5 mg, from 0.125 mg to 3.75 mg, or from 0.125 mg to 3 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with fluoxetine, in the above dose / unit form).

[0233] If said pramipexole or pharmaceutically acceptable salt of solvate thereof is pramipexole dihydrochloride monohydrate, the dose-range is from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg, from 0.125 mg to 5 mg, from 0.125 mg to 3.75 mg, or from 0.125 mg to 3 mg per IR-unit form, depending on safety and tolerability (in combination with fluoxetine, at the above dose / unit form).

[0234] The dose / unit form of pramipexole in an ER formulation, including slow-release compositions and transdermal therapeutic systems such as transdermal patches, will range from 1.5 mg to 3000 mg, said dose / unit form including a (S)-isomer amount per ER-form equivalent to from 1.5 mg to 20 mg, from 1.5 mg to 15 mg, from 1.5 mg to 10 mg, from 1.5 mg to 7.5 mg, or from 1.5 to 6 mg of pramipexole dihydrochloride monohydrate, depending on the tolerability in combination with fluoxetine, at the above dose / unit form.

[0235] The dose of pramipexole or pharmaceutically acceptable salt thereof, per ER-unit form, will be equivalent to from 1.5 mg to 20 mg, from 1.5 mg to 15 mg, from 1.5 mg to 10 mg, from 1.5 mg to 7.5 mg, or from 1.5 mg to 6 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with fluoxetine, in the above dose / unit form).

[0236] Normally, if said pramipexol is pramipexole dihydrochloride monohydrate orpramipexole base, the dose-range / unit form (in pramipexole dihydrochloride monohydrate), will be from 1.5 mg to 20 mg, from 1.5 mg to 15 mg, from 1.5 mg to 10 mg, from 1.5 mg to7.5 mg or from 1.5 mg to 6 mg per ER-unit form.

[0237] For the use of the combination of the present invention in the treatment of retinal degeneration, including AMD, fluoxetine or a pharmaceutically acceptable salt thereof is administered, preferably as fluoxetine hydrochloride, at a daily dose (in fluoxetine base) of from 4 mg to 40 mg in a IR- or ER-form or at a weekly dose of 90 mg, in an ER-form; and the pramipexole or pharmaceutically acceptable salt thereof is administered at a daily dose equivalent to from 1.5 mg to 3000 mg of pramipexole dihydrochloride monohydrate in IR- or ER-form, said daily dose including a (S)-isomer amount per IR- or ER-form equivalent to from1.5 mg to 20 mg, from 1.5 mg to 15 mg, from 1.5 mg to 10 mg, from 1.5 mg to 7.5 mg, or from1.5 to 6 mg of pramipexole dihydrochloride monohydrate.

[0238] If, in said combination, said pramipexole is pramipexole or a pharmaceutically acceptable salt thereof, it is administered at a daily dose that is equivalent to from 1.5 mg to 20 mg, from 1.5 mg to 15 mg, from 1.5 mg to 10 mg, from 1.5 mg to 7.5 mg, or from 1.5 mg to 6 mg of pramipexole dihydrochloride monohydrate, preferably as pramipexole dihydrochloride monohydrate at a daily dose of from 1.5 mg to 20 mg, from 1.5 mg to 15 mg, from 1.5 mg to 10 mg, from 1.5 mg to 7.5 mg, or from 1.5 mg to 6 mg.

[0239] As described above, for the intended use, the combination of the invention comprises(m) fluoxetine or a pharmaceutically acceptable salt or solvate thereof; and(n) a pramipexole or a pharmaceutically acceptable salt or solvate thereof, each co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle; or(a / b) fluoxetine or a pharmaceutically acceptable salt or solvate thereof; and a pramipexole or a pharmaceutically acceptable salt or solvate thereof, mixed together in a pharmaceutical composition in dosage unit form, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle, as a fixed dose combination.

[0240] In the pharmaceutical compositions of the present invention for oral, subcutaneous, intravenous, transdermal or topical administration, the active ingredients are preferably administered in the form of dosage units, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with the classic pharmaceutical carriers or vehicles.

[0241] The dosage, i.e. the amount of active ingredient in a single dose to be administered to a patient suffering from retinal degeneration, including AMD, patient, can vary widely depending on the age, weight, and the health condition of the patient, as also illustrated herein above. This dosage includes the administration of a dose per unit form of from 2 mg to 40 mg of fluoxetine, and from 0.125 mg to 1500 mg of pramipexol, according to the age of the patient, from one to three times a day by intravenous, subcutaneous, oral, or transcutaneous administration, according to the strength of the doses of the each of the active ingredients.

[0242] If fluoxetine is as hydrochloride, said dosage is from 2 mg to 90 mg (in fluoxetine base).

[0243] If pramipexole is pramipexole or a pharmaceutically acceptable salt thereof, said dosage is equivalent to from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg or from 0.125 mg to 6 mg of pramipexole dihydrochloride monohydrate.

[0244] If pramipexole is pramipexole dihydrochloride monohydrate, said dosage ranges from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg or from 0.125 mg to 6 mg.

[0245] Thus, according to a preferred embodiment the present invention provides a fixed-dose combination consisting of a pharmaceutical composition comprising(o) fluoxetine or a pharmaceutically acceptable salt thereof, in an amount per unit form equivalent to from 2 mg to 90 mg of fluoxetine base; and(p) pramipexole or a pharmaceutically acceptable salt thereof, in an amount per unit form equivalent to a range selected from the group consisting of from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg or from 0.125 mg to 6 mg of pramipexole dihydrochloride monohydrate, co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a pharmaceutical carrier or vehicle.

[0246] The pharmaceutical compositions of the present invention are formulated with the classic excipients suitable for different ways of administration. Particularly advantageous are the formulations in the form of tablets, multi-score tablets, coated tables, orally disintegrating tablets, extended release tablets, hard or soft capsules, extended-release capsules, patches for transdermal administration, liquid oral solutions, syrups or suspensions in a predetermined unit form, and vials for the intravenous or subcutaneous administration.

[0247] Thus, for example, a pharmaceutical composition according to the present invention to be chronically administered in combination with pramipexole, preferably pramipexoledihydrochloride monohydrate, in an amount / unit dose of from 0.125 mg to 20 mg, from 0.125 mg to 15 mg, from 0.125 mg to 10 mg, from 0.125 mg to 7.5 mg or from 0.125 mg to 6 mg to be administered at a daily dose of from 1.5 mg to 20 mg, from 1.5 mg to 15 mg, from 1.5 mg to 10 mg, from 1.5 mg to 7.5 mg, or from 1.5 mg to 6 mg, comprises fluoxetine hydrochloride, in an amount / unit dose (in fluoxetine) of from 2 mg to 90 mg to be administered at a daily dose of from 4 mg to 40 mg in IR or ER-form or at a weekly dose of 90 mg, in ER-form only.

[0248] The pharmaceutical compositions may be formulated in oral forms such as tablets or gelatin capsules, wherein fluoxetine or a pharmaceutically acceptable salt or solvate thereof; or the pramipexole, preferably pramipexole or a pharmaceutically acceptable salt or solvate thereof; or both the active ingredients, are co-formulated in a pharmaceutical composition (fixed-dose combination), e.g., in admixture with a carrier or vehicle. Said carrier or vehicle may include a diluent, such as cellulose, dextrose, lactose, mannitol, sorbitol or sucrose; a lubricant, such as, acid, calcium or magnesium stearate, polyethylene glycol, silica, or talc; and if needed, a binder such as magnesium aluminum silicate, gelatin, methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone.

[0249] Said oral forms may be tablets coated with sucrose or with various polymers.

[0250] Alternatively, the tablets can be manufactured by using carriers such as acrylic and methacrylic acid polymers and copolymers; cellulose derivatives such as hydroxypropylethylcellulose; or other appropriate materials. These materials confer a prolonged or delayed activity by progressively releasing a predetermined quantity of fluoxetine (or pharmaceutically acceptable salt thereof) or pramipexole (or pharmaceutically acceptable salt or solvate thereof).

[0251] The oral formulations can also be in form of capsules allowing the extended release of fluoxetine (or a pharmaceutically acceptable salt or solvate thereof); of pramipexole (or pharmaceutically acceptable salt or solvate thereof); or of both the active ingredients.

[0252] In embodiments, the formulations of the present disclosure are administered directly into or around the eye via any ophthalmic administration methods known in the art.

[0253] A fixed-dose combination according to the present invention may be a dosage unit form consisting of a capsule comprising for example fluoxetine hydrochloride Component (a), in an amount equivalent to 10 mg of fluoxetine base; and pramipexole dihydrochloride monohydrate Component (b), in an amount of 6.5 mg, co-formulated in a pharmaceutical composition (fixed- dose combination), e.g., in admixture with a pharmaceutical carrier.

[0254] Another fixed-dose combination may be formulated in tablets in which fluoxetinehydrochloride Component (a), in an amount equivalent to 10 mg of fluoxetine base is in an IR- formulation and pramipexole dihydrochloride monohydrate, in an amount of 7.5 mg, is in controlled-release formulation, for example as a dispersion of said component in hydroxypropyl methyl cellulose or in a film-coated microgranule. Said tablet may be a tablet with two superimposed layers, or a bilayer tablet wherein pramipexole dihydrochloride dihydrate, in ER-formulation is in the core and the fluoxetine, in IR-formulation, is in the outer layer. The core or both the core and the outer layer may coated with a film.

[0255] The pharmaceutical compositions may also be formulated in TTS, such as a patch formulation wherein the active ingredient or the mixture of the active ingredients may comprise adjuvants such as D-sorbitol, gelatin, kaolin, methyl paraben, polysorbate 80, propylene glycol, propyl paraben, povidone, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water. A patch formulation may also contain skin permeability enhancer such as lactate esters (e.g., lauryl lactate), triacetin or diethylene glycol monomethyl or monoethylether.

[0256] In the above pharmaceutical compositions, the preferred fluoxetine, or a pharmaceutically acceptable salt or solvate thereof, active ingredient is fluoxetine base or its hydrochloride and the preferred pramipexol active ingredient, or a pharmaceutically acceptable salt thereof, is pramipexole base or its dihydrochloride monohydrate.Embodiments1. A method for treating a patient suffering from retinal degeneration, which comprises treating said patient with a 5HT3 or an NK1 antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.2. The method of embodiment 1, wherein, in said combination, said 5HT3 -antagonist is administered at a daily dose of from 1 pg to 300 mg.3. The method of embodiment 1 , wherein said 5HT3 -antagonist is selected from the group consisting of azasetron and pharmaceutically acceptable salts and solvates thereof, dolasetron and pharmaceutically acceptable salts and solvates thereof, granisetron and pharmaceutically acceptable salts and solvates thereof, ondansetron and pharmaceutically acceptable salts and solvates thereof, palonosetron and pharmaceutically acceptable salts and solvates thereof, ramosetron and pharmaceutically acceptable salts and solvates thereof; and tropisetron and pharmaceutically acceptable salts and solvates thereof.4. The method of embodiment 1, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate.5. The method of embodiment 1, wherein, in said combination, said 5HT3 -antagonist is selected from the group consisting of ondansetron and a pharmaceutically acceptable salt thereof, administered at a daily dose equivalent to from 2 mg to 32 mg of ondansetron base; and dolasetron and pharmaceutically acceptable salts thereof, administered at a daily dose equivalent to from 75 mg to 200 mg of dolasetron mesylate; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate.6. The method of embodiment 5, wherein, in said combination, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.7. The method of embodiment 5, wherein, in said combination, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.8. The method of embodiment 5, wherein, in said combination, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.9. The method of embodiment 1, wherein, in said combination, said 5HT3 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are each formulated in a pharmaceutical composition with a pharmaceutical carrier or vehicle.10. The method of embodiment 1, wherein, in said combination, said 5HT3 -antagonist is formulated in a pharmaceutical composition in dosage unit form comprising said 5HT3 -antagonist in an amount per unit form of from 0.1 mg to 300 mg, in admixture with a pharmaceutical carrier or vehicle; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is formulated in a pharmaceutical composition in dosage unit form comprising said pramipexole or a pharmaceutically acceptable salt or solvate thereof in an amount per unit form equivalent to from 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate, in admixture with a pharmaceutical carrier or vehicle.11. The method of embodiment 10, whereinsaid 5HT3-antagonist in said composition is selected from the group consisting of ondansetron and a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from 2 mg to 32 mg of ondansetron base, and dolasetron and pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from from 25 mg to 200 mg of dolasetron mesylate; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof in said composition is present in an amount of from 1.5 mg to 45 mg.12. The method of embodiment 11, wherein, in said composition, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is present in an amount per unit form equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.13. The method of embodiment 11, wherein, in said composition, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is present in an amount per unit form equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.14. The method of embodiment 11, wherein, in said composition, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is present in an amount per unit form equivalent to from 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate.15. A 5HT3 -antagonist for use in the treatment of retinal degeneration in a patient in need of said treatment, in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.16. Use of a 5HT3 -antagonist for the preparation of a medicament for the treatment of retinal degeneration in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.17. The use of embodiment 16, wherein, in said combination, said medicament is a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said 5HT3 -antagonist with a pharmaceutical carrier or vehicle, and said pramipexole or a pharmaceutically acceptable salt or solvate thereof in a separate pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said pramipexole or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutical carrier or vehicle.18. The use of embodiment 17, wherein said combination is a fixed-dose combination consisting of a pharmaceutical composition in dosage unit form comprising an effective amount per unit of said 5HT3 -antagonist, and an effective amount per unit form of said pramipexole or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutical carrier or vehicle.EXAMPLEEXAMPLE 1

[0257] A phase 1, multiple ascending dose study to evaluate the safety and tolerability of increasing doses of pramipexole when given either alone, or with ondansetron, or with aprepitant to healthy subjects was conducted. This was a single center, multiple ascending dose, study in a single group of healthy subjects conducted at Pharmaron CPC, 800 W. Baltimore St., 5thFloor, Baltimore, MD 21201. over a period of approximately 10 weeks.

[0258] The Primary objective of the study was to measure, in healthy volunteers, the individually determined maximum tolerated doses (MTD) of orally administered pramipexole when either given alone, or when given together with orally administered ondansetron, or when given together with orally administered aprepitant.

[0259] The secondary: objective of the study was.to evaluate the safety and tolerability of orally administered pramipexole either when given alone, or when given together with orally administered ondansetron, or when given together with orally administered aprepitant.

[0260] Another objective was to evaluate the pharmacokinetics profile of pramipexole, ondansetron and aprepitant.

[0261] Study Design:

[0262] The clinical trial was conducted in three parts.

[0263] Period 1

[0264] All participants were first admitted to Period 1, in which rising single daily doses of pramipexole up to the first intolerable dose (FID1) or to maximum allowed dose by the protocol (6 mg / day) were administered once per day in the morning.

[0265] Parti cipants completed Period 1 on the day they reached the FID1 or the maximum protocol-allowed dose (6 mg / day).

[0266] Subjects who tolerated the maximum protocol-allowed dose of 6 mg were excluded from continuing in the study and the Exit Visit for that subject was scheduled.

[0267] Period 2

[0268] Following a 5 to 20-day washout, participants entered Period 2 of the study. During this period, subjects received rising doses of pramipexole according to the same upward dose titration schedule as in Period 1; pramipexole was titrated upward daily to the first intolerable dose (FID2) or the maximum protocol allowed dose (6 mg / day), but this time pramipexole was administered together with a single ondansetron 8 mg tablet, given at the same time as the pramipexole dose.

[0269] If a subject reached FID2 during Period 2 at the same or lower dose than FID1, and providing the investigator judged there were no safety issues and the subjects were consenting, the subject received the same dose of pramipexole (FID2) with ondansetron 16 mg on the next day and continued for the remainder of the dose titration with ondansetron 16 mg until the intolerable dose (FID2+) or the maximum protocol-allowed dose of pramipexole were reached. All other provisions of the protocol remained unchanged. Assessments were the same as those planned for the dose escalation day.

[0270] Period 3

[0271] Following a 5- to 20-day washout, participants then entered Period 3 of the study. During this period, subjects received rising doses of pramipexole according to the same upward dose titration schedule as in Period 1; pramipexole was titrated upward daily to the first intolerable dose (FID3) or the maximum protocol allowed dose (6 mg / day), but this time administered together with a single 80 mg aprepitant tablet, given at the same time as the pramipexole dose.

[0272] If a subject reached FID3 during Period 3 at the same or lower dose than FID1, and providing the investigator judged there were no safety issues and the subjects were consenting, the subject received the same dose of pramipexole (FID3) with aprepitant 120 mg on the next day and continued for the remainder of the dose titration with aprepitant 120 mg until the intolerable dose (FID3+) or the maximum protocol-allowed dose of pramipexole were reached. All other provisions of the protocol remained unchanged. Assessments were the same as those planned for the dose escalation day.

[0273] For each subject, the dose escalation of pramipexole whether administered alone or with ondansetron or with aprepitant was discontinued if the subject has the following dose limiting side effects:

[0274] One (1) episode of vomiting; or

[0275] Two (2) episodes of retching; or

[0276] One (1) episode of severe nausea (Grade 3; defined as nausea interfering with activities of daily living or inadequate oral caloric or fluid intake; tube feeding, total parenteral nutrition or hospitalization indicated) lasting more than 1 hour; or

[0277] Three (3) consecutive episodes at every 4-hour ratings of moderate nausea (Grade 2; defined as subjectively symptomatic, but not interfering with activities of daily living); or

[0278] Symptomatic tachycardia corresponding to a > Grade 1 severity according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria.

[0279] The Investigator could terminate pramipexole dose escalation at his discretion if the dose escalation was deemed to place the subject at risk.

[0280] The dose at which each subject experienced any of the above dose-limiting AEs was defined as the FID.

[0281] Male and female subjects aged 20-45 years old in good health and having given Informed Consent were enrolled in the study.

[0282] Table 1 summarizes by subject the FID and MTD values for pramipexole when administered alone (FID1 and MTD1) and when administered with ondansetron (FID2 and MTD2).Table 1. FID and MTD of Pramipexole Given Alone (FID1; MTD1) or with Ondansetron (FID2; MTD2) by Subject

[0283] *: #1005 reached FID2 at 1.5 mg pramipexole with 8 mg ondansetron (the subject had moderate nausea). This subject then repeated the 1.5 mg dose of pramipexole, but with 16 mgof ondansetron, which was tolerated. The subject continued the study with 16 mg of ondansetron and reached FID2+ at 3.0 mg pramipexole.[0284JFID =first intolerable dose; MTD=maximum tolerated dose; SD=standard deviation; NA=not available

[0285] As shown in Table 1, the mean (± SD) MTD1 (pramipexole alone) was found to be lower than 1.8 ± 1.4 mg, whereas the mean (± SD) MTD2 (pramipexole with ondansetron) was greater than > 4.2 ± 2.6 mg. The data summarized in Table 1 also reveals a clinically relevant increase in the mean MTD of pramipexole IR when co-administered with ondansetron as evidenced by a 2.6-fold or more increase in the mean MTD2 to MTD1 ratio (paired t-test p=0.061). For 3 out of 5 (60%) subjects (No 1001; 1007; 1008), the MTD2 was not reached and was therefore greater than the highest protocol-allowed pramipexole dose of 6 mg.

[0286] Table 2 summarizes the plasma concentrations of pramipexole at MTD1 (pramipexole alone) and at MTD2 (pramipexole with ondansetron) by subject number.

[0287] Table 2. Plasma Concentrations of Pramipexole at MTD1 (Pramipexole Alone) and MTD2 (Pramipexole with Ondansetron) by Subject0288]MTD=maximum tolerated dose; SD=standard deviation

[0289] As shown in Table 2, the mean (± SD) peak (at 2 hours post dose) plasma concentrations of pramipexole increased from 2,468.1 ± 1,729.4 pg / mL (pramipexole given alone) to 6,702.8 ± 5,820.5 pg / mL (pramipexole + ondansetron). In keeping with the increase in pramipexole MTD, and for each subject, the tolerated plasma concentrations of pramipexole were higher when pramipexole was co-administered with ondansetron. This finding demonstrates that the increase in the pramipexole DLT was not due to a decrease in the absorption of pramipexolefrom the gastro-intestinal tract. Furthermore, the increase in pramipexole plasma concentrations, was dose proportional and was no evidence of a PK interaction between pramipexole and ondansetron.

[0290] Table 3 presents the dose limiting side effects reported at the FID1 (pramipexole alone) and at FID2 (pramipexole + ondansetron) for each subject.Table 3. Comparison by Subject of Dose Limiting Side Effects of Pramipexole at FID1 (Pramipexole Alone) and FID2 (Pramipexole with Ondansetron)with 8 mg ondansetron with 16 mg ondansetronPi’s decision by several AEs (Vaginal Spotting, Insomnia, Chills, Slowed Thoughts / Perception, and Tremors)[0291JFID =first intolerable dose; TEAE=treatment emergent adverse event

[0292] Bolded TEAEs were dose limiting TEAEs

[0293] Overall, co-administration of the 5-HT3 antagonist ondansetron with pramipexole in healthy volunteers resulted in a at least 2.6-fold mean increase in the pramipexole MTD, associated with a 2.7-fold or more increase in the pramipexole plasma concentration at 2 hours post MTD dosing.

[0294] Pramipexole IR with Aprepitant (Periods 1 and 3)

[0295] The primary objective of Period 3 was to determine if co-administration of aprepitant with pramipexole would enable a safe increase in the MTD of pramipexole given alone. The primary endpoint of Period 3 was the change in the pramipexole MTD1 (pramipexole alone) when aprepitant was co-administered with pramipexole (MTD3). A total 4 subjects completed Period 3.

[0296] Table 4 summarizes by subject the FID and MTD values for pramipexole whenadministered alone (FID1 and MTD1) and when administered with aprepitant (FID3 and MTD3).

[0297] All 4 of 4 subjects (100%) enrolled in Period 3 tolerated the maximum dose allowed by the protocol of 6 mg. The MTD3 was therefore not determined for any of the 4 subjects, but was greater than 6 mg for all subjects.Table 4. FID and MTD of Pramipexole Given Alone (FID1; MTD1) or with Aprepitant (FID3; MTD3) by Subject Number[0298JFID =first intolerable dose; MTD=maximum tolerated dose; SD=standard deviation;NA=not available

[0299] The data in Table 4 reveals a clinically relevant increase in the mean MTD of pramipexole IR when co-administered with aprepitant as evidenced by a > 5.6-fold increase in the mean MTD3 to MTD1 ratio (paired t-test p=0.013).

[0300] Table 5 summarizes the plasma concentrations of pramipexole at MTD1 (pramipexole alone) and at MTD3 (pramipexole + aprepitant) by subject number.Table 5. Plasma Concentrations of Pramipexole at MTD1 (Pramipexole Alone) and MTD2 (Pramipexole with Aprepitant) by Subject Number0301]MTD=maximum tolerated dose; SD=standard deviation* Excluding 1008 (not evaluable)REFERENCES

[0302] Wolf G. Lipofuscin and macular degeneration. Nutr Rev. 2003 Oct;61(10):342.

[0303] Shibagaki K, Okamoto K, Katsuta O, Nakamura M. Beneficial protective effect of pramipexole on light-induced retinal damage in mice. Exp Eye Res. 2015 Oct; 139:64-72. doi: 10.1016 / j.exer.2015.07.007. Epub 2015 Jul 26. PMID: 26213307

Claims

CLAIMS1. A pharmaceutical composition comprising (i) pramipexole or a pharmaceutically acceptable salt or solvate thereof, (ii) an antagonist selected from the group consisting of a 5HT3 -antagonist and an NK1 -antagonist, and (iii) a pharmaceutically acceptable carrier suitable for ocular administration.

2. The pharmaceutical composition of claim 1, wherein the pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate.

3. The pharmaceutical composition of claim 1, wherein the antagonist is a 5HT3- antagonist.

4. The pharmaceutical composition of claim 3, wherein the 5HT3-antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof.

5. The pharmaceutical composition of claim 3, wherein the 5HT3-antagonist is ondansetron hydrochloride dihydrate.

6. The pharmaceutical composition of claim 1, wherein the antagonist is an NK1- antagonist.

7. The pharmaceutical composition of claim 6, wherein the NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof.

8. The pharmaceutical composition of claim 6, wherein the NK1 -antagonist is aprepitant.

9. The pharmaceutical composition of claim 1, wherein the composition is in a dosage unit form comprising pramipexole or a pharmaceutically acceptable salt orsolvate thereof in an amount equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate.

10. The pharmaceutical composition of claim 1, wherein the composition is in a dosage unit form comprising pramipexole or a pharmaceutically acceptable salt or solvate thereof in an amount equivalent to more than 4.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.

11. The pharmaceutical composition of claim 1, wherein the composition is in a dosage unit form comprising pramipexole or a pharmaceutically acceptable salt or solvate thereof in an amount equivalent to 6 mg to 45 mg of pramipexole dihydrochloride monohydrate.

12. The pharmaceutical composition of claim 1, wherein the composition is in a dosage unit form comprising pramipexole or a pharmaceutically acceptable salt or solvate thereof in an amount equivalent to 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.

13. The pharmaceutical composition of claim 3, wherein the composition is in a dosage unit form comprising the 5HT3 -antagonist in an amount of from 1 pg to 300 mg.

14. The pharmaceutical composition of claim 4, wherein the composition is in a dosage unit form comprising ondansetron or a pharmaceutically salt or solvate thereof in an amount of from 2 mg to 32 mg of ondansetron base.

15. The pharmaceutical composition of claim 6, wherein the composition is in a dosage unit form comprising the NK1 -antagonist in an amount of from 1 pg to 600 mg.

16. The pharmaceutical composition of claim 8, wherein the composition is in a dosage unit form comprising aprepitant in an amount of from 10 mg to 250 mg.

17. The pharmaceutical composition of any one of claims 1-16, wherein ocular administration is topical administration to the eye, intraocular administration, periocular administration or administration by ocular device or a combination thereof.

18. The pharmaceutical composition of any one of claims 1-16, wherein the composition is in the form of a liquid, suspension, emulsion, ointment or gel.

19. A method for treating eye disease, comprising administering an effective amount of a pharmaceutical composition of any one of claims 1-18 to a patient in need thereof.

20. The method of claim 19, wherein the eye disease is age-related macular degeneration.

21. The method of claim 19, wherein the eye disease is dry age-related macular degeneration.

22. The method of claim 19, wherein the eye disease is geographic atrophy.

23. The method of claim 19, wherein the eye disease is diabetic retinopathy.

24. The method of claim 19, wherein the eye disease is Stargardt disease.

25. The method of claim 19, wherein the composition is administered by oral, subcutaneous, intravenous, transdermal, topical, or intraocular administration.

26. The method of claim 19, wherein the composition is administered in the form of a tablet, capsule, eye drop, or ocular injection.

27. A method for treating eye disease, comprising administering an effective amount of the pharmaceutical composition of claim 3, wherein pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; and said 5HT3-antagonist is administered at a daily dose of from 1.5 mg to 200 mg.

28. A method for treating eye disease, comprising administering an effective amount of the pharmaceutical composition of claim 6, wherein pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; and said NK1 -antagonist is administered at a daily dose of from 1 mg to 600 mg.

29. The method of claim 27, wherein said 5HT3-antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof administered at a daily dose equivalent to from 4 mg to 32 mg of ondansetron base.

30. The method of claim 28, wherein said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof administered at a daily dose equivalent to from 10 mg to 250 mg.

31. Use of the pharmaceutical composition comprising (i) pramipexole or a pharmaceutically acceptable salt or solvate thereof, (ii) an antagonist selected from the group consisting of a 5HT3 -antagonist and an NK1 -antagonist, for treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein the eye disease is selected from the group consisting of age- related macular degeneration, dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, and Stargardt disease.

32. The use of claim 31, wherein the eye disease is age-related macular degeneration.

33. The use of claim 31, wherein the eye disease is dry age-related macular degeneration.

34. The use of claim 31, wherein the eye disease is geographic atrophy.

35. The use of claim 31, wherein the eye disease is diabetic retinopathy.

36. The use of claim 31, wherein the eye disease is Stargardt disease.

37. The use of claim 31, wherein the composition is administered by oral, subcutaneous, intravenous, transdermal, topical, or intraocular administration.

38. The use of claim 31, wherein the composition is administered in the form of a tablet, capsule, eye drop, or ocular injection.

39. Use of the pharmaceutical composition of claim 3 for treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; and said 5HT3 -antagonist is administered at a daily dose of from 1.5 mg to 200 mg.

40. Use of the pharmaceutical composition of claim 6 for treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; and said NK1 -antagonist is administered at a daily dose of from 1 mg to 600 mg.

41. The use of claim 39, wherein said 5HT3 -antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof administered at a daily dose equivalent to from 4 mg to 32 mg of ondansetron base.

42. The use of claim 40, wherein said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof administered at a daily dose equivalent to from 10 mg to 250 mg.

43. The pharmaceutical composition comprising (i) pramipexole or a pharmaceutically acceptable salt or solvate thereof, (ii) an antagonist selected from the group consisting of a 5HT3 -antagonist and an NK1 -antagonist, for use in a method of treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein the eye disease is selected from the group consisting of age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, and Stargardt disease.

44. The pharmaceutical composition for use of claim 43, wherein the eye disease is age-related macular degeneration.

45. The pharmaceutical composition for use of claim 43, wherein the eye disease is dry age-related macular degeneration.

46. The pharmaceutical composition for use of claim 43, wherein the eye disease is geographic atrophy.

47. The pharmaceutical composition for use of claim 43, wherein the eye disease is diabetic retinopathy.

48. The pharmaceutical composition for use of claim 43, wherein the eye disease is Stargardt disease.

49. The pharmaceutical composition for use of claim 44, wherein the composition is administered by oral, subcutaneous, intravenous, transdermal, topical, or intraocular administration.

50. The pharmaceutical composition for use of claim 43, wherein the composition is administered in the form of a tablet, capsule, eye drop, or ocular injection.

51. The pharmaceutical composition of claim 3 for use in a method of treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; and said 5HT3 -antagonist administered at a daily dose of from 1.5 mg to 200 mg.

52. The pharmaceutical composition of claim 6 for use in a method of treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; and said NK1 -antagonist is administered at a daily dose of from 1 mg to 600 mg.

53. The pharmaceutical composition for use of claim 51, wherein said 5HT3- antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof administered at a daily dose equivalent to from 4 mg to 32 mg of ondansetron base.

54. The pharmaceutical composition for use of claim 52, wherein said NK1- antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof administered at a daily dose equivalent to from 10 mg to 250 mg.

55. Use of the pharmaceutical composition of any one of claims 1-19 for the preparation of a medicament for treating eye disease by administering an effectiveamount of said pharmaceutical composition to a patient in need thereof, wherein the eye disease is selected from the group consisting of age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, and Stargardt disease.

56. The use of claim 55, wherein the eye disease is age-related macular degeneration.

57. The use of claim 55, wherein the eye disease is dry age-related macular degeneration.

58. The use of claim 55, wherein the eye disease is geographic atrophy.

59. The use of claim 55, wherein the eye disease is diabetic retinopathy.

60. The use of claim 55, wherein the eye disease is Stargardt disease.

61. The use of claim 55, wherein the medicament is formulated for oral, subcutaneous, intravenous, transdermal, topical, or intraocular administration.

62. The use of claim 55 wherein the medicament is in the form of a tablet, capsule, eye drop, or ocular injection.

63. Use of the pharmaceutical composition of claim 3 for the preparation of a medicament for treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein the medicament is formulated for administering said pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; and said 5HT3-antagonist at a daily dose of from 1.5 mg to 200 mg.

64. Use of the pharmaceutical composition of claim 6 for the preparation of a medicament for treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein the medicament if formulated for administering said pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; and said NK1 -antagonist at a daily dose of from 1 mg to 600 mg.

65. The use of claim 63, wherein said 5HT3 -antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof, and the medicament is formulated for administering said ondansetron or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 4 mg to 32 mg of ondansetron base.

66. The use of claim 64, wherein said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof, and the medicament is formulated for administering said aprepitant or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 10 mg to 250 mg.

67. A method of manufacturing a pharmaceutical composition, comprising mixing (i) pramipexole or a pharmaceutically acceptable salt or solvate thereof, (ii) an antagonist selected from the group consisting of a 5HT3 -antagonist and an NK1- antagonist, and (iii) a pharmaceutically acceptable carrier suitable for ocular administration to form a pharmaceutical composition of any one of claims 1-18.

68. A pharmaceutical composition comprising (i) pramipexole or a pharmaceutically acceptable salt or solvate thereof, (ii) a 5HT3 -antagonist, an NK1- antagonist, and / or fluoxetine of a pharmaceutically acceptable salt or solvate thereof and (iii) a pharmaceutically acceptable carrier suitable for ocular administration.

69. A pharmaceutical composition comprising (i) pramipexole or a pharmaceutically acceptable salt or solvate thereof, (ii) an antagonist selected fromthe group consisting of a 5HT3 -antagonist and an NK1 -antagonist, and (iii) fluoxetine or a pharmaceutically acceptable salt or solvate thereof.

70. The pharmaceutical composition of claim 69, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate.

71. The pharmaceutical composition of claim 69, wherein the antagonist is a 5HT3 -antagonist.

72. The pharmaceutical composition of claim 71, wherein the 5HT3-antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof.

73. The pharmaceutical composition of claim 71, wherein the 5HT3-antagonist is ondansetron hydrochloride dihydrate.

74. The pharmaceutical composition of claim 68, wherein the antagonist is an NK1 -antagonist.

75. The pharmaceutical composition of claim 74, wherein the NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof.

76. The pharmaceutical composition of claim 74, wherein the NK1 -antagonist is aprepitant.

77. The pharmaceutical composition of claim 68, wherein the composition is in a dosage unit form comprising pramipexole or a pharmaceutically acceptable salt or solvate thereof in an amount equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate.

78. The pharmaceutical composition of claim 68, wherein the composition is in a dosage unit form comprising pramipexole or a pharmaceutically acceptable salt or solvate thereof in an amount equivalent to more than 4.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.

79. The pharmaceutical composition of claim 68, wherein the composition is in a dosage unit form comprising pramipexole or a pharmaceutically acceptable salt or solvate thereof in an amount equivalent to 6 mg to 45 mg of pramipexole dihydrochloride monohydrate.

80. The pharmaceutical composition of claim 68, wherein the composition is in a dosage unit form comprising pramipexole or a pharmaceutically acceptable salt or solvate thereof in an amount equivalent to 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.

81. The pharmaceutical composition of claim 71, wherein the composition is in a dosage unit form comprising the 5HT3 -antagonist in an amount of from 1 pg to 300 mg.

82. The pharmaceutical composition of claim 72, wherein the composition is in a dosage unit form comprising ondansetron or a pharmaceutically salt or solvate thereof in an amount of from 2 mg to 32 mg of ondansetron base.

83. The pharmaceutical composition of claim 74, wherein the composition is in a dosage unit form comprising the NK1 -antagonist in an amount of from 1 pg to 600 mg.

84. The pharmaceutical composition of claim 76, wherein the composition is in a dosage unit form comprising aprepitant in an amount of from 10 mg to 250 mg.

85. The pharmaceutical composition of claim 68, wherein the composition is in a dosage unit form comprising fluoxetine in an amount of from 1 mg to 100 mg.

86. The pharmaceutical composition of claim 68, wherein the composition is in a dosage unit form comprising fluoxetine in an amount of from 10 mg to 80 mg.

87. The pharmaceutical composition of claim 68, wherein the composition further comprises a pharmaceutically acceptable carrier suitable for ocular administration.

88. The pharmaceutical composition of claim 87, wherein ocular administration is topical administration to the eye, intraocular administration, periocular administration or administration by ocular device or a combination thereof.

89. A method for treating eye disease, comprising administering an effective amount of the pharmaceutical composition of any one of claims 1-88 to a patient in need thereof.

90. The method of claim 89, wherein the eye disease is age-related macular degeneration.

91. The method of claim 89, wherein the eye disease is dry age-related macular degeneration.

92. The method of claim 89, wherein the eye disease is geographic atrophy.

93. The method of claim 89, wherein the eye disease is diabetic retinopathy.

94. The method of claim 89, wherein the eye disease is Stargardt disease.

95. The method of claim 89, wherein the composition is administered by oral, subcutaneous, intravenous, transdermal, topical, or intraocular administration.

96. The method of claim 89, wherein the composition is administered in the form of a tablet, capsule, eye drop, or ocular injection.

97. A method for treating eye disease, comprising administering an effective amount of the pharmaceutical composition of claim 72, wherein pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; said 5HT3 -antagonist is administered at a daily dose of from 1.5 mg to 200 mg; and said fluoxetine or pharmaceutically acceptable salt thereof is administered at a daily dose equivalent to from 4 mg to 40 mg of fluoxetine base.

98. A method for treating eye disease, comprising administering an effective amount of the pharmaceutical composition of claim 75, wherein pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; said NK1 -antagonist is administered at a daily dose of from 1 mg to 600 mg; and said fluoxetine or pharmaceutically acceptable salt thereof is administered at a daily dose equivalent to from 4 mg to 40 mg of fluoxetine base.

99. The method of claim 97, wherein said 5HT3 -antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof administered at a daily dose equivalent to from 4 mg to 32 mg of ondansetron base.

100. The method of claim 98, wherein said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof administered at a daily dose equivalent to from 10 mg to 250 mg.

101. The method of any one of claims 97-100, wherein the eye disease, is selected from the group consisting of age-related macular degeneration, dry age-relatedmacular degeneration, geographic atrophy, diabetic retinopathy, and Stargardt disease.

102. Use of the pharmaceutical composition of any one of claims 1-88 for treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof.

103. The use of claim 102, wherein the eye disease is age-related macular degeneration.

104. The use of claim 102, wherein the eye disease is dry age-related macular degeneration.

105. The use of claim 102, wherein the eye disease is geographic atrophy.

106. The use of claim 102, wherein the eye disease is diabetic retinopathy.

107. The use of claim 100, wherein the eye disease is Stargardt disease.

108. The use of claim 102, wherein the composition is administered by oral, subcutaneous, intravenous, transdermal, topical, or intraocular administration.

109. The use of claim 102, wherein the composition is administered in the form of a tablet, capsule, eye drop, or ocular injection.

110. Use of the pharmaceutical composition of claim 72 for treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; said 5HT3-antagonist is administered at a daily dose of from 1.5 mg to 200 mg; and said fluoxetine or pharmaceuticallyacceptable salt thereof is administered at a daily dose equivalent to from 4 mg to 40 mg of fluoxetine base.

111. Use of the pharmaceutical composition of claim 75 for treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; said NK1 -antagonist is administered at a daily dose of from 1 mg to 600 mg; and said fluoxetine or pharmaceutically acceptable salt thereof is administered at a daily dose equivalent to from 4 mg to 40 mg of fluoxetine base.

112. The use of claim 110, wherein said 5HT3 -antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof administered at a daily dose equivalent to from 4 mg to 32 mg of ondansetron base.

113. The use of claim 110, wherein said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof administered at a daily dose equivalent to from 10 mg to 250 mg.

114. The use of any one of claims 110-113, wherein the eye disease, is selected from the group consisting of age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, and Stargardt disease.

115. The pharmaceutical composition of any one of claims 1-88 for use in a method of treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof.

116. The pharmaceutical composition for use of claim 115, wherein the eye disease is age-related macular degeneration.

117. The pharmaceutical composition for use of claim 115, wherein the eye disease is dry age-related macular degeneration.

118. The pharmaceutical composition for use of claim 115, wherein the eye disease is geographic atrophy.

119. The pharmaceutical composition for use of claim 115, wherein the eye disease is diabetic retinopathy.

120. The pharmaceutical composition for use of claim 115, wherein the eye disease is Stargardt disease.

121. The pharmaceutical composition for use of claim 115, wherein the composition is administered by oral, subcutaneous, intravenous, transdermal, topical, or intraocular administration.

122. The pharmaceutical composition for use of claim 115, wherein the composition is administered in the form of a tablet, capsule, eye drop, or ocular injection.

123. The pharmaceutical composition of claim 72 for use in a method of treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; said 5HT3 -antagonist administered at a daily dose of from 1.5 mg to 200 mg; and said fluoxetine or pharmaceutically acceptable salt thereof is administered at a daily dose equivalent to from 4 mg to 40 mg of fluoxetine base.

124. The pharmaceutical composition of claim 75 for use in a method of treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein pramipexole or a pharmaceutically acceptablesalt or solvate thereof is administered at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; said NK1 -antagonist is administered at a daily dose of from 1 mg to 600 mg; and said fluoxetine or pharmaceutically acceptable salt thereof is administered at a daily dose equivalent to from 4 mg to 40 mg of fluoxetine base.

125. The pharmaceutical composition for use of claim 123, wherein said 5HT3- antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof administered at a daily dose equivalent to from 4 mg to 32 mg of ondansetron base.

126. The pharmaceutical composition for use of claim 124, wherein said NK1- antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof administered at a daily dose equivalent to from 10 mg to 250 mg.

127. The pharmaceutical composition for use of any one of claims 120-123, wherein the eye disease, is selected from the group consisting of age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, and Stargardt disease.

128. Use of the pharmaceutical composition of any one of claims 1-88 for the preparation of a medicament for treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof.

129. The use of claim 128, wherein the eye disease is age-related macular degeneration.

130. The use of claim 128, wherein the eye disease is dry age-related macular degeneration.

131. The use of claim 128, wherein the eye disease is geographic atrophy.

132. The use of claim 128, wherein the eye disease is diabetic retinopathy.

133. The use of claim 128, wherein the eye disease is Stargardt disease.

134. The use of claim 128, wherein the medicament is formulated for oral, subcutaneous, intravenous, transdermal, topical, or intraocular administration.

135. The use of claim 128, wherein the medicament is in the form of a tablet, capsule, eye drop, or ocular injection.

136. Use of the pharmaceutical composition of claim 72 for the preparation of a medicament for treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein the medicament is formulated for administering said pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; said 5HT3-antagonist at a daily dose of from 1.5 mg to 200 mg; and said fluoxetine or pharmaceutically acceptable salt thereof at a daily dose equivalent to from 4 mg to 40 mg of fluoxetine base.

137. Use of the pharmaceutical composition of claim 75 for the preparation of a medicament for treating eye disease by administering an effective amount of said pharmaceutical composition to a patient in need thereof, wherein the medicament if formulated for administering said pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate; said NK1 -antagonist at a daily dose of from 1 mg to 600 mg; and said fluoxetine or pharmaceutically acceptable salt thereof at a daily dose equivalent to from 4 mg to 40 mg of fluoxetine base.

138. The use of claim 128, wherein said 5HT3 -antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof, and the medicament is formulated for administering said ondansetron or a pharmaceutically acceptable saltor solvate thereof at a daily dose equivalent to from 4 mg to 32 mg of ondansetron base.

139. The use of claim 128, wherein said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof, and the medicament is formulated for administering said aprepitant or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 10 mg to 250 mg.

140. The use of any one of claims 128-139, wherein the eye disease, is selected from the group consisting of age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, and Stargardt disease.

141. A method of manufacturing a pharmaceutical composition, comprising mixing (i) pramipexole or a pharmaceutically acceptable salt or solvate thereof, (ii) an antagonist selected from the group consisting of a 5HT3 -antagonist and an NK1- antagonist, and (iii) a pharmaceutically acceptable carrier to form a pharmaceutical composition of any one of claims 1-88.

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