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WO2025145022A1 - Compositions and methods for treating anhedonia - Google Patents

Compositions and methods for treating anhedonia Download PDF

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Publication number
WO2025145022A1
WO2025145022A1 PCT/US2024/062080 US2024062080W WO2025145022A1 WO 2025145022 A1 WO2025145022 A1 WO 2025145022A1 US 2024062080 W US2024062080 W US 2024062080W WO 2025145022 A1 WO2025145022 A1 WO 2025145022A1
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WIPO (PCT)
Prior art keywords
pramipexole
solvate
acceptable salt
pharmaceutically acceptable
antagonist
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French (fr)
Inventor
Thomas N. Chase
Kathleen E. Clarence-Smith
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Chase Therapeutics Corp
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Chase Therapeutics Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention pertains to the field of the treatment of anhedonia.
  • the present disclosure relates to pharmaceutical compositions containing pramipexole or a pharmaceutically acceptable salt or solvate thereof in combination with an antagonist of the 5-hydroxytryptamine receptor subtype-3 (“5HT3-antagonisf ') and/or an antagonist of the neurokinin receptor subtype- 1 (“NK1 -antagonist”). and the use of said compositions for the treatment of anhedonia.
  • an antagonist of the 5-hydroxytryptamine receptor subtype-3 (“5HT3-antagonisf ') and/or an antagonist of the neurokinin receptor subtype- 1 (“NK1 -antagonist”.
  • Anhedonia is defined as an inability to feel pleasure; it is a common and core symptom of depression, and it is reported in other neurological disorders such as Parkinson’s disease, PTSD, and substance abuse disorder. It is also observed in neuroinflammation, and more generally in neuroinflammatory diseases, and in patients with cancer where it can impede recovery from cancer (Dichter G, 2010; Uher H, 2012; Watanabe et al, 2022; Sharpley el al, 2023).
  • GI Gastro-Intestinal
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th edition.
  • MADRS Montgomery and Asberg Depression Rating Scale.
  • MDD Major Depressive Disorder.
  • MAOls Monoamine oxidase inhibitors.
  • Persistent depressive disorder also called dysthymia.
  • PMDD Premenstrual Dysphoric Disorder
  • 5HT3-antagonisf an antagonist of the serotonin receptor subtype-3, in the literature also referred to as a 5HT3 receptor antagonist or a 5HT3 receptor inhibitor.
  • Effective daily dose of 5HT3-antagonist refers to a daily dose of said 5HT3- antagonist of from 1 pg to 300 mg.
  • Effective dose/unit form of a 5HT3-antagonist or “effective dose per unit form of a 5HT3- antagonisf an amount of said 5HT3-antagonist per unit form in the range of from 1 pg to 300 mg.
  • NKl-antagonist an antagonist of the neurokinin receptor subty pe- 1, in the literature also referred to as NK1 receptor antagonist or NK1 receptor inhibitor.
  • NKl-antagonist a daily dose of said NKl-antagonist of from 1 pg to 600 mg.
  • NKl-antagonist or “effective dose per unit form of a 5HT3- antagonisf ’: an amount of said NKl-antagonist per unit form in the range of from 1 pg to 600 mg.
  • Effective daily dose of pramipexole or “therapeutically effective dose of pramipexole”: a daily pramipexole dose equivalent to at least a pramipexole dihydrochloride monohydrate approved daily dose for the symptomatic treatment of PD, this effective daily dose including low daily doses used during the titration period.
  • Effective dose/unit form or “effective dose per unit form”, in reference to pramipexole: a pramipexole amount per unit form equivalent to at least a pramipexole dihydrochloride monohydrate amount per unit form approved for the symptomatic treatment of PD, this amount including low amounts per unit form used during the titration period.
  • “Pharmaceutically acceptable salt” with reference to NK1 -antagonists, 5HT3-antagonists or pramipexole, refers to any salt which retains the physiological activity of the corresponding compound and is suitable for administration to a human.
  • NKl-antagonists or pramipexole refers to a pharmaceutically acceptable salt solvated with any suitable solvent, for example, water.
  • SSRIs Selective serotonin reuptake inhibitors.
  • NDRIs Norepinephrine-dopamine reuptake inhibitors.
  • TTS Transdermal Therapeutic System
  • Depressive disorders include, but are not limited to, maj or depressive disorder (MDD), persistent depressive disorder (dysthymia), Bipolar depression, seasonal affective disorder (SAD), psychotic depression, premenstrual dysphoric disorder (PDD), peripartum (postpartum) depression, situational depression, and atypical depression.
  • MDD major or depressive disorder
  • DMD persistent depressive disorder
  • SAD seasonal affective disorder
  • PPD premenstrual dysphoric disorder
  • peripartum postpartum depression
  • situational depression and atypical depression.
  • the common feature of these depressive disorders is the presence of sad, empty, or irritable mood, accompanied by somatic and cognitive changes that significantly affect the individual's capacity’ to function. The difference among these disorders are issues of duration, timing or presumed etiology. See Depressive Disorders, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, dsm.psychiatryonline.org/doi/10.1176/appi.books.9780890425596
  • Maximum tolerated dose “maximal tolerated dose” or “MTD” refers to, and is defined as the highest dose of a drug or treatment that does not cause unacceptable side effects. For instance, the maximum tolerated dose is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found.
  • depression is one of the largest contributors to chronic disease burden; it affects more than one in six individuals in the United States. MDD suffers from a vast treatment gap worldwide, and large numbers of individuals who require treatment do not receive adequate care. Dysregulation of brain dopamine (DA) systems are believed to be central in the pathophysiology of MDD leading to new treatment targets focused on DA-modulated microcircuits (reviewed in Bekhbat et al, 2022). Neurodevelopmental factors have also been suggested as a risk for later emergence of MDD, possibly through dopaminergic substrates in the brain (reviewed in Bekhbat M et al, 2022).
  • DA brain dopamine
  • Anhedonia is defined as an inability to feel pleasure; it is a common and core symptom of depression, and it is reported in other neurological disorders such as Parkinson’s disease, PTSD, substance abuse disorder. It is also observed in neuroinflammation, and more generally in neuroinflammatory diseases, and in patients with cancer where it can impede recovery from cancer (Dichter G, 2010; Uher H, 2012; Watanabe et al, 2022; Sharpley et al, 2023).
  • Anhedonia is considered to be a major contributor to disability in MDD, and it is a particularly difficult symptom to treat.
  • current first-line treatment options e.g., selective serotonin reuptake inhibitors [SSRIs]
  • SSRIs selective serotonin reuptake inhibitors
  • Spravato esketamine nasal spray
  • NMDA N-methyl D-aspartate
  • TRD treatment-resistant depression
  • Trintellix (vortioxetine oral tablets) is approved for the treatment of MDD; its MOA is not fully understood, but the drug increases serotonin levels (Trintellix Package Insert). Data from 2 open-label 52-week trials suggest that Trintellix improves anhedonia, but the effect size is modest (Mattingly GW, 2023). Note a suggestion of perinatal pulmonary adverse events with Trintellix.
  • Pramipexole is a dopamine receptor agonist with high affinity and selectivity for D3 dopaminergic receptors. It is indicated for the treatment of Parkinson’s disease in doses ⁇ 4.5 mg/day.
  • pramipexole showed possible efficacy in the treatment of anhedonic depression (Ventorp et al., 2022), but this study was only conducted with adjunctive pramipexole (as an add-on with one or more antidepressants) titrated to a maximum dose of 4.5 mg salt/day (which is within the approved dose of pramipexole) and nowhere suggests that higher doses would have been more efficacious.
  • the present invention relates to increasing the therapeutic window for pramipexole, for the treatment of anhedonia, to safely enable its full anti-anhedonic efficacy.
  • the present invention relates to a combination of pramipexole with a 5HT3 -antagonist and/or an NK1 -antagonist to increase the therapeutic window for pramipexole.
  • pramipexole dihydrochloride monohydrate its combination with said 5HT3 -antagonist allows the administration of a therapeutically effective dose of said pramipexole dihydrochloride monohydrate that, in many patients, significantly exceeds the aforementioned maximum recommended dose (4.5 mg/day) of pramipexole dihydrochloride monohydrate for the treatment of the symptoms of PD, thus increasing its efficacy in the treatment of a patient suffering from anhedonia.
  • 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 mg to 20 mg of pramipexole dihydrochloride monohydrate provide safe treatment for patients suffering from anhedonia.
  • the present invention provides a pharmaceutical combination compnsing
  • the present invention provides the use of (or a method using) a 5HT3- antagonist for enabling the full anti-anhedonic efficacy of pramipexole in the treatment of anhedonia.
  • the invention provides a 5HT3-antagonist, for use in the treatment of anhedonia, in combination with an effective daily dose of pramipexole.
  • Said effective pramipexole daily dose may be higher, and even much higher than the maximum daily dose recommended in the treatment of PD.
  • the invention also provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a 5HT3 -antagonist, in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
  • Said effective daily dose in pramipexole dihydrochloride monohydrate
  • the method provides the safe administration of a 5HT3-antagonist in combination with pramipexole daily doses (in pramipexole dihydrochloride monohydrate) of from 0.375 mg to 45 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.
  • the invention provides a method (or the use of said 5HT3-antagonist) for treating a patient suffering from anhedonia, which comprises treating said patient with said 5HT3-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.
  • 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.
  • the invention provides the use of said 5HT3 -antagonist for the preparation of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said 5HT3-antagonist, in 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 anhedonia, and also, principally, for administering said pramipexole to a patent suffering from anhedonia at doses higher, and even much higher than the maximum recommended doses approved for the treatment of PD, thus increasing the pramipexole efficacy in combating anhedonia.
  • the invention provides the use of a 5HT3- antagonist for the preparation of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said 5HT3-antagonist, in admixture with a pharmaceutical carrier or vehicle, for the treatment of anhedonia in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides the use of a 5HT3-antagonist for the manufacture of a medicament for the safe treatment of anhedonia, 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 exceed the maximum dose of pramipexole dihydrochloride monohydrate recommended for the symptomatic treatment of Parkinson’s disease.
  • said daily dose in pramipexole dihydrochloride monohydrate 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.
  • said 5HT3 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are each formulated in a pharmaceutical composition in 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 anhedonia. Normally, said compositions are in dosage unit form.
  • said 5HT3 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are mixed together and formulated in a phannaceutical composition (fixed-dose combination), in admixture with a pharmaceutical carrier or vehicle, to be administered to the patient suffering from anhedonia, in need of said treatment.
  • a phannaceutical composition fixed-dose combination
  • said compositions are in dosage unit form.
  • a 5HT3 -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 that is generally currently indicated for treating PD, or with a higher, and even much higher dose.
  • the use of this combination significantly improves the conditions of patients suffering from anhedonia by concurrently mitigating or even eliminating the pramipexole adverse effects, otherwise intolerable when using said pramipexole alone.
  • said 5HT3 -antagonists used 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.
  • 5HT3 receptor inhibitors known to block nausea, vomiting, and diarrhea induced by chemotherapeutic drugs, have been shown, in particular when administered at high doses, to also block the gastro-intestinal side effects of pramipexole without affecting its efficacy in treating said anhedonia.
  • the invention provides a pharmaceutical fixed- dose combination consisting of a pharmaceutical composition comprising an effective dose/unit form of a 5HT3-antagonist and an effective dose/unit form of pramipexole. in admixture with a pharmaceutical carrier or vehicle.
  • a 5HT3 -antagonist is present in said composition in an amount per unit form of from 1 pg to 300 mg; and pramipexole or a pharmaceutically acceptable salt or solvate thereof 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.
  • the dose per unit form of pramipexole or a pharmaceutically acceptable salt or solvate thereof, in pramipexole dihydrochloride monohydrate will normally be in a range selected from the group consisting of 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.
  • an NK1 -antagonist by reducing or even abrogating the side effects of high doses of pramipexole, enables the full antidepressant potential of pramipexole.
  • the safe administration of pramipexole doses that are higher, and even much higher than the maximum tolerated dose for the relief of symptoms of Parkinson's disease (such as motor symptoms), provides significant improvement to patients suffering from anhedonia.
  • pramipexole or a pharmaceutically acceptable salt or solvate thereof with a NK1 -antagonist allows the administration of a therapeutic effective dose that may be equivalent to from up to 10 times, from up to 4.7 times, or from 1.1 times to 10 times higher than the aforementioned maximum dose of pramipexole dihydrochloride monohydrate recommended for the treatment of the symptoms of PD.
  • a NK1 -antagonist with pramipexole or a pharmaceutically acceptable salt or solvate thereof acts by enabling the full antidepressant efficacy of pramipexole, due to the high pramipexole doses that may be used in combination with said NK1 -antagonist.
  • a NK1 -antagonist in combination with daily doses of pramipexole or a pharmaceutically acceptable salt or solvate thereof that are equivalent to from more than 4.5 mg to 21 mg/day and even from more than 6 mg to 21 mg or from 15 mg to 21 mg of pramipexole dihydrochloride monohydrate, also offers significant efficacy and a fast onset of action.
  • the present invention provides a pharmaceutical combination comprising
  • the present invention provides a pharmaceutical combination comprising
  • pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose (in pramipexole dihydrochloride monohydrate) that is higher than the maximum dose of pramipexole dihydrochloride monohydrate recommended for the relief of the motor symptoms of PD, for use for the treatment of anhedonia.
  • Said pramipexole daily dose in said combination is from up to 10 times, from up to 4.7 times, or from 1.1 times to 10 times higher than the maximum dose of pramipexole dihydrochloride monohydrate recommended for the relief of the motor symptoms of PD.
  • the present invention further provides the use of a NK1 -antagonist for enabling the full efficacy of pramipexole in the treatment of anhedonia.
  • the invention provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a NK1 -antagonist, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a NK1 -antagonist, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose (in pramipexole dihydrochloride monohydrate) from up to 10 times, from up to 4.7 times, or from 1. 1 times to 10 times higher than the maximum daily dose recommended for the relief of the symptoms of Parkinson’s disease such as motor symptoms (4.5 mg/day).
  • a daily dose in pramipexole dihydrochloride monohydrate
  • the daily dose of the NK1 -antagonist is from 1 pg to 600 mg and the pramipexole daily dose (in pramipexole dihydrochloride monohydrate), depending on the degree of gravity of the illness and the age and condition of the patient and including low doses for use during the titration period, will range from 0.375 mg to 45 mg, normally from 0.375 mg to 21 mg.
  • said daily dose preferably is 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, nonnally from more than 4.5 mg to 21 mg, in particular from more than 6 mg to 21 mg, from 10 mg to 21 mg, from 13 mg to 21 mg or from 15 mg to 21 mg.
  • said NK1 -antagonist in an amount per unit form of from 1 pg to 600 mg or from 1 mg to 600 mg, and said pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount equivalent to from 0. 125 mg to 45 mg, from more than 4.5 mg to 21 mg or from more than 6 mg to 21 mg. are each formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle and separately administered, concurrently or sequentially, to a patient in need of treatment with said combination, and in particular to a patient suffering from anhedonia.
  • said NK1 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are mixed together and formulated in a pharmaceutical composition (fixed-dose combination), in admixture with a pharmaceutical carrier, to be administered to a patient in need of said treatment.
  • said NK1 -antagonist in an amount of from 1 pg to 600 mg or from 1 mg to 600 mg, and said pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount equivalent to from 0.125 mg to 45 mg, preferably from more than 4.5 mg to 45 mg, from more than 6 mg to 45 mg, from 10 mg to 45 mg.
  • said NK1 -antagonist may also be formulated in a pharmaceutical composition
  • a pharmaceutical composition comprising said NK1 -antagonist in an amount per unit form of from 1 pg to 600 mg or from 1 mg to 600 mg, in admixture with a phannaceutical carrier or vehicle, for use for preventing or curing the adverse effects of pramipexole daily doses that for some patients may be higher, and even much higher, than the maximum dose (4.5 mg/day) presently recommended for the relief of the motor symptoms of Parkinson’s disease.
  • pramipexole is formulated in a pharmaceutical composition in dosage unit form comprising said pramipexole in an amount per IR- or ER-form (including low doses to be used during the titration period) equivalent to from 0. 125 mg to 45 mg, advantageously 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 of pramipexole dihydrochloride monohydrate.
  • pramipexole is formulated in a pharmaceutical composition in dosage unit form comprising said pramipexole an amount per IR-form (including low doses to be used during the titration period) equivalent to from 0. 125 mg to 22.5 mg, advantageously from 1.5 mg to 22.5 mg, from more than 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 of pramipexole dihydrochloride monohydrate.
  • pramipexole for said use in combination with a NK1 -antagonist, pramipexole, is formulated in a pharmaceutical composition in dosage unit form comprising said pramipexole an amount per ER-form (including low doses to be used during the titration period) equivalent to from 0.375 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, from 10 mg to 45 mg from 13 mg to 45 mg, or from 15 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • the dose of pramipexole or pharmaceutically acceptable salt or solvate thereof, in pramipexole dihydrochloride monohydrate, per IR- or ER-unit form. will range from 0.125 mg to 21 mg, advantageously from 1.6 mg to 21 mg. from 1.8 mg to 21 mg, from 2.4 mg to 21 mg, from 3 mg to 21 mg, more advantageously from more than 4.5 mg to 21 mg, preferably from more than 6 mg to 21 mg, from 10 mg to 21 mg, from 13 mg to 21 mg, or from 15 mg to 21 mg.
  • the dose per unit form of pramipexole or a pharmaceutically acceptable salt or solvate thereof in an ER formulation will range from an amount that is equivalent to from more than 4.5 mg to 21 mg, in particular from 6.0 mg to 21 mg or from more than 6 mg to 21 mg of pramipexole dihydrochloride monohydrate, depending on the tolerability (in combination with said NK1- antagomst).
  • the dose/unit form will range from 10 mg to 250 mg;
  • the dose/unit fonn will range from 30 mg to 270 mg.
  • the disclosure provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a 5HT3-antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
  • the 5HT3 -antagonist is administered at a daily dose of from 1 pg to 300 mg.
  • the 5HT3-antagonist is selected from the group consisting of azasetron or a pharmaceutically acceptable salt or solvate thereof, dolasetron or a pharmaceutically acceptable salt or solvate thereof, granisetron or a pharmaceutically acceptable salt or solvate thereof, ondansetron or a pharmaceutically acceptable salt or solvate thereof, palonosetron or a pharmaceutically acceptable salt or solvate thereof, ramosetron or a pharmaceutically acceptable salt or solvate thereof, and tropisetron or a pharmaceutically acceptable salt or solvate thereof.
  • pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate.
  • said 5HT3 -antagonist is selected from the group consisting of ondansetron or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 2 mg to 32 mg of ondansetron base, and dolasetron or a pharmaceutically acceptable salt or solvate thereof 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 at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • said 5HT3-antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are each formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
  • said 5HT3 -antagonist is selected from the group consisting of ondansetron or 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 or a pharmaceutically acceptable salt or solvate thereof in an amount per unit form equivalent to from 25 mg to 200 mg of dolasetron mesylate; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate. In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate.
  • said medicament comprises a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said 5HT3-antagonist in admixture with a pharmaceutical carrier or vehicle, and another pharmaceutical composition in dosage unit form comprising 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.
  • said medicament comprises a fixed-dose combination of an effective amount per unit form 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.
  • the effective amount per unit form of said 5HT3-antagonist is 1 pg to 300 mg and said effective amount per unit form of said pramipexole or a pharmaceutically acceptable salt or solvate thereof is equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • the present disclosure provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a combination of a 5HT3- antagonist with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof, wherein another active compound with an antidepressant efficacy is not concurrently administered.
  • the present disclosure provides a 5HT3-antagonist for use in the treatment of anhedonia 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, wherein another active compound with an antidepressant efficacy is not concurrently administered.
  • the present disclosure provides a fixed dose combination for the treatment of anhedonia in a patient in need thereof, wherein the fixed dose combination contains active ingredients and inactive ingredients, and the active ingredients consist of pramipexole or a pharmaceutically acceptable salt or solvate thereof and a 5HT3 -antagonist.
  • the present disclosure provides a pharmaceutical composition for the treatment of anhedonia in a patient in need thereof, wherein the pharmaceutical composition contains active ingredients and inactive ingredients, and the active ingredients consist of pramipexole or a pharmaceutically acceptable salt or solvate thereof and a 5HT3-antagonist.
  • anhedonia is a symptom of a depressive disorder.
  • anhedonia is a symptom of a major depressive disorder.
  • the patient does not have a depressive disorder.
  • anhedonia is due to or is a symptom of a neuroinflammatory disease.
  • anhedonia is associated with a neurodegenerative disorder which is one or more selected from the group consisting of Parkinson’s disease, Alzheimer’s disease, post-traumatic stress disorder, and a substance abuse disorder.
  • anhedonia is due to neurodegeneration of dopaminergic nigral neurons. In some embodiments, anhedonia is due to Alzheimer’s disease.
  • anhedonia is due to Parkinson’s Disease.
  • anhedonia is due to post-traumatic stress disorder.
  • anhedonia is due to substance abuse disorder.
  • anhedonia is due to a synucleinopathy.
  • anhedonia is a symptom of or is associated with one or more selected from the group consisting of bipolar disorder, schizophrenia, schizoaffective disorder, personality disorder, mild cognitive impairment, an autoimmune disorder, rheumatoid arthritis, psoriasis, multiple sclerosis, and anticancer treatment.
  • the present disclosure provides a method for enabling the use of a dose of pramipexole sufficient for the effective treatment of anhedonia in humans comprising administering a dose of a 5-HT3 antagonist in combination with the dose of pramipexole, wherein the dose of the 5-HT3 antagonist is selected to reduce to tolerable levels the dose limiting adverse effects of the dose of pramipexole.
  • the present disclosure provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with an NK1 -antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
  • said NK1 -antagonist is administered at a daily dose of from 1 pg to 600 mg.
  • said NK1 -antagonist is selected from the group consisting of aprepitant or a pharmaceutically acceptable salt or solvate thereof, fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, casopitant or a pharmaceutically acceptable salt or solvate thereof, maropitant or a pharmaceutically acceptable salt or solvate thereof, eziopitant or a pharmaceutically acceptable salt or solvate thereof, lanepitant or a pharmaceutically acceptable salt or solvate thereof, netupitant or a pharmaceutically acceptable salt or solvate thereof, orvapitant or a pharmaceutically acceptable salt or solvate thereof, rolapitant or a phamraceutically acceptable salt or solvate thereof, serlopitant or a pharmaceutically acceptable salt or solvate thereof, vestipitant or a pharmaceutically acceptable salt or solvate thereof, vofopitant or a pharmaceutically acceptable salt or solvate thereof, and netupitant-300/palonosetron-0.5.
  • said pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate.
  • said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof at a daily dose of from 10 mg to 250 mg; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • said NK1 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are each formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
  • said NK1 -antagonist is formulated in a pharmaceutical composition in dosage unit form comprising said NK1 -antagonist in an amount per unit form of from 1 pg to 600 mg, in admixture with a phannaceutical carrier or vehicle; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is formulated 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 in an amount per unit fonn equivalent to from 0. 125 mg to 45 mg of pramipexole dihydrochloride monohydrate, in admixture with a phannaceutical carrier or vehicle.
  • said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof in an amount per unit form equivalent to from 10 mg to 250 mg of aprepitant, or rolapitant or a pharmaceutically acceptable salt or solvate thereof in an amount per unit form equivalent to from 15 mg to 270 mg of rolapitant; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • the present disclosure provides a use of an NK1 -antagonist for the preparation of a medicament for the treatment of anhedonia in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
  • Anhedonia is defined as an inability to feel pleasure; it is a common and core symptom of depression, and it is reported in other neurological disorders such as Parkinson’s disease, PTSD, and substance abuse disorder. It is also observed in neuroinflammation, and more generally in neuroinflammatory diseases, and in patients with cancer where it can impede recovery from cancer (Dichter G, 2010; Uher H, 2012; Watanabe et al, 2022; Sharpley et al, 2023).
  • Anhedonia is a symptom that is commonly associated with various mental health disorders. It refers to the inability to experience pleasure or interest in activities that were once enjoyable. Some of the primary mental health conditions linked to anhedonia include:
  • Bipolar Disorder Both the depressive and manic phases of bipolar disorder can involve symptoms of anhedonia. During depressive episodes, individuals may experience a profound lack of interest, pleasure, and motivation.
  • Schizophrenia Anhedonia is commonly observed in individuals with schizophrenia, a severe mental disorder characterized by distorted thinking, emotions, and perceptions.
  • Post-Traumatic Stress Disorder Anhedonia can be a symptom of PTSD, especially when it is associated with a loss of interest in activities or social interactions.
  • Anhedonia can be a feature of certain personality’ disorders, such as schizoid personality disorder.
  • Chronic Medical Conditions Some chronic medical conditions, such as Parkinson's disease, Alzheimer’s disease, mild cognitive impairment, certain autoimmune disorders including rheumatoid arthritis, psoriasis, multiple sclerosis, and certain anticancer treatments, can be associated with anhedonia.
  • anhedonia is a complex symptom and can manifest in various ways across different individuals and conditions. Additionally, it can be a symptom of other underly ing medical or neurological issues. If someone is experiencing symptoms of anhedonia or other mental health concerns, it is crucial for them to seek professional help for a proper diagnosis and treatment.
  • any of the 5HT3 -antagonists especially those shown 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 that is generally currently used for treating PD, or with a higher and even much higher dose.
  • said 5HT3 -antagonists used are those approved for preventing nausea and vomiting following cancer chemotherapy.
  • a useful 5HT3-antagonist is selected from the group consisting of 5-methyl-2-[(4- methyl-lH-imidazol-5-yl)methyl]-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one (alosetron) or a pharmaceutically acceptable salt or solvate thereof, especially its hydrochloride, disclosed in US 5,360,800; ( ⁇ )-6-chloro,3,4-dihydro-4-methyl-3-oxo-N-(quinuclidinyl)-27f-l,4- benzoxazine-8-carboxamide (azasetron) or a pharmaceutically acceptable salt or solvate thereof, especially its hydrochloride, disclosed in US 4,892,872; [(lS,57?)-8-methyl-8- azabicyclo[3.2.1]octan-3-yl] 3,5-dichlorobenzoate (bemesetron, CAS: 40796-97-2); (107?)
  • said 5HT3 -antagonist is selected from the group consisting of azasetron or a pharmaceutically acceptable salt or solvate thereof, dolasetron or a pharmaceutically acceptable salt or solvate thereof, granisetron and or a pharmaceutically acceptable salt or solvate thereof, ondansetron or a phannaceutically acceptable salt or solvate thereof, palonosetron or a pharmaceutically acceptable salt or solvate thereof, ramosetron or a pharmaceutically acceptable salt or solvate thereof and tropisetron or a pharmaceutically acceptable salt or solvate thereof.
  • 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 on
  • Illustrative examples of pharmaceutically acceptable salts of basic advantageous NKl- 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.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, phosphoric acid and the like
  • organic acids such as formic acid, acetic acid, propionic acid
  • Illustrative examples of pharmaceutically acceptable salts of acidic NKl-antagonists such as fosaprepitant include salts wi th 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 is incorporated herein in its entirety by reference.
  • An advantageous NK1 -antagonists to be used in combination with 6-propylamino- 4,5,6,7-tetrahydro-l,3-benzothiazole-2-amine is selected from the group consisting of
  • 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 is commercially available (Emend®) in capsules containing 40 mg, 80 mg, or 125 mg aprepitant or, as fosaprepitant dimeglumine (Emend® Injection), in vials containing 115 mg or 150 mg fosaprepitant; rolapitant is available (Varubi*) in 90-mg tablets; and netupitant is available (Akynzeo®) in a fixed-dose combination in capsules containing 300 mg of netupitant and 0.5 mg of the 5HT3 -antagonist palonosetron (as hydrochloride), herein below referred to as “netupitant300mg/palonosetron0.5 mg'’.
  • Each of these preparations is a particularly advantageous NK1 -antagonist for the combination with pramipexole or pharmaceutical
  • said NKl-antagonst is present in an amount per unit form and is 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.
  • said NK1 -antagonist is selected from the group consisting of aprepitant or a phannaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; rolapitant or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 15 mg to 270 mg of rolapitant; netupitant or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 300 mg to 600 mg of netupitant; and netupitant-300/palonosetron-0.5.
  • said NK1 -antagonist is aprepitant at a daily oral dose of from 10 mg to 250 mg; rolapitant, at a daily oral dose of from 30 mg to 270 mg or netupitant300mg/palonosetron 0.5mg, orally administered once a day, each in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from up to 10 times, from up to 4.7 times, or from 1 .1 times to 10 times higher than the maximum recommended dose for the treatment of the motor symptoms of Parkinson’s disease.
  • said NK1 -antagonist is aprepitant at a daily oral dose of from 10 mg to 250 mg; rolapitant, at a daily oral dose of from 30 mg to 270 mg or netupitant300mg/palonosetron 0.5mg, orally administered once a day, each in combination with pramipexole or a phannaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 1.1 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone.
  • each of the above NK1 -antagonists is formulated in a phannaceutical composition in dosage unit form comprising, as an active ingredient, said NK1 -antagonist, in admixture with a pharmaceutical carrier or vehicle.
  • said NKl-antagonist active ingredient of said pharmaceutical composition is selected from the group consisting of aprepitant or a pharmaceutically acceptable salt or solvate thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; rolapitant or a pharmaceutically acceptable salt or solvate 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 of netupitant; and netupitant- 300/palonosetron-0.5.
  • the beneficial action of the 5HT3- antagonist or an NKl-antagonist counteracting the adverse effects of pramipexole in patients suffering from anhedonia, allows for the safe administration of pramipexole daily doses otherwise not tolerable in most of said patients even within the currently approved dose-range (from 0.375 mg to 4.5 mg per day) of pramipexole dihydrochloride monohydrate.
  • pramipexole In high doses, as enabled by the co-administration of 5HT3-antagonists or by NK1- antagonists, pramipexole has additional anti-inflammatory properties. It is indicated for the treatment of Parkinson’s disease in doses ⁇ 4.5 mg/day. In a preliminary open-label study. pramipexole showed possible efficacy in the treatment of anhedonic depression (Ventorp et al., 2022).
  • a 5HT3-antagonist or an NK1 -antagonist renders it possible to safely treat said patients with daily doses of pramipexole or a pharmaceutically acceptable salt or solvate 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.
  • salts of pramipexole are those with inorganic or organic acids 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- hydroxyethanesulfonic (isethionic) acid, p-toluenesulfonic acid.
  • inorganic or organic acids such as, but not limited to. hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric 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.
  • said pramipexole or pharmaceutically acceptable salt or solvate 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.
  • said pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered to said patient in combination with said 5HT3-antagonist, administered by any administration route.
  • a 5HT3-antagonist/pramipexole fixed-dose combination normally for use in the treatment of anhedonia, 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; 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 in admixture with a pharmaceutical carrier or vehicle.
  • 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
  • the 5HT3 -antagonist is formulated in a pharmaceutical composition, wherein said 5HT3- antagonist is in admixture with a pharmaceutical carrier or vehicle.
  • 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 phannaceutically acceptable salt or solvate thereof that is equivalent to from 0.
  • 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.
  • transdennal 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 the at least one surface of the support layer as described in US 8.877,235, a patch using a monoglycende 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
  • compositions containing an NKl-antagonist and pramipexole and their use
  • the invention provides a NKl -antagonist for use in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof for the treatment of anhedonia in a patient in need of said treatment.
  • this aspect of the present invention provides
  • this aspect of the present invention provides a NK1 -antagonist, in an amount per unit form of from 1 pg to 600 mg. normally from 1 mg to 600 mg or from 1 mg to 300 mg, for use in combination with a daily dose of said pramipexole or a pharmaceutically acceptable salt or solvate thereof (including low doses used in the titration period) equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate, for the treatment of anhedonia in a patient in need of said treatment.
  • the NK1- antagonist for its use for the treatment of anhedonia according to the present invention, is administered to a patient in need of said treatment in combination with pramipexole at the aforementioned effective daily dose, as described herein.
  • the invention provides said NK1- antagonist in a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, said NK1- antagonist, in admixture with a pharmaceutical carrier or vehicle, for use for the treatment of anhedonia in a patient, in combination w ith pramipexole or a pharmaceutically acceptable salt or solvate thereof, also in a pharmaceutical composition, in admixture with a pharmaceutical carrier or vehicle, to be administered to said patient at a daily dose that is equivalent to from up to 10 times, from up to 4.7 times, or from 1.1 times to 10 times higher than the maximum pramipexole dihydrochloride monohydrate daily dose recommended for the relief of the motor symptoms of Parkinson’s disease (such a motor symptoms).
  • the invention provides NK1 -antagonist in a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, said NK1 -antagonist, in admixture with a pharmaceutical carrier or vehicle, for use in the treatment of anhedonia in a patient, 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, to be administered to said patient at a daily dose that is equivalent to a dose from 1.1 times to 10 times higher than a maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone.
  • Such a daily dose includes but is not limited to, a daily dose that is equivalent to a dose from 1.1 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 1.5 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 2.5 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 3 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 4 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment
  • Said pharmaceutical composition in dosage unit form comprises said NK1 -antagonist in an amount of from 1 pg to 600 mg, in admixture with a pharmaceutical carrier or vehicle, and is for use for the treatment of anhedonia in a patient, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof in doses, in pramipexole dihydrochloride monohydrate, from up to 10 times, from up to 4.7 times, or from 1.1 times to 10 times higher than the daily dose approved for the relief of the symptoms of PD (such as motor symptoms).
  • Said pharmaceutical composition in dosage unit form comprises said NK1 -antagonist in an amount of from 1 pg to 600 mg, in admixture with a pharmaceutical carrier or vehicle, and is for use for the treatment of anhedonia in a patient, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof in doses, in pramipexole dihydrochloride monohydrate, from 1.1 times to 10 times higher than a maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone.
  • a dose includes but is not limited to, a daily dose that is equivalent to a dose from 1.
  • said NK1 -antagonist in an amount per unit form of from 1 pg to 600 mg, is for use in the treatment of anhedonia in a patient in combination with a pramipexole, also in a pharmaceutical composition in dosage unit form comprising said pramipexole in an amount per unit form equivalent to 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.
  • Pramipexole in said combination, may be formulated in a pharmaceutical composition in IR- or ER-form, in an amount per unit form as described herein and administered twice to three times per day in an IR-formulation or once a day in an ER-fonnulation, at the aforementioned daily doses, in combination with the NK1 -antagonist.
  • NKl-antagonist for the preparation of a medicament for the treatment of anhedonia
  • This aspect of the invention provides the use of said NKl-antagonist for the preparation of a medicament consisting of a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, said NKl-antagonist, in an amount of from 1 pg to 600 mg, in admixture with a pharmaceutical carrier or vehicle, for the treatment of anhedonia in a patient, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, at a daily dose, (in pramipexole dihydrochloride monohydrate) from up to 10 times, from up to 4.7 times, or from 1. 1 times to 10 times higher than the daily dose approved for the relief of the symptoms of PD (such as motor symptoms).
  • This aspect of the invention also provides the use of said NKl-antagonist for the preparation of a medicament consisting of a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, said NKl-antagonist, in an amount of from 1 pg to 600 mg, in admixture with a pharmaceutical carrier or vehicle, for the treatment of anhedonia in a patient, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose, (in pramipexole dihydrochloride monohydrate) from 1.1 times to 10 times higher than a maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone.
  • Such a daily dose includes but is not limited to, a daily dose that is equivalent to a daily dose that is equivalent to a dose from 1.1 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a dose from 1.5 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 2.5 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 3 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 4 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment
  • compositions for use for the treatment of anhedonia in a patient, normally are in dosage unit form, in an IR or ER formulation, and each of said compositions may comprise
  • both said NK1 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof in a fixed-dose combination comprising said NK1 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof in admixture with a phannaceutical carrier or vehicle.
  • the above pramipexole dose-range (daily and per unit form) includes low' doses to be used during the titration period.
  • 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, to be administered at a daily dose equivalent to from 0.375 mg to 45 mg, preferably 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 of pramipexole dihydrochloride monohydrate.
  • NK1 -antagonists may be used as an active ingredient of the pharmaceutical composition of the combination according to this aspect of the invention.
  • said NK1 -antagonist 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.
  • the above pharmaceutical composition may also comprise, as a second active ingredient, palonosetron or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from 0. 1 mg to 0.5 mg of palonosetron base.
  • palonosetron or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 0.125 mg to 45 mg, in particular 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 of pramipexole dihydrochloride monohydrate.
  • the dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof per IR-unit form, for the treatment of anhedonia will range from an amount equivalent to from 0.125 mg to 22.5 mg, from 1.5 to 22.5 mg, from more than 3 mg to 22.5 mg, from 5 mg to 22.5 mg, from 6.5 mg to 22.5 mg, or from 10 mg to 22.5 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with the NK1 -antagonist).
  • the dose per unit form of pramipexole or a pharmaceutically acceptable salt or solvate thereof in an ER formulation will range from an amount that is equivalent to from 0.375 mg to 45 mg, from 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 of pramipexole dihydrochloride monohydrate, depending on the tolerability (in combination with said NK1- antagonist).
  • pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 0.125 mg to 21 mg, in particular from 0.125 mg to less than 1.6 mg, from 1.6 mg to 21 mg, from more than 4.5 mg to 21 mg or from more than 6 mg to 21 mg of pramipexole dihydrochloride monohydrate.
  • the dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof per IR-unit form, for the treatment of anhedonia will range from an amount equivalent to from 1.6 mg to 10.5 mg, from 1.8 to 10.5 mg, from 2.4 mg to 10.5 mg or from 3 mg to 10.5 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with the NK1 -antagonist).
  • the dose per unit form of pramipexole or a pharmaceutically acceptable salt or solvate thereof in an ER formulation will range from an amount that is equivalent to from more than 4.5 mg to 30 mg, more than 4.5 mg to 21 mg, in particular from 6 mg to 21 mg, or from more than 6 mg to 21 mg of pramipexole dihydrochloride monohydrate, depending on the tolerability (in combination with said NK1 -antagonist).
  • each of them can be packaged in a kit comprising said NK1 -antagonist, in admixture with a pharmaceutical carrier or vehicle, in a container; and said pramipexole, in admixture with a pharmaceutical carrier or vehicle, in another, separate container.
  • the NK1 -antagonist is formulated in a pharmaceutical composition, wherein said NK1- antagonist is in admixture with a pharmaceutical carrier or vehicle.
  • said NK1 -antagonist and said pramipexole may also be formulated together and with a pharmaceutical carrier or vehicle, in a pharmaceutical composition (fixed-dose combination).
  • compositions comprising pramipexole and an NKl-antagonist
  • the present invention includes a method for safely treating anhedonia in patients suffering from anhedonia, with pramipexole by concurrently administering to said patients a NKl-antagonist.
  • the invention provides a method for treating a patient suffering from anhedonia which comprises administering to a patient in need of said treatment an effective dose of said NKl-antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
  • said NKl-antagonist is selected from the group consisting of aprepitant or a pharmaceutically acceptable salt or solvate thereof, fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, rolapitant or a pharmaceutically acceptable salt or solvate thereof, netupitant or a pharmaceutically acceptable salt or solvate thereof, and netupitant- 300/palonosetron-0.5; each at a daily dose described herein, except for netupitant- 300/palonosetron-0.5 which is provided once a day or every 2-4 days; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose as described herein.
  • the NKl-antagonist is aprepitant, fosaprepitant meglumine, or rolapitant and the pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate, each at the daily doses described in the respective sections.
  • the daily dose of these NK1- antagonists is at least as high as that for preventing or treating nausea and vomiting in patients undergoing a surgical operation or cancer chemotherapy according to the current protocols for said treatment or prevention.
  • Said daily dose is from 1 pg to 600 mg, normally from 1 mg to 600 mg, or from 1 mg to 300 mg.
  • the pramipexole or a pharmaceutically acceptable salt or solvate thereof daily dose is equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate, including daily doses used during the titration period.
  • a NKl-antagonist selected from the group consisting of aprepitant or a pharmaceutically acceptable salt or solvate thereof and rolapitant or a pharmaceutically acceptable salt or solvate thereof is a particularly advantageous NK1 -antagonist.
  • said NKl-antagonist is aprepitant and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate.
  • said NKl-antagonist in said combination is aprepitant, at an effective daily dose of from 10 mg to 250 mg and said pramipexole or a pharmaceutically acceptable salt or solvate thereof in said combination is pramipexole dihydrochloride monohydrate, at an effective daily dose in a range selected from the group consisting of from more than 4.5 mg to 45 mg, from 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.
  • said NKl-antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are each formulated in a pharmaceutical composition in dosage unit form comprising, respectively, said NKl- antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof, each in admixture with a pharmaceutical carrier or vehicle.
  • Said pramipexole dose per unit form consists of or includes an amount per unit form equivalent to a range selected from the group consisting of from 0.125 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, from 10 mg to 45 mg, from 13 mg to 45 mg, and from 15 mg to 45 mg of pramipexole dihydrochloride monohydrate.
  • compositions may also be formulated as a transdermal therapeutic system (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.
  • Females of childbearing potential must agree to be abstinent or else use any two of the following medically acceptable forms of contraception from the Screening Period through 14 days after the study Exit Visit: condom with spermicidal jelly, diaphragm or cervical cap with spermicidal jelly, or intrauterine device (IUD).
  • IUD intrauterine device
  • a female whose male partner has had a vasectomy must agree to use one additional form of medically acceptable contraception.
  • Subjects must agree to practice the above birth control methods for 14 days after the final visit as a safety precaution.
  • Males with female partners of childbearing potential must agree to use a highly effective, medically acceptable form of contraception from the Screening Period through 14 days after the study Exit Visit.
  • Males with female partners of childbearing potential who themselves are surgically sterile (status post vasectomy) must agree to use condoms with spermicide over the same period of time.
  • Male subjects must agree to practice the above birth control methods for 14 days after the final visit as a safety precaution.
  • Subjects must be in good health as determined by their medical history including personal and family psychiatric history and results of physical examination, electrocardiogram (ECG), vital signs, and laboratory tests.
  • ECG electrocardiogram
  • a subject with a medical abnormality may be included only if the investigator or designee considers that the abnormality will not introduce significant additional risk to the subject's health or interfere with study objectives.6.
  • Subjects must be able to clearly and reliably communicate changes in their medical condition.
  • BMI body mass index
  • Table 1 summarizes the demographic characteristics of the subjects.
  • Period 1 All participants were first admitted to Period 1 , in which rising single daily doses of pramipexole IR up to the first intolerable dose (FID1) or maximum allowed dose (6 mg/day) were administered once a day in the morning.
  • the starting dose of pramipexole was 0.5 mg and the dose was increased daily by 0.5 mg increments.
  • FID-1 first intolerable dose
  • upward dose escalation was discontinued. Participants completed Period 1 on the day they reached the FID1 or maximum allow ed dose (6 mg/day).
  • FID was defined as:
  • a Phase I study was conducted in subjects receiving a single oral dose of pramipexole dihydrochloride monohydrate (“pramipexole”) with or without a single oral dose of aprepitant.
  • This study was a single center, multiple ascending dose study in a single group of healthy subjects.
  • the objective of the study was to demonstrate that aprepitant could safely attenuate the gastro-intestinal side effects of pramipexole given in doses equivalent or higher than those approved in the treatment of Parkinson’s Disease or show n in clinical trials to be effective in the treatment of anhedonia.
  • the primary objective of this study was to evaluate if treatment with oral aprepitant in combination with pramipexole would facilitate a safe increase in the MTD of pramipexole.
  • the primary endpoint of the study w as the measurement of the change in pramipexole MTD in the 4 subjects who completed the pramipexole + aprepitant; prtiod compared to the MTD in the same 4 subjects receiving pramipexole IR alone in Period 1 (MTD1).
  • the primary endpoint of the study was the difference in the individually determined MTD (defined as one dose below' the FID) of pramipexole when given alone or with aprepitant.
  • Males with female partners of childbearing potential must agree to use a highly effective, medically acceptable form of contraception from the Screening Period through 14 days after the study Exit Visit.
  • Males with female partners of childbearing potential who themselves are surgically sterile (status post vasectomy) must agree to use condoms with spermicide over the same period of time.
  • Male subjects must agree to practice the above birth control methods for 14 days after the final visit as a safety precaution.
  • Subjects must be in good health as determined by their medical history including personal and family psychiatric history and results of physical examination, electrocardiogram (ECG), vital signs, and laboratory tests.
  • ECG electrocardiogram
  • a subject with a medical abnormality may be included only if the investigator or designee considers that the abnormality will not introduce significant additional risk to the subject's health or interfere with study objectives.
  • FID first intolerable dose
  • MTD maximum tolerated dose
  • SD standard deviation

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Abstract

The present invention describes the combination of a 5HT3-antagonist and/or NK1-antagonist with pramipexole to reduce or eliminate the adverse effects associated with the use of pramipexole and to enable the use of high doses of pramipexole for treating anhedonia.

Description

COMPOSITIONS AND METHODS FOR TREATING ANHEDONIA
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 63/615,619, filed December 28, 2023, the disclosure of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention pertains to the field of the treatment of anhedonia.
OBJECT OF THE INVENTION
The present disclosure relates to pharmaceutical compositions containing pramipexole or a pharmaceutically acceptable salt or solvate thereof in combination with an antagonist of the 5-hydroxytryptamine receptor subtype-3 (“5HT3-antagonisf ') and/or an antagonist of the neurokinin receptor subtype- 1 (“NK1 -antagonist”). and the use of said compositions for the treatment of anhedonia.
DEFINITIONS
- Anhedonia is defined as an inability to feel pleasure; it is a common and core symptom of depression, and it is reported in other neurological disorders such as Parkinson’s disease, PTSD, and substance abuse disorder. It is also observed in neuroinflammation, and more generally in neuroinflammatory diseases, and in patients with cancer where it can impede recovery from cancer (Dichter G, 2010; Uher H, 2012; Watanabe et al, 2022; Sharpley el al, 2023).
- ’‘CGI”: Clinical Global Impression.
- “CNS”: Central Nervous System.
- “IR”: Immediate Release of the active ingredient from a composition.
- “ER”: Extended Release of the active ingredient from a composition.
- “GI”: Gastro-Intestinal.
- “AE(s)”: Adverse Effect(s).
- “DSM-5”: Diagnostic and Statistical Manual of Mental Disorders, 5th edition.
- “HAMD": Hamilton Depression Rating Scale.
- “MADRS”: Montgomery and Asberg Depression Rating Scale. - “MDD”: Major Depressive Disorder.
- “MAOls”: Monoamine oxidase inhibitors.
- ’‘NIMH”: National Institute of Mental Health.
- “PD”: Parkinson’s Disease.
- “Persistent depressive disorder”: also called dysthymia.
- “PMDD”: Premenstrual Dysphoric Disorder.
- “5HT3-antagonisf ’: an antagonist of the serotonin receptor subtype-3, in the literature also referred to as a 5HT3 receptor antagonist or a 5HT3 receptor inhibitor.
- “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.
- “Effective dose/unit form of a 5HT3-antagonist” or “effective dose per unit form of a 5HT3- antagonisf an amount of said 5HT3-antagonist per unit form in the range of from 1 pg to 300 mg.
- “NKl-antagonist”: an antagonist of the neurokinin receptor subty pe- 1, in the literature also referred to as NK1 receptor antagonist or NK1 receptor inhibitor.
- “Effective daily dose of NKl-antagonist”: a daily dose of said NKl-antagonist of from 1 pg to 600 mg.
- “Effective dose/unit form of a NKl-antagonist” or “effective dose per unit form of a 5HT3- antagonisf ’: an amount of said NKl-antagonist per unit form in the range of from 1 pg to 600 mg.
- “Pramipexole”: the (S)-6-propylamino-4,5,6,7-tetrahydro-l,3-benzothiazole-2-amine, as active principle including the free base and its pharmaceutically acceptable salts and solvates, unless otherwise specified.
- “Effective daily dose of pramipexole” or “therapeutically effective dose of pramipexole”: a daily pramipexole dose equivalent to at least a pramipexole dihydrochloride monohydrate approved daily dose for the symptomatic treatment of PD, this effective daily dose including low daily doses used during the titration period.
- “Effective dose/unit form” or “effective dose per unit form”, in reference to pramipexole: a pramipexole amount per unit form equivalent to at least a pramipexole dihydrochloride monohydrate amount per unit form approved for the symptomatic treatment of PD, this amount including low amounts per unit form used during the titration period.
- “Pharmaceutically acceptable salt”, with reference to NK1 -antagonists, 5HT3-antagonists or pramipexole, refers to any salt which retains the physiological activity of the corresponding compound and is suitable for administration to a human.
- "Pharmaceutically acceptable solvate”, with reference to 5HT3-antagomsts. NKl-antagonists or pramipexole refers to a pharmaceutically acceptable salt solvated with any suitable solvent, for example, water.
- “SSRIs”: Selective serotonin reuptake inhibitors.
- “NDRIs”: Norepinephrine-dopamine reuptake inhibitors.
- “TCAs”: Tricyclic antidepressants.
- "TTS": Transdermal Therapeutic System.
- “Depressive disorders”: include, but are not limited to, maj or depressive disorder (MDD), persistent depressive disorder (dysthymia), Bipolar depression, seasonal affective disorder (SAD), psychotic depression, premenstrual dysphoric disorder (PDD), peripartum (postpartum) depression, situational depression, and atypical depression. The common feature of these depressive disorders is the presence of sad, empty, or irritable mood, accompanied by somatic and cognitive changes that significantly affect the individual's capacity’ to function. The difference among these disorders are issues of duration, timing or presumed etiology. See Depressive Disorders, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, dsm.psychiatryonline.org/doi/10.1176/appi.books.9780890425596.dsm04.
- “Maximum tolerated dose,” “maximal tolerated dose” or “MTD” refers to, and is defined as the highest dose of a drug or treatment that does not cause unacceptable side effects. For instance, the maximum tolerated dose is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found.
BACKGROUND OF THE INVENTION
Depression is one of the largest contributors to chronic disease burden; it affects more than one in six individuals in the United States. MDD suffers from a vast treatment gap worldwide, and large numbers of individuals who require treatment do not receive adequate care. Dysregulation of brain dopamine (DA) systems are believed to be central in the pathophysiology of MDD leading to new treatment targets focused on DA-modulated microcircuits (reviewed in Bekhbat et al, 2022). Neurodevelopmental factors have also been suggested as a risk for later emergence of MDD, possibly through dopaminergic substrates in the brain (reviewed in Bekhbat M et al, 2022). A picture is emerging where trauma in early infancy (<5years of age) can lead to changes in brain dopaminergic circuitry, that results in chronic anhedonia starting in adolescence (McIntyre personal communication). On this background of chronic anhedonia, relapsing-remitting depression will develop in certain patients. Long COVID and certain forms of cancer have also been implicated in the development of anhedonia (Ceban et al, 2022; Sharpley et al, 2023).
Anhedonia is defined as an inability to feel pleasure; it is a common and core symptom of depression, and it is reported in other neurological disorders such as Parkinson’s disease, PTSD, substance abuse disorder. It is also observed in neuroinflammation, and more generally in neuroinflammatory diseases, and in patients with cancer where it can impede recovery from cancer (Dichter G, 2010; Uher H, 2012; Watanabe et al, 2022; Sharpley et al, 2023).
Anhedonia is considered to be a major contributor to disability in MDD, and it is a particularly difficult symptom to treat. In MDD patients, increasing evidence suggests that current first-line treatment options (e.g., selective serotonin reuptake inhibitors [SSRIs]) do not improve anhedonia (reviewed in Watanabe et al, 2022), and do not adequately address motivational and reward-processing deficits in depression (Treadway MT, Zald DH, 2011).
Safe and effective pharmacotherapy is highly desirable for the treatment of anhedonia (Hbflich A et al, 2019). Only 3 FDA-approved treatments have been suggested to be efficacious in anhedonia, namely, Spravato, Tritellix, and Transcranial Magnetic Stimulation (TMS).
• Spravato (esketamine nasal spray) is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist indicated for treatment-resistant depression (TRD). but safety issues are such that the drug is only available through a restricted program in certain FDA- approved clinical centers (Spravato Package Insert).
• Trintellix (vortioxetine oral tablets) is approved for the treatment of MDD; its MOA is not fully understood, but the drug increases serotonin levels (Trintellix Package Insert). Data from 2 open-label 52-week trials suggest that Trintellix improves anhedonia, but the effect size is modest (Mattingly GW, 2023). Note a suggestion of perinatal pulmonary adverse events with Trintellix.
• TMS was reported to improve anhedonia in a naturalistic trial (Fukuda et al, 2021).
• Pramipexole (Mirapex) is a dopamine receptor agonist with high affinity and selectivity for D3 dopaminergic receptors. It is indicated for the treatment of Parkinson’s disease in doses <4.5 mg/day. In a preliminary open-label study, pramipexole showed possible efficacy in the treatment of anhedonic depression (Ventorp et al., 2022), but this study was only conducted with adjunctive pramipexole (as an add-on with one or more antidepressants) titrated to a maximum dose of 4.5 mg salt/day (which is within the approved dose of pramipexole) and nowhere suggests that higher doses would have been more efficacious. Another study concerned the reversal of stress-induced anhedonia by the dopamine receptor agonist pramipexole (Willner et al., 1994), but that study was done in animals (not humans), and the high doses which were used were possible because rodents do not vomit; also, animal models are usually not predictive of human psychiatric conditions.
SUMMARY OF THE INVENTION
The present invention relates to increasing the therapeutic window for pramipexole, for the treatment of anhedonia, to safely enable its full anti-anhedonic efficacy. In particular, the present invention relates to a combination of pramipexole with a 5HT3 -antagonist and/or an NK1 -antagonist to increase the therapeutic window for pramipexole.
In a double-blind, placebo-controlled, 8-week study described herein, high dose pramipexole (formulated as CTC-501, a fixed dose combination of pramipexole and ondansetron) showed major efficacy on anhedonia, and was well tolerated and safe.
It has been found that ondansetron or a pharmaceutically acceptable salt or solvate thereof, by reducing or even abrogating the dose-limiting GI side effects of high doses of pramipexole, enables the full antidepressant potential of pramipexole.
It has also been found that, by using said 5HT3-antagonist, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, it is possible to safely treat a patient suffering from anhedonia by maintaining a therapeutically effective pramipexole daily dose with minimal adverse effect.
The combination of said 5HT3 -antagonist with pramipexole or a pharmaceutically acceptable salt or solvate thereof enables the full anti-anhedonic efficacy of pramipexole.
For example, in the case of pramipexole dihydrochloride monohydrate, its combination with said 5HT3 -antagonist allows the administration of a therapeutically effective dose of said pramipexole dihydrochloride monohydrate that, in many patients, significantly exceeds the aforementioned maximum recommended dose (4.5 mg/day) of pramipexole dihydrochloride monohydrate for the treatment of the symptoms of PD, thus increasing its efficacy in the treatment of a patient suffering from anhedonia.
More particularly, it has been found that, in patients suffering from anhedonia, 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, offer significant efficacy. Advantageously, in combination with a 5HT3-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 mg to 20 mg of pramipexole dihydrochloride monohydrate provide safe treatment for patients suffering from anhedonia.
Hitherto, notwithstanding the aforementioned literature reporting the possibility of pramipexole anti-anhedonic efficacy, no one suspected that anhedonia could be safely cured by using a pramipexole/5HT3-antagonist combination at the currently used pramipexole daily doses and also at daily doses higher, and even much higher than those recommended for the treatment of PD, and substantially without the inherent pramipexole adverse effects.
Thus, the present invention provides a pharmaceutical combination compnsing
(a) a 5HT3-antagonist; and
(b) pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an effective daily dose, for use for the treatment of anhedonia.
In one aspect, the present invention provides the use of (or a method using) a 5HT3- antagonist for enabling the full anti-anhedonic efficacy of pramipexole in the treatment of anhedonia.
More precisely, according to this aspect, the invention provides a 5HT3-antagonist, for use in the treatment of anhedonia, in combination with an effective daily dose of pramipexole. Said effective pramipexole daily dose may be higher, and even much higher than the maximum daily dose recommended in the treatment of PD.
According to this aspect, the invention also provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a 5HT3 -antagonist, in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof. Said effective daily dose (in pramipexole dihydrochloride monohydrate) can significantly and safely exceed the maximum dose of pramipexole dihydrochloride monohydrate recommended for the symptomatic treatment of PD.
Thus, according to this aspect, the method (or use) provides the safe administration of a 5HT3-antagonist in combination with pramipexole daily doses (in pramipexole dihydrochloride 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 particular, the invention provides a method (or the use of said 5HT3-antagonist) for treating a patient suffering from anhedonia, which comprises treating said patient with said 5HT3-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.
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.
According to this aspect, the invention provides the use of said 5HT3 -antagonist for the preparation of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said 5HT3-antagonist, in 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 anhedonia, and also, principally, for administering said pramipexole to a patent suffering from anhedonia at doses higher, and even much higher than the maximum recommended doses approved for the treatment of PD, thus increasing the pramipexole efficacy in combating anhedonia.
In particular, according to this aspect, the invention provides the use of a 5HT3- antagonist for the preparation of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said 5HT3-antagonist, in admixture with a pharmaceutical carrier or vehicle, for the treatment of anhedonia in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
Preferably, according to this aspect, the invention provides the use of a 5HT3-antagonist for the manufacture of a medicament for the safe treatment of anhedonia, 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 exceed the maximum dose of pramipexole dihydrochloride monohydrate recommended for the symptomatic treatment of Parkinson’s disease. As described above, said daily dose (in pramipexole dihydrochloride monohydrate) 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. According to an embodiment, for said method (or use), said 5HT3 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are each formulated in a pharmaceutical composition in 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 anhedonia. Normally, said compositions are in dosage unit form.
According to another embodiment, for said use or said method, said 5HT3 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are mixed together and formulated in a phannaceutical composition (fixed-dose combination), in admixture with a pharmaceutical carrier or vehicle, to be administered to the patient suffering from anhedonia, in need of said treatment. Normally, said compositions are in dosage unit form.
A 5HT3 -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 that is generally currently indicated for treating PD, or with a higher, and even much higher dose. The use of this combination significantly improves the conditions of patients suffering from anhedonia by concurrently mitigating or even eliminating the pramipexole adverse effects, otherwise intolerable when using said pramipexole alone.
According to the present invention, preferably, said 5HT3 -antagonists used 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 receptor inhibitors, known to block nausea, vomiting, and diarrhea induced by chemotherapeutic drugs, have been shown, in particular when administered at high doses, to also block the gastro-intestinal side effects of pramipexole without affecting its efficacy in treating said anhedonia.
This finding is surprising because, notw ithstanding the gravity of the illnesses and the fact that both said 5HT3-antagonists and pramipexole were two families of products in use during more than a decade, each in its own indication, to date no one thought that, by combining an effective dose of said 5HT3-antagonist with an effective dose of pramipexole, it would be possible to safely improve the conditions of patients suffering from anhedonia, by also allowing an increase of the pramipexole therapeutic dose, in particular the dose of pramipexole dihydrochloride monohydrate.
According to yet a further embodiment, the invention provides a pharmaceutical fixed- dose combination consisting of a pharmaceutical composition comprising an effective dose/unit form of a 5HT3-antagonist and an effective dose/unit form of pramipexole. in admixture with a pharmaceutical carrier or vehicle.
In said combination, a 5HT3 -antagonist is present in said composition in an amount per unit form of from 1 pg to 300 mg; and pramipexole or a pharmaceutically acceptable salt or solvate thereof 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.
The dose per unit form of pramipexole or a pharmaceutically acceptable salt or solvate thereof, in pramipexole dihydrochloride monohydrate, will normally be in a range selected from the group consisting of 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.
Further, it has also been found that an NK1 -antagonist, by reducing or even abrogating the side effects of high doses of pramipexole, enables the full antidepressant potential of pramipexole.
Thus, the safe administration of pramipexole doses that are higher, and even much higher, than the maximum daily dose recommended for the relief of the symptoms of Parkinson’s disease (such as motor symptoms), provides significant improvement to patients suffering from anhedonia.
Alternatively, the safe administration of pramipexole doses that are higher, and even much higher than the maximum tolerated dose for the relief of symptoms of Parkinson's disease (such as motor symptoms), provides significant improvement to patients suffering from anhedonia.
More particularly, it has been found that, in the case of pramipexole-dihydrochloride monohydrate, its combination with said NK1 -antagonist allows the administration of a therapeutic effective dose of said pramipexole dihydrochloride monohydrate that will significantly exceed the maximum recommended dose (4.5 mg/day) of pramipexole dihydrochloride monohydrate for the treatment of the symptoms of PD, thus increasing its efficacy in the treatment of a patient suffering from anhedonia.
More particularly, it has been found that the combination of pramipexole or a pharmaceutically acceptable salt or solvate thereof with a NK1 -antagonist allows the administration of a therapeutic effective dose that may be equivalent to from up to 10 times, from up to 4.7 times, or from 1.1 times to 10 times higher than the aforementioned maximum dose of pramipexole dihydrochloride monohydrate recommended for the treatment of the symptoms of PD.
The combination of a NK1 -antagonist with pramipexole or a pharmaceutically acceptable salt or solvate thereof acts by enabling the full antidepressant efficacy of pramipexole, due to the high pramipexole doses that may be used in combination with said NK1 -antagonist.
It has also been found that, in patients suffering from PD, an NK1 -antagonist prevented the dose-limiting side effects of pramipexole without affecting the efficacy thereof. The results suggest that aprepitant inhibition of the dose-limiting adverse effects of pramipexole allows the safe and tolerable administration of clinically relevant higher doses of pramipexole.
It has been found that, in the treatment of patients suffering from a depressive disorder, the use of a NK1 -antagonist in combination with daily doses of pramipexole or a pharmaceutically acceptable salt or solvate thereof that are equivalent to from more than 4.5 mg to 21 mg/day and even from more than 6 mg to 21 mg or from 15 mg to 21 mg of pramipexole dihydrochloride monohydrate, also offers significant efficacy and a fast onset of action.
It has also been found that, by using said NK1 receptor antagonist in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, it is possible to treat a patient suffering from anhedonia by maintaining an effective pramipexole or a pharmaceutically acceptable salt or solvate thereof daily dose with minimal adverse effect.
Thus, the present invention provides a pharmaceutical combination comprising
(a) a NK1 -antagonist; and
(b) pramipexole or a phamiaceutically acceptable salt or solvate thereof.
In particular, the present invention provides a pharmaceutical combination comprising
(a) a NK1 -antagonist; and
(b) pramipexole or a pharmaceutically acceptable salt or solvate thereof, at a daily dose (in pramipexole dihydrochloride monohydrate) that is higher than the maximum dose of pramipexole dihydrochloride monohydrate recommended for the relief of the motor symptoms of PD, for use for the treatment of anhedonia.
Said pramipexole daily dose in said combination is from up to 10 times, from up to 4.7 times, or from 1.1 times to 10 times higher than the maximum dose of pramipexole dihydrochloride monohydrate recommended for the relief of the motor symptoms of PD.
The present invention further provides the use of a NK1 -antagonist for enabling the full efficacy of pramipexole in the treatment of anhedonia.
Moreover, the invention provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a NK1 -antagonist, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof.
Moreover, the invention provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a NK1 -antagonist, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose (in pramipexole dihydrochloride monohydrate) from up to 10 times, from up to 4.7 times, or from 1. 1 times to 10 times higher than the maximum daily dose recommended for the relief of the symptoms of Parkinson’s disease such as motor symptoms (4.5 mg/day).
The daily dose of the NK1 -antagonist is from 1 pg to 600 mg and the pramipexole daily dose (in pramipexole dihydrochloride monohydrate), depending on the degree of gravity of the illness and the age and condition of the patient and including low doses for use during the titration period, will range from 0.375 mg to 45 mg, normally from 0.375 mg to 21 mg. For treating anhedonia, said daily dose preferably is 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, nonnally from more than 4.5 mg to 21 mg, in particular from more than 6 mg to 21 mg, from 10 mg to 21 mg, from 13 mg to 21 mg or from 15 mg to 21 mg.
According to an embodiment, for said use or said method, said NK1 -antagonist, in an amount per unit form of from 1 pg to 600 mg or from 1 mg to 600 mg, and said pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount equivalent to from 0. 125 mg to 45 mg, from more than 4.5 mg to 21 mg or from more than 6 mg to 21 mg. are each formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle and separately administered, concurrently or sequentially, to a patient in need of treatment with said combination, and in particular to a patient suffering from anhedonia.
According to another embodiment, said NK1 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are mixed together and formulated in a pharmaceutical composition (fixed-dose combination), in admixture with a pharmaceutical carrier, to be administered to a patient in need of said treatment.
According to this embodiment, said NK1 -antagonist, in an amount of from 1 pg to 600 mg or from 1 mg to 600 mg, and said pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount equivalent to from 0.125 mg to 45 mg, preferably 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, from 15 mg to 45 mg, from more than 4.5 mg to 21 mg or from more than 6 mg to 21 mg, from 10 mg to 21 mg, from 13 mg to 21 mg, or from 15 mg to 21 mg of pramipexole dihydrochloride monohydrate, are mixed together and formulated in a pharmaceutical composition (fixed-dose combination), in admixture with a pharmaceutical carrier or vehicle, to be administered to a patient in need of said treatment.
According to the invention, said NK1 -antagonist may also be formulated in a pharmaceutical composition comprising said NK1 -antagonist in an amount per unit form of from 1 pg to 600 mg or from 1 mg to 600 mg, in admixture with a phannaceutical carrier or vehicle, for use for preventing or curing the adverse effects of pramipexole daily doses that for some patients may be higher, and even much higher, than the maximum dose (4.5 mg/day) presently recommended for the relief of the motor symptoms of Parkinson’s disease.
For its use for the treatment of anhedonia, in combination with a NK1 -antagonist, pramipexole is formulated in a pharmaceutical composition in dosage unit form comprising said pramipexole in an amount per IR- or ER-form (including low doses to be used during the titration period) equivalent to from 0. 125 mg to 45 mg, advantageously 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 of pramipexole dihydrochloride monohydrate.
In particular, for said use in combination with a NK1 -antagonist, pramipexole is formulated in a pharmaceutical composition in dosage unit form comprising said pramipexole an amount per IR-form (including low doses to be used during the titration period) equivalent to from 0. 125 mg to 22.5 mg, advantageously from 1.5 mg to 22.5 mg, from more than 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 of pramipexole dihydrochloride monohydrate.
For said use in combination with a NK1 -antagonist, pramipexole, is formulated in a pharmaceutical composition in dosage unit form comprising said pramipexole an amount per ER-form (including low doses to be used during the titration period) equivalent to from 0.375 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, from 10 mg to 45 mg from 13 mg to 45 mg, or from 15 mg to 45 mg of pramipexole dihydrochloride monohydrate.
According to an embodiment, the dose of pramipexole or pharmaceutically acceptable salt or solvate thereof, in pramipexole dihydrochloride monohydrate, per IR- or ER-unit form. will range from 0.125 mg to 21 mg, advantageously from 1.6 mg to 21 mg. from 1.8 mg to 21 mg, from 2.4 mg to 21 mg, from 3 mg to 21 mg, more advantageously from more than 4.5 mg to 21 mg, preferably from more than 6 mg to 21 mg, from 10 mg to 21 mg, from 13 mg to 21 mg, or from 15 mg to 21 mg.
Preferably, according to this embodiment, the dose per unit form of pramipexole or a pharmaceutically acceptable salt or solvate thereof in an ER formulation, including slow- release compositions and transdermal therapeutic systems such as transdermal patches, for the treatment of anhedonia, will range from an amount that is equivalent to from more than 4.5 mg to 21 mg, in particular from 6.0 mg to 21 mg or from more than 6 mg to 21 mg of pramipexole dihydrochloride monohydrate, depending on the tolerability (in combination with said NK1- antagomst).
In the aforementioned combinations with pramipexole, at the above doses/unit form,
- if the NK1 -antagonist is aprepitant, the dose/unit form will range from 10 mg to 250 mg;
- if the NK1 -antagonist is rolapitant. the dose/unit fonn will range from 30 mg to 270 mg.
In one aspect, the disclosure provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a 5HT3-antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, the 5HT3 -antagonist is administered at a daily dose of from 1 pg to 300 mg.
In some embodiments, the 5HT3-antagonist is selected from the group consisting of azasetron or a pharmaceutically acceptable salt or solvate thereof, dolasetron or a pharmaceutically acceptable salt or solvate thereof, granisetron or a pharmaceutically acceptable salt or solvate thereof, ondansetron or a pharmaceutically acceptable salt or solvate thereof, palonosetron or a pharmaceutically acceptable salt or solvate thereof, ramosetron or a pharmaceutically acceptable salt or solvate thereof, and tropisetron or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate.
In some embodiments, said 5HT3 -antagonist is selected from the group consisting of ondansetron or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 2 mg to 32 mg of ondansetron base, and dolasetron or a pharmaceutically acceptable salt or solvate thereof 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 at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said 5HT3-antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are each formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
In some embodiments, 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 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 in an amount per unit fonn equivalent to from 0. 125 mg to 45 mg of pramipexole dihydrochloride monohydrate, in admixture with a phannaceutical carrier or vehicle.
In some embodiments, said 5HT3 -antagonist is selected from the group consisting of ondansetron or 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 or a pharmaceutically acceptable salt or solvate thereof in an amount per unit form equivalent to from 25 mg to 200 mg of dolasetron mesylate; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate. In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate.
In another aspect, the present disclosure provides a 5HT3-antagonist for use in the treatment of anhedonia 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.
In another aspect, the present disclosure provides a use of a 5HT3-antagonist for the preparation of a medicament for the treatment of anhedonia in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, said medicament comprises a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said 5HT3-antagonist in admixture with a pharmaceutical carrier or vehicle, and another pharmaceutical composition in dosage unit form comprising 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.
In some embodiments, said medicament comprises a fixed-dose combination of an effective amount per unit form 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.
In some embodiments, the effective amount per unit form of said 5HT3-antagonist is 1 pg to 300 mg and said effective amount per unit form of said pramipexole or a pharmaceutically acceptable salt or solvate thereof is equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said effective amount per unit form of said 5HT3 -antagonist is 1 pg to 300 mg and said effective amount per unit form of said pramipexole or a pharmaceutically acceptable salt or solvate thereof is equivalent to 0. 125 mg to 45 mg of pramipexole dihydrochloride monohydrate. In another aspect, the present disclosure provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a combination of a 5HT3- antagonist with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof, wherein the combination does not contain any additional active compounds having an antidepressant efficacy.
In another aspect, the present disclosure provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a combination of a 5HT3- antagonist with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof, wherein another active compound with an antidepressant efficacy is not concurrently administered.
In another aspect, the present disclosure provides a 5HT3-antagonist for use in the treatment of anhedonia 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, wherein another active compound with an antidepressant efficacy is not concurrently administered.
In another aspect, the present disclosure provides a fixed dose combination for the treatment of anhedonia in a patient in need thereof, wherein the fixed dose combination contains active ingredients and inactive ingredients, and the active ingredients consist of pramipexole or a pharmaceutically acceptable salt or solvate thereof and a 5HT3 -antagonist.
In another aspect, the present disclosure provides a pharmaceutical composition for the treatment of anhedonia in a patient in need thereof, wherein the pharmaceutical composition contains active ingredients and inactive ingredients, and the active ingredients consist of pramipexole or a pharmaceutically acceptable salt or solvate thereof and a 5HT3-antagonist.
In some embodiments, anhedonia is a symptom of a depressive disorder.
In some embodiments, anhedonia is a symptom of a major depressive disorder.
In some embodiments, the patient does not have a depressive disorder.
In some embodiments, anhedonia is due to or is a symptom of a neuroinflammatory disease.
In some embodiments, anhedonia is associated with a neurodegenerative disorder which is one or more selected from the group consisting of Parkinson’s disease, Alzheimer’s disease, post-traumatic stress disorder, and a substance abuse disorder.
In some embodiments, anhedonia is due to neurodegeneration of dopaminergic nigral neurons. In some embodiments, anhedonia is due to Alzheimer’s disease.
In some embodiments, anhedonia is due to Parkinson’s Disease.
In some embodiments, wherein anhedonia is due to post-traumatic stress disorder.
In some embodiments, anhedonia is due to substance abuse disorder.
In some embodiments, anhedonia is due to a synucleinopathy.
In some embodiments, anhedonia is a symptom of or is associated with one or more selected from the group consisting of bipolar disorder, schizophrenia, schizoaffective disorder, personality disorder, mild cognitive impairment, an autoimmune disorder, rheumatoid arthritis, psoriasis, multiple sclerosis, and anticancer treatment.
In another aspect, the present disclosure provides a method for enabling the use of a dose of pramipexole sufficient for the effective treatment of anhedonia in humans comprising administering a dose of a 5-HT3 antagonist in combination with the dose of pramipexole, wherein the dose of the 5-HT3 antagonist is selected to reduce to tolerable levels the dose limiting adverse effects of the dose of pramipexole.
In another aspect, the present disclosure provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with an NK1 -antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, said NK1 -antagonist is administered at a daily dose of from 1 pg to 600 mg.
In some embodiments, said NK1 -antagonist is selected from the group consisting of aprepitant or a pharmaceutically acceptable salt or solvate thereof, fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, casopitant or a pharmaceutically acceptable salt or solvate thereof, maropitant or a pharmaceutically acceptable salt or solvate thereof, eziopitant or a pharmaceutically acceptable salt or solvate thereof, lanepitant or a pharmaceutically acceptable salt or solvate thereof, netupitant or a pharmaceutically acceptable salt or solvate thereof, orvapitant or a pharmaceutically acceptable salt or solvate thereof, rolapitant or a phamraceutically acceptable salt or solvate thereof, serlopitant or a pharmaceutically acceptable salt or solvate thereof, vestipitant or a pharmaceutically acceptable salt or solvate thereof, vofopitant or a pharmaceutically acceptable salt or solvate thereof, and netupitant-300/palonosetron-0.5.
In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate. In some embodiments, said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof at a daily dose of from 10 mg to 250 mg; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said NK1 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are each formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
In some embodiments, said NK1 -antagonist is formulated in a pharmaceutical composition in dosage unit form comprising said NK1 -antagonist in an amount per unit form of from 1 pg to 600 mg, in admixture with a phannaceutical carrier or vehicle; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is formulated 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 in an amount per unit fonn equivalent to from 0. 125 mg to 45 mg of pramipexole dihydrochloride monohydrate, in admixture with a phannaceutical carrier or vehicle.
In some embodiments, said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof in an amount per unit form equivalent to from 10 mg to 250 mg of aprepitant, or rolapitant or a pharmaceutically acceptable salt or solvate thereof in an amount per unit form equivalent to from 15 mg to 270 mg of rolapitant; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate. In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate.
In another aspect, the present disclosure provides an NK1 -antagonist for use in the treatment of anhedonia in a patient in need of said treatment, in combination with an effective daily dose of pramipexole or a phannaceutically acceptable salt or solvate thereof.
In another aspect, the present disclosure provides a use of an NK1 -antagonist for the preparation of a medicament for the treatment of anhedonia in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, said medicament comprises a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said NK1 -antagonist in admixture with a pharmaceutical carrier or vehicle and another pharmaceutical composition in dosage unit form comprising 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.
In some embodiments, said medicament comprises a fixed-dose combination of an effective amount per unit form of said NK1 -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.
In some embodiments, said effective amount per unit form of said NK1 -antagonist is 1 pg to 600 mg and said effective amount per unit form of said pramipexole or a pharmaceutically acceptable salt or solvate thereof is equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In some embodiments, said effective amount per unit form of said NK1 -antagonist is 1 pg to 600 mg and said effective amount per unit form of said pramipexole or a pharmaceutically acceptable salt or solvate thereof is equivalent to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate.
In another aspect, the present disclosure provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a combination of an NK1 -antagonist with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof, wherein the combination does not contain any additional active compounds having an antidepressant efficacy.
In another aspect, the present disclosure provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with a combination of a NK1 - antagonist with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof, wherein another active compound with an antidepressant efficacy is not concurrently administered.
In another aspect, the present disclosure provides an NK1 -antagonist for use in the treatment of anhedonia 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, wherein another active compound with an antidepressant efficacy is not concurrently administered.
In another aspect, the present disclosure provides a fixed dose combination for the treatment of anhedonia in a patient in need thereof, wherein the fixed dose combination contains active ingredients and inactive ingredients, and the active ingredients consist of pramipexole or a pharmaceutically acceptable salt or solvate thereof and an NK1 -antagonist.
In another aspect, the present disclosure provides a pharmaceutical composition for the treatment of anhedonia in a patient in need thereof, wherein the pharmaceutical composition contains active ingredients and inactive ingredients, and the active ingredients consist of pramipexole or a pharmaceutically acceptable salt or solvate thereof and an NK1 -antagonist.
In some embodiments, anhedonia is a symptom of a depressive disorder.
In some embodiments, anhedonia is a symptom of a major depressive disorder.
In some embodiments, the patient does not have a depressive disorder.
In some embodiments, anhedonia is due to or is a symptom of a neuroinflammatory disease.
In some embodiments, anhedonia is associated with a neurodegenerative disorder which is one or more selected from the group consisting of Parkinson’s disease, Alzheimer’s disease, post-traumatic stress disorder, and a substance abuse disorder.
In some embodiments, anhedonia is due to neurodegeneration of dopaminergic nigral neurons.
In some embodiments, anhedonia is due to Alzheimer’s disease.
In some embodiments, anhedonia is due to Parkinson’s Disease.
In some embodiments, anhedonia is due to post-traumatic stress disorder.
In some embodiments, anhedonia is due to substance abuse disorder. In some embodiments, anhedonia is due to a synucleinopathy.
In some embodiments, anhedonia is a symptom of or is associated with one or more selected from the group consisting of bipolar disorder, schizophrenia, schizoaffective disorder, personality disorder, mild cognitive impairment, an autoimmune disorder, rheumatoid arthritis, psoriasis, multiple sclerosis, and anticancer treatment.
In another aspect, the present disclosure provides a method for enabling the use of a dose of pramipexole sufficient for the effective treatment of anhedonia in humans comprising administering a dose of an NK1 -antagonist in combination with the dose of pramipexole, wherein the dose of the NK1 -antagonist is selected to reduce to tolerable levels the dose limiting adverse effects of the dose of pramipexole.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG 1. Depicts MADRS anhedonia sub-scale analysis. Mean (SMS) results to end of treatment or week 8 of the study are shown
FIG. 2. Depicts CGI-S analysis at week 6 of the study with CTC-003.
DETAILED DESCRIPTION
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 of the chemotherapy-induced nausea and vomiting, for use for the treatment of anhedonia in combination with pramipexole; and to the use of a pharmaceutical combination comprising said 5HT3 -antagonist and/or an NK1- antagonist and pramipexole, for the preparation of a medicament for treatment of anhedonia comprising an effective dose per unit form of pramipexole. Said effective dose may be higher, and even much higher than the pramipexole maximum daily dose recommended in the treatment of PD.
More particularly, the invention concerns, according to its aspects:
- A method for the treatment of anhedonia in a patient in need of said treatment, which comprises administering to said patient a 5HT3-antagonist in combination with a therapeutically effective pramipexole daily dose.
- A 5HT3 -antagonist for use for the treatment of anhedonia in a patient in need of said treatment, in combination with a therapeutically effective daily dose of pramipexole.
- The use of a 5HT3 -antagonist for the manufacture of a medicament for the treatment of anhedonia in a patient in need of said treatment, in combination with a therapeutically effective daily dose of pramipexole, which can be higher that the currently approved dose.
- The use of a 5HT3-antagonist for the manufacture of a medicament for the treatment of anhedonia in a patient in need of said treatment, in combination with a therapeutically effective daily dose of pramipexole, which can be higher that the currently approved dose.
- The use of said 5HT3 -antagonist for the preparation of a medicament for the treatment of anhedonia in a fixed-dose combination consisting of a pharmaceutical composition comprising said 5HT3-antagonist and said pramipexole.
- A method for the treatment of anhedonia in a patient in need of said treatment, which comprises administering to said patient an NK1 -antagonist in combination with a therapeutically effective pramipexole daily dose.
- An NK1 -antagonist for use for the treatment of anhedonia in a patient in need of said treatment, in combination with a therapeutically effective daily dose of pramipexole.
- The use of an NK1 -antagonist for the manufacture of a medicament for the treatment of anhedonia in a patient in need of said treatment, in combination with a therapeutically effective daily dose of pramipexole, which can be higher that the currently approved dose.
- The use of said NK1 -antagonist for the preparation of a medicament for the treatment of anhedonia in a fixed-dose combination consisting of a pharmaceutical composition comprising said NK1 -antagonist and said pramipexole.
Anhedonia
Anhedonia is defined as an inability to feel pleasure; it is a common and core symptom of depression, and it is reported in other neurological disorders such as Parkinson’s disease, PTSD, and substance abuse disorder. It is also observed in neuroinflammation, and more generally in neuroinflammatory diseases, and in patients with cancer where it can impede recovery from cancer (Dichter G, 2010; Uher H, 2012; Watanabe et al, 2022; Sharpley et al, 2023).
Disorders commonly associated with anhedonia:
• Depression.
• Schizophrenia.
• Bipolar disorder.
• Substance use disorder.
• Parkinson's disease.
• Post-traumatic stress disorder. • Traumatic brain injury.
Anhedonia is a symptom that is commonly associated with various mental health disorders. It refers to the inability to experience pleasure or interest in activities that were once enjoyable. Some of the primary mental health conditions linked to anhedonia include:
1. Major Depressive Disorder (MDD): Anhedonia is a key symptom of major depression. Individuals with MDD often experience a persistent lack of interest or pleasure in activities they used to enjoy.
2. Bipolar Disorder: Both the depressive and manic phases of bipolar disorder can involve symptoms of anhedonia. During depressive episodes, individuals may experience a profound lack of interest, pleasure, and motivation.
3. Schizophrenia: Anhedonia is commonly observed in individuals with schizophrenia, a severe mental disorder characterized by distorted thinking, emotions, and perceptions.
4. Post-Traumatic Stress Disorder (PTSD): Anhedonia can be a symptom of PTSD, especially when it is associated with a loss of interest in activities or social interactions.
5. Schizoaffective Disorder: This disorder combines features of schizophrenia and mood disorders, and anhedonia is often present during depressive or psychotic episodes.
6. Substance Use Disorders: Anhedonia can be a consequence of substance abuse or withdrawal from certain substances.
7. Personality Disorders: Anhedonia can be a feature of certain personality’ disorders, such as schizoid personality disorder.
8. Chronic Medical Conditions: Some chronic medical conditions, such as Parkinson's disease, Alzheimer’s disease, mild cognitive impairment, certain autoimmune disorders including rheumatoid arthritis, psoriasis, multiple sclerosis, and certain anticancer treatments, can be associated with anhedonia.
It is important to note that anhedonia is a complex symptom and can manifest in various ways across different individuals and conditions. Additionally, it can be a symptom of other underly ing medical or neurological issues. If someone is experiencing symptoms of anhedonia or other mental health concerns, it is crucial for them to seek professional help for a proper diagnosis and treatment.
5HT3-antagonists
Any of the 5HT3 -antagonists, especially those shown 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 that is generally currently used for treating PD, or with a higher and even much higher dose.
The chronic use of this combination improves the condition of a patient suffering from anhedonia, by concurrently mitigating or even eliminating the adverse effects induced by said pramipexole.
According to the present invention, preferably, said 5HT3 -antagonists used are those approved for preventing nausea and vomiting following cancer chemotherapy.
A useful 5HT3-antagonist is selected from the group consisting of 5-methyl-2-[(4- methyl-lH-imidazol-5-yl)methyl]-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one (alosetron) or a pharmaceutically acceptable salt or solvate thereof, especially its hydrochloride, disclosed in US 5,360,800; (±)-6-chloro,3,4-dihydro-4-methyl-3-oxo-N-(quinuclidinyl)-27f-l,4- benzoxazine-8-carboxamide (azasetron) or a pharmaceutically acceptable salt or solvate thereof, especially its hydrochloride, disclosed in US 4,892,872; [(lS,57?)-8-methyl-8- azabicyclo[3.2.1]octan-3-yl] 3,5-dichlorobenzoate (bemesetron, CAS: 40796-97-2); (107?)-10- [(2-methyl- 17/-i mi dazol - 1 -y l)methy 1] -5.6.9.10-tetrahy dro-4H-pyrido(3 ,2, 1 -y'Zr)carbazol - 11 - one (cilansetron) or a pharmaceutically acceptable salt or solvate thereof, especially its hydrochloride monohydrate, disclosed in US 4,939,136; (37?)-10-oxo-8- azatricyclo[5.3.1.03 8]undec-5-yl I H-indole-3-carboxylate (dolasetron) or a pharmaceutically acceptable salt or solvate thereof, especially its monomethanesulfonate monohydrate, disclosed in US 4,906755; (+)-(7?)-8.9-dihydro-10-methyl-7-[(5-methylimidazol-4- yl)methyl]pyrido[l ,2-a]indol-6(77/)-one (fabesetron) or a pharmaceutically acceptable salt or solvate thereof, especially its hydrochloride or maleate, disclosed in US 5,141,945; 1-methyl- A-((lA,3r,5S)-9-methyl-9-azabicyclo[3.3. l]nonan-3-yl)-127-indazole-3-carboxamide (granisetron)or a pharmaceutically acceptable salt or solvate thereof, especially its hydrochloride, disclosed in US 4,886,808;2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2. l]oct-3- yl)-2-oxo-177-benzimidazole-l -carboxamide (itasetron)or a pharmaceutically acceptable salt or solvate thereof, especially its hydrochloride, disclosed in US 5,223,511; l-phenylmethyl-2- ( I -piperazinyl)- IT/-benzimidazole (lerisetron) or a pharmaceutically acceptable salt or solvate thereof, specially its hydrochloride, disclosed in US 5,256,665 and. in a transdennal preparation, in US 6,136,807; 6-fluoro-5-methyl-2-[(5-methyl-17f-imidazol-4-yl)methyl]- 2,3,4,5-tetrahydro-177-pyrido[4,3-b]indol-l-one (lurosetron, CAS 128486-54-4) or a pharmaceutically acceptable salt or solvate thereof, especially its mesylate (GR 87445 N); (±) l .2.3.9-lelrahydro-9-methyl-3-|(2-methyl-l 7/-imidazol-l -yl)melhyl |-47/-carbazol-4-one (ondansetron) or a pharmaceutically acceptable salt or solvate thereof, especially its hydrochloride dihydrate, disclosed in US 4,695578; (3aS)-2-[(S)-l-azabicyclo [2.2.2]oct-3-yl]- 2,3,3a,4,5,6-hexahydro-l-oxo-l//-benz[<7e]isoquinolme (palonosetron) or a pharmaceutically acceptable salt or solvate thereof, especially its hydrochloride, disclosed in US 5,202,333; 1- methylindol-3-yl)-[(52?)-4,5,6,7-tetrahydro-377-benzimidazol-5-yl]methanone (ramosetron) or a pharmaceutically acceptable salt or solvate thereof, especially its fumarate, disclosed in US 5,344,927; ewdo-jV-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3.3-dimethyl-indole- 1 -carboxamide (3.3-dimethyl-N- laH.5a//-tropan-3a-yl- l -indolinecarboxamide. ricasetron, CAS 117086-68-7) or a pharmaceutically acceptable salt or solvate thereof, especially its hydrochloride; the (3-ew<7o)-8-methyl-8-azabicyclo[3.2. l]oct-3-yl ester of l/f-indole-3- carboxylic acid (3-tropanylindole-3-carboxylate, tropisetron) or a pharmaceutically acceptable salt or solvate 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) or a pharmaceutically acceptable salt or solvate thereof, especially its maleate, disclosed in US 5,563,148; the disclosures of all the US patents cited in this paragraph being incorporated herein in their entirety by reference.
Advantageously, said 5HT3 -antagonist is selected from the group consisting of azasetron or a pharmaceutically acceptable salt or solvate thereof, dolasetron or a pharmaceutically acceptable salt or solvate thereof, granisetron and or a pharmaceutically acceptable salt or solvate thereof, ondansetron or a phannaceutically acceptable salt or solvate thereof, palonosetron or a pharmaceutically acceptable salt or solvate thereof, ramosetron or a pharmaceutically acceptable salt or solvate thereof and tropisetron or a pharmaceutically acceptable salt or solvate thereof.
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, 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.
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 12.5mg/0.625ml 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 0.28mg/5mL injection and 0.56 mg capsule and in 0.075mg/1.5ml or 0.25mg/5ml (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 2.256mg/2ml vials for intravenous injection, and in 5.64-mg vials for intravenous or subcutaneous injection; are particularly advantageous 5HT3-antagomsts.
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, in 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 anhedonia.
Thus, for example, an oral phannaceutical composition according to the present invention to be chronically administered in combination with pramipexole may comprise a 5HT3-antagonist selected from the group consisting of azasetron or a pharmaceutically acceptable salt or solvate 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 or a pharmaceutically acceptable salt or solvate 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 or a pharmaceutically acceptable salt or solvate 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 or a pharmaceutically acceptable salt or solvate 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 or a pharmaceutically acceptable salt or solvate 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 or a pharmaceutically acceptable salt or solvate 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.
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 0.25 mg 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.
This composition is destined to be administered to a patient suffering from anhedonia, 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.
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.
The pharmaceutical composition in dosage unit form comprising said 5HT3-antagonist as described above may contain another active ingredient, in particular pramipexole, coformulated with said 5HT3-antagonist, in admixture with a pharmaceutical carrier or vehicle in a fixed-dose combination.
NKl-antagonists
Any of the NKl-antagonists disclosed in the literature may be a useful adverse effect inhibitor of pramipexole and may be safely used in combination with a dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof that is equivalent to from 1.1 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone. Such a dose includes, but is not limited to a dose from 1.1 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone, a dose from 1.5 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone, a dose from 2.5 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone, a dose from 3 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone, a dose from 4 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone, and a dose from 6 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone.
Advantageously, said NK1 -antagonist is selected from the group consisting of
- 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, and 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 disclosure is incorporated herein in its entirety7 by reference);
- [3-{[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4-
11 uorophenyl)morpholin-4-yl] methyl} -5-oxo-2H- 1 ,2,4-triazol-l -yl]phosphonic acid(fosaprepitant). disclosed, for example as meglumine salt in US 5,691,336 and as di(cyclohexylamine) salt in US 2016/355533, the disclosures 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 disclosure of which incorporated 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 its entirety by reference;
- (2S,3S)-2-Diphenylmethyl-3-[(5-isopropyl-2-methoxybenzyl)amino]quinuclidine (eziopitant), disclosed by Evangelista S (2001). " Eziopitant. Pfizer"; Current Opinion in Investigational Drugs: 2 (10): 1441-3; reviewed in Drugs : the Investigational Drugs Journal 6 (8 ): 758-72;
- (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- 1 -y Ipiperidin- 1 -y l)acetamide (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 6,719,996 and US 6,593,472, 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”,l described in US 8,951.969. the disclosures of which are incorporated herein in their entirety by reference;
- {4-[5-{2-[3,5-bis(trifluoromethyl)phenyl]-A,2-dimethylpropanamido}-4-(2- methylphenyl)py ridin-2-yl] - 1 -methy Ipiperazin- 1 -ium- 1 -yl } methyl hydrogen phosphate
(INN: fosnetupitant). described in WO 2013/082102 and. in a pure crystalline fonn, in US 2017/0096442, available in an injectable composition, comprising 235 mg of fosnetupitant and palonosetron hydrochloride in an amount equivalent to 0.25 mg of palonosetron base (Akynzeo® for injection), herein below referred to as “netupitant-235palonosetron-0.25”, the disclosures 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 maleate (orvepitant), described in US 7,652,012 and US 8,309,553, the disclosures 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 disclosures 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 disclosures of which are incorporated herein in their entirety by reference;
- 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-l- carboxylic acid [l-(R)-(3,5-bis- trifluoromethyl-phenyl)-ethyl]-methyl-amide (vestipitant), described in WO 2001/25219 and, in intravenous formulation having a reduced tendency to cause hemolysis, in WO 2012/175434. the disclosure of which is incorporated herein in their entirety by reference; and
- (2S,3S)-N-[(2-methoxy-5-[5-(trifluoromethyl)tetrazol-l-yl]phenylmethyl]-2- phenylpiperidin-3-amine (GR2015171, vofopitant), described in US 5,703,240 (see also US 8,093,268) and also disclosed by Gardner CJ et al. RegulPept. 1996 Aug 27;65( l):45-53, the disclosures of which are incorporated herein in their entirety by reference; and pharmaceutically acceptable salts of each of said NKl-antagonists.
Illustrative examples of pharmaceutically acceptable salts of basic advantageous NKl- 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.
Illustrative examples of pharmaceutically acceptable salts of acidic NKl-antagonists such as fosaprepitant include salts wi th 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 is incorporated herein in its entirety by reference. An advantageous NK1 -antagonists to be used in combination with 6-propylamino- 4,5,6,7-tetrahydro-l,3-benzothiazole-2-amine is selected from the group consisting of
- aprepitant or a pharmaceutically acceptable salt or solvate thereof,
- fosaprepitant or a pharmaceutically acceptable salt or solvate thereof,
- casopitant or a phannaceutically acceptable salt or solvate thereof,
- maropitant or a pharmaceutically acceptable salt or solvate thereof,
- eziopitant or a pharmaceutically acceptable salt or solvate thereof,
- lanepitant or a pharmaceutically acceptable salt or solvate thereof,
- netupitant or a pharmaceutically acceptable salt or solvate thereof,
- orvapitant or a pharmaceutically acceptable salt or solvate thereof,
- rolapitant or a pharmaceutically acceptable salt or solvate thereof,
- serlopitant or a pharmaceutically acceptable salt or solvate thereof,
- vestipitant or a pharmaceutically acceptable salt or solvate thereof,
- vofopitant or a pharmaceutically acceptable salt or solvate thereof, and
- netupitant-300/palonosetron-0.5.
Aprepitant, fosaprepitant meglumine, fosaprepitant di(cyclohexylamine), rolapitant, rolapitant hydrochloride and netupitant-300/palonosetron-0.5 are particularly advantageous NK1 -antagonists.
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. In particular, aprepitant is commercially available (Emend®) in capsules containing 40 mg, 80 mg, or 125 mg aprepitant or, as fosaprepitant dimeglumine (Emend® Injection), in vials containing 115 mg or 150 mg fosaprepitant; rolapitant is available (Varubi*) in 90-mg tablets; and netupitant is available (Akynzeo®) in a fixed-dose combination in capsules containing 300 mg of netupitant and 0.5 mg of the 5HT3 -antagonist palonosetron (as hydrochloride), herein below referred to as “netupitant300mg/palonosetron0.5 mg'’. Each of these preparations is a particularly advantageous NK1 -antagonist for the combination with pramipexole or pharmaceutically acceptable salts and solvates thereof according to the present invention.
In the aforementioned method, use and combination, including fixed-dose combinations, said NKl-antagonst is present in an amount per unit form and is 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.
More particularly, in said combination, said NK1 -antagonist is selected from the group consisting of aprepitant or a phannaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; rolapitant or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 15 mg to 270 mg of rolapitant; netupitant or a pharmaceutically acceptable salt or solvate thereof, at a daily dose equivalent to from 300 mg to 600 mg of netupitant; and netupitant-300/palonosetron-0.5.
Preferably, for said use in the treatment of anhedonia, said NK1 -antagonist is aprepitant at a daily oral dose of from 10 mg to 250 mg; rolapitant, at a daily oral dose of from 30 mg to 270 mg or netupitant300mg/palonosetron 0.5mg, orally administered once a day, each in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from up to 10 times, from up to 4.7 times, or from 1 .1 times to 10 times higher than the maximum recommended dose for the treatment of the motor symptoms of Parkinson’s disease.
Preferably, for said use in the treatment of anhedonia, said NK1 -antagonist is aprepitant at a daily oral dose of from 10 mg to 250 mg; rolapitant, at a daily oral dose of from 30 mg to 270 mg or netupitant300mg/palonosetron 0.5mg, orally administered once a day, each in combination with pramipexole or a phannaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 1.1 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone. Such a daily dose includes, but is not limited to a dose from 1.1 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone, a dose from 1.5 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone, a dose from 2.5 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone, a dose from 3 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone, a dose from 4 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone, and a dose from 6 to 10 times higher than the maximal tolerated dose of pramipexole for the treatment of anhedonia when administered alone.
For its administration to a patient suffering from anhedonia, in combination with pramipexole, each of the above NK1 -antagonists is formulated in a phannaceutical composition in dosage unit form comprising, as an active ingredient, said NK1 -antagonist, in admixture with a pharmaceutical carrier or vehicle.
In particular, said NKl-antagonist active ingredient of said pharmaceutical composition is selected from the group consisting of aprepitant or a pharmaceutically acceptable salt or solvate thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; rolapitant or a pharmaceutically acceptable salt or solvate 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 of netupitant; and netupitant- 300/palonosetron-0.5.
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.
As set forth above, by using a NKl-antagonist in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, it is possible to treat a patient suffering from anhedonia by maintaining an effective pramipexole or a pharmaceutically acceptable salt or solvate thereof daily dose with minimal adverse effect.
Thus, in order to assure a sure, safe and concurrent administration of said NKl- antagonist and said pramipexole, 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 NKl-antagonist and an effective amount per unit form of pramipexole, in admixture with a pharmaceutical carrier or vehicle.
These NKl-antagonist/pramipexole fixed-dose combinations are described in below.
Pramipexole
In the combination of the present invention, the beneficial action of the 5HT3- antagonist or an NKl-antagonist, counteracting the adverse effects of pramipexole in patients suffering from anhedonia, allows for the safe administration of pramipexole daily doses otherwise not tolerable in most of said patients even within the currently approved dose-range (from 0.375 mg to 4.5 mg per day) of pramipexole dihydrochloride monohydrate.
In high doses, as enabled by the co-administration of 5HT3-antagonists or by NK1- antagonists, pramipexole has additional anti-inflammatory properties. It is indicated for the treatment of Parkinson’s disease in doses <4.5 mg/day. In a preliminary open-label study. pramipexole showed possible efficacy in the treatment of anhedonic depression (Ventorp et al., 2022).
A 5HT3-antagonist or an NK1 -antagonist, 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 a pharmaceutically acceptable salt or solvate 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.
Pharmaceutically acceptable salts of pramipexole are those with inorganic or organic acids 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- hydroxyethanesulfonic (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.
For its administration in combination with a 5HT3-antagonist or an NK1 -antagonist, pramipexole or a pharmaceutically acceptable salt or solvate thereof is formulated in a pharmaceutical composition in dosage unit form comprising an effective dose per unit form of said pramipexole or a pharmaceutically acceptable salt or solvate thereof or solvate, as an active ingredient, in admixture with a pharmaceutical carrier or vehicle. Said active ingredient is formulated according to known technologies for any administration route.
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 for the treatment of anhedonia. The contents of these documents are incorporated herein in their entirety by reference.
In pharmaceutical compositions with a 5HT3-antagonist or an NK1 -antagonist, the dose per unit form of pramipexole or a 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.
The dose of pramipexole or a 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 safeh' and tolerability (in combination with the 5HT3 -antagonist and/or NK1 -antagonist).
The dose per unit form of pramipexole or a 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 an NK1 -antagonist).
As set forth in the Definitions, the above pramipexole doses per unit form 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 anhedonia.
If said 5HT3 -antagonist is ondansetron, the dose per unit form (in ondansetron base) will range from 8 mg to 32 mg.
If said 5HT3-antagonist is dolasetron, the dose per unit form (in dolasetron mesylate) in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, at the above doses/unit form, will range from 1.5 mg to 200 mg. If said NK1 -antagonist is netupitant, in an amount per unit form of from 100 mg to 600 mg, the above pharmaceutical composition may also comprise, as a second active ingredient, palonosetron or a pharmaceutically acceptable salt or solvate thereof. Palonosetron may be in an amount per unit form equivalent to from 0.1 mg to 0.5 mg of palonosetron base.
Compositions containing a 5HT3-antagonist and pramipexole and their use
As mentioned above, the present invention provides a pharmaceutical composition comprising
(a) said 5HT3 -antagonist, and
(b) said pramipexole or a phannaceutically acceptable salt or solvate thereof, at an effective daily dose. for use for the treatment of anhedonia.
According to this aspect, the embodiments of the present invention include a 5HT3-antagonist, for use for the treatment of anhedonia in a patient in need of said treatment in combination with an effective daily dose of pramipexole or of a phannaceutically acceptable salt or solvate thereof; and a method for treating a patient suffering from anhedonia, which comprises administering to a patient in need of said treatment a 5HT3 -antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
In particular, the present invention provides a method for treating a patient suffering from anhedonia, which comprises treating said patient with an effective dose of a 5HT3- antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
Nonnally, said 5HT3-antagonist is 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.
As known in the art, in the case of the treatment of patients with drugs potentially inducing severe adverse effects, pramipexole may be used at the lowest doses (daily from 0.375 mg to less than 3 mg or to less than 4.5 mg), in combination with a 5HT3-antagonist, but another advantage provided by the present invention is an increase in the safe titration threshold dose, due to the concomitant presence of said 5HT3-antagonist.
In addition, according to the present invention, the concomitant administration of a 5HT3-antagonist allows for the administration of pramipexole daily doses much higher than the pramipexole dihydrochloride monohydrate maximum daily dose recommended in the treatment of PD.
A 5HT3 -antagonist indicated for the prevention of post-operative nausea and vomiting or of chemotherapy-induced nausea and vomiting may be successfully used in combination with pramipexole according to the present invention.
In this case, in carrying out the method (or according to the use) of the present invention, the daily dose of these 5HT3-antagonists is 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.
Nonnally, in the method (or use) for the treatment of anhedonia according to the present invention, pramipexole or a 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.
According to a particular embodiment, in said method (or use), said pramipexole or pharmaceutically acceptable salt or solvate 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 a pharmaceutically acceptable salt or solvate thereof is administered to said patient in combination with said 5HT3-antagonist, administered by any administration route.
Preferably, in the method (or use) for treating anhedonia 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 or solvate 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, 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.
Normally, in said method (or use), said 5HT3 -antagonist is ondansetron or a pharmaceutically acceptable salt or solvate 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 dihydrochloride monohydrate) of from 1.5 mg to 20 mg, advantageously from 3 mg to 20 mg, preferably from 5 mg to 20 mg.
For their administration for the treatment of anhedonia, said pramipexole or a pharmaceutically acceptable salt or solvate thereof and said 5HT3-antagonist are each formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle. 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 in admixture with a pharmaceutical carrier or vehicle; and, respectively, said pramipexole or a pharmaceutically acceptable salt or solvate thereof is also formulated 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 in admixture with a pharmaceutical carrier or vehicle.
More particularly, 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.
Preferably, in said combination said 5HT3-antagonist in said composition is selected from the group consisting of ondansetron or 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 or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from from 25 mg to 200 mg of dolasetron mesylate.
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.
The pharmaceutical compositions thus obtained are concurrently or sequentially administered to a patient suffering from anhedonia.
Said pramipexole or a pharmaceutically acceptable salt or solvate thereof and said 5HT3-antagonist may also be formulated together in a fixed-dose combination consisting of a pharmaceutical composition comprising said pramipexole or a pharmaceutically acceptable salt or solvate thereof and said 5HT3-antagonist, in admixture with a pharmaceutical carrier or vehicle.
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, 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.
The fixed-dose combinations assure the safe, concurrent administration of pramipexole or a pharmaceutically acceptable salt or solvate thereof and of the 5HT3 -antagonist.
As set forth above, when using a 5HT3 -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 5HT3 -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.
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.
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, nonnally from 4 mg to 32 mg. 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.
If said pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate, the dose-range per oral IR-unit form, depending on safety and tolerability (in combination with the 5HT3-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.
In an ER formulation, including slow-release compositions and transdermal therapeutic systems such as transdermal patches, said pramipexole or a pharmaceutically acceptable salt or solvate thereof 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).
If the 5HT3 -antagonist is ondansetron or a pharmaceutically acceptable salt or solvate thereof, the dose/ER-unit form (in ondansetron) will range from 8 mg to 32 mg.
If the 5HT3-antagonist is dolasetron or a pharmaceutically acceptable salt or solvate thereof, the dose/unit form (in dolasetron mesylate) in combination with pramipexole, at the above doses/unit form, will range from 1.5 mg to 200 mg.
Preparation of a medicament containing a 5HT3-antagonist and pramipexole
Another aspect of the present invention provides the use of said 5HT3-antagonist for the preparation of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said 5HT3-antagonist, in admixture with a pharmaceutical carrier or vehicle, for the treatment of anhedonia in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
A first embodiment of this aspect of the invention provides the use of said 5HT3- antagonist for the preparation of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said 5HT3-antagonist, in admixture with a pharmaceutical carrier or vehicle, for the treatment of anhedonia 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.
Said pramipexole daily doses may be much higher than the pramipexole dihydrochloride monohydrate maximum daily dose recommended for the treatment of symptoms of PD.
A second embodiment of this aspect provides the use of said 5HT3 -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 -antagonist, in admixture with a pharmaceutical carrier, for the treatment of anhedonia in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof in doses, in pramipexole dihydrochloride monohydrate, at least as high as a dose approved for the symptomatic treatment of PD.
In particular, the 5HT3-antagonist is formulated in a pharmaceutical composition comprising said 5HT3 -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, in admixture with a pharmaceutical carrier or vehicle.
A preferred 5HT3-antagonist in said pharmaceutical composition, for its indication for the treatment of anhedonia in combination with said pramipexole, is selected from the group consisting of azasetron or a pharmaceutically acceptable salt or solvate thereof, in particular its hydrochloride, in an amount/unit form equivalent to from 5 mg to 10 mg of azasetron hydrochloride; dolasetron or a pharmaceutically acceptable salt or solvate thereof, in particular its mesylate monohydrate, in an amount/unit form equivalent to from 20 mg to 200 mg of dolasetron mesylate; granisetron or a pharmaceutically acceptable salt or solvate thereof, in particular its hydrochloride, in an amount/unit form 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 form equivalent to from 2 mg to 32 mg, normally from 2 mg to 16 mg of ondansetron base; palonosetron or a pharmaceutically acceptable salt or solvate 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 or a pharmaceutically acceptable salt or solvate thereof, in particular its hydrochloride, in an amount/unit form equivalent to from 2.5 pg to 100 pg of ramosetron hydrochloride; and tropisetron or a pharmaceutically acceptable salt or solvate thereof, in particular its hydrochloride, in an amount/unit form equivalent to from 2.5 mg to 5 mg tropisetron base.
Methods for treating anhedonia with compositions comprising pramipexole and a 5HT3-antagonist
In another aspect, the present invention provides methods of treatment of anhedonia with compositions comprising pramipexole and a 5HT3-antagonist.
A 5HT3 -antagonist in a pharmaceutical composition comprising a 5HT3-antagonist in admixture with a pharmaceutical carrier or vehicle, is administered, concurrently or sequentially, in combination with pramipexole, also in a pharmaceutical composition, in admixture with a pharmaceutical carrier or vehicle, for the treatment of anhedonia in a patient in need of said treatment. Said pharmaceutical compositions and the daily doses are illustrated above, in “The pramipexole” section.
These pharmaceutical compositions for the first time allow the use of pramipexole high doses for a substantial and efficacious treatment of a patient suffering from anhedonia. In fact, a pharmaceutical composition as described according to this aspect of the invention allows for the safe treatment of a patient suffering from anhedonia. 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 alleviating and even resolving the anhedonic state 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.
In the treatment of anhedonia, the 5HT3-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 and 6-propylamino-4,5,6,7-tetrahydro-1.3-benzothiazole-2- amine, together in admixture with a pharmaceutically acceptable carrier or vehicle.
The 5HT3-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, or transdermal device.
In the case of separate (concurrent or sequential) administration of said 5HT3- 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-antagonist, in admixture with a phamiaceutical carrier or vehicle, in a container; and said pramipexole, in admixture with a pharmaceutical carrier or vehicle, in another, separate container. In the case of a concurrent administration, as also set forth above, said 5HT3-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-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.
A third embodiment of this aspect of the invention provides the use of said 5HT3- antagonist for the preparation of a medicament for the treatment of anhedonia, said medicament being a fixed-dose combination consisting of a pharmaceutical composition comprising, as an active ingredient, said 5HT3-antagonist and, as a second active ingredient, pramipexole or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutical carrier or vehicle.
According to this embodiment of this aspect of the invention, said fixed-dose combination consists of a phamiaceutical composition comprising
(a) said 5HT3 -antagonist; and
(b) 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 form approved for the treatment of PD, in admixture with a pharmaceutical carrier or vehicle, for use for the treatment of anhedonia.
Advantageously, according to this third embodiment of this aspect of the invention, said fixed-dose combination consists of a pharmaceutical composition in dosage unit form comprising
(a) said 5HT3-antagonist, in an amount/unit form at least at least as high as an amount/unit form approved for the prevention of chemotherapy-induced nausea and vomiting; and
(b) 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 approved for the treatment of PD, in admixture with a pharmaceutical carrier or vehicle, for the treatment of anhedonia.
In general, in the above pharmaceutical composition said 5HT3-antagonist is present in an amount of from 1 pg to 300 mg and said pramipexole is present in an amount of from 0. 125 mg to 45 mg.
If the 5HT3 -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. Said 5HT3-antagonists and their amounts per unit form in pharmaceutical compositions for use in the treatment of anhedonia are illustrated in the “The 5HT3-antagonsf ’ section.
In these 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.
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.
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.
An advantageous fixed-dose combination consists of a pharmaceutically composition in dosage unit form comprising
(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 its hydrochloride, 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 phannaceutically 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; and (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, in admixture with a pharmaceutical carrier or vehicle.
According to an embodiment, said advantageous composition comprises, as active ingredients,
(a) 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; and
(b) pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount (in pramipexole dihydrochloride monohydrate) of from 0.125 mg to 45 mg, in admixture with a pharmaceutical carrier or vehicle..
Said advantageous composition preferably comprises pramipexole or a pharmaceutically acceptable salt or solvate 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.
A 5HT3-antagonist/pramipexole fixed-dose combination, normally for use in the treatment of anhedonia, 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; 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 in admixture with a pharmaceutical carrier or vehicle.
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 anhedonia.
For the intended use in the treatment of anhedonia in combination with pramipexole, the 5HT3 -antagonist is formulated in a pharmaceutical composition, wherein said 5HT3- antagonist is in admixture with a pharmaceutical carrier or vehicle. 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 phannaceutically acceptable salt or solvate 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 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. If the 5HT3-antagonist is ondansetron hydrochlonde dihydrate, said dosage (single dose) ranges from 4 mg to 16 mg (in ondansetron base): and, if the pramipexole or a pharmaceutically acceptable salt or solvate 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 may7 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 fonnulations 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 atached 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 descnbed in US 8,915,879, a portable infusion drug delivery7 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 transdennal 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 the at least one surface of the support layer as described in US 8.877,235, a patch using a monoglycende 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 entirety7. Preferably, the transdermal drug deliver}7 system is a patch, a patch pump, an infusion pump, or a micropump.
Compositions containing an NKl-antagonist and pramipexole and their use
According to another aspect, the invention provides a NKl -antagonist for use in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof for the treatment of anhedonia in a patient in need of said treatment.
In particular, this aspect of the present invention provides
(a) a NKl-antagonist, in combination with
(b) pramipexole or a pharmaceutically acceptable salt or solvate thereof, at a dose level (in pramipexole dihydrochloride monohydrate) that is from up to 10 times, from up to 4.7 times, or from 1.1 times to 10 times higher than the maximum pramipexole dihydrochloride monohydrate daily dose recommended for the relief of the symptoms of Parkinson's disease (such as motor symptoms), for use for the treatment of anhedonia in a patient.
Any of the NK1 -antagonists described herein may be used, normally in a dosage unit form, according to this aspect of the invention.
In particular, this aspect of the present invention provides a NK1 -antagonist, in an amount per unit form of from 1 pg to 600 mg. normally from 1 mg to 600 mg or from 1 mg to 300 mg, for use in combination with a daily dose of said pramipexole or a pharmaceutically acceptable salt or solvate thereof (including low doses used in the titration period) equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate, for the treatment of anhedonia in a patient in need of said treatment.
For the use according to this aspect of present invention, the daily dose of said NK1- antagonist is at least as high as that for preventing or treating nausea and vomiting in patients undergoing a surgical operation or cancer chemotherapy according to the current protocols for said treatment or prevention. Said daily dose will range from 1 pg to 600 mg, normally from 1 mg to 600 mg or from 1 mg to 300 mg.
For its use for the treatment of anhedonia according to the present invention, the NK1- antagonist, at the aforementioned effective daily dose, as described herein, is administered to a patient in need of said treatment in combination with pramipexole at the aforementioned effective daily dose, as described herein.
Normally, for its use according to this aspect, the invention provides said NK1- antagonist in a pharmaceutical composition comprising, as an active ingredient, said NK1- antagonist, in admixture with a pharmaceutical carrier or vehicle, for use for the treatment of anhedonia in a patient, in combination w ith pramipexole or a pharmaceutically acceptable salt or solvate thereof, also in a pharmaceutical composition, in admixture with a pharmaceutical carrier or vehicle, to be administered to said patient at a daily dose that is equivalent to from up to 10 times, from up to 4.7 times, or from 1.1 times to 10 times higher than the maximum pramipexole dihydrochloride monohydrate daily dose recommended for the relief of the motor symptoms of Parkinson’s disease (such a motor symptoms).
As another use according to this aspect, the invention provides NK1 -antagonist in a pharmaceutical composition comprising, as an active ingredient, said NK1 -antagonist, in admixture with a pharmaceutical carrier or vehicle, for use in the treatment of anhedonia in a patient, 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, to be administered to said patient at a daily dose that is equivalent to a dose from 1.1 times to 10 times higher than a maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone. Such a daily dose, includes but is not limited to, a daily dose that is equivalent to a dose from 1.1 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 1.5 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 2.5 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 3 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 4 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, and a daily dose that is equivalent to a dose from 6 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone.
Said pharmaceutical composition in dosage unit form comprises said NK1 -antagonist in an amount of from 1 pg to 600 mg, in admixture with a pharmaceutical carrier or vehicle, and is for use for the treatment of anhedonia in a patient, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof in doses, in pramipexole dihydrochloride monohydrate, from up to 10 times, from up to 4.7 times, or from 1.1 times to 10 times higher than the daily dose approved for the relief of the symptoms of PD (such as motor symptoms).
Said pharmaceutical composition in dosage unit form comprises said NK1 -antagonist in an amount of from 1 pg to 600 mg, in admixture with a pharmaceutical carrier or vehicle, and is for use for the treatment of anhedonia in a patient, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof in doses, in pramipexole dihydrochloride monohydrate, from 1.1 times to 10 times higher than a maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone. Such a dose, includes but is not limited to, a daily dose that is equivalent to a dose from 1. 1 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 1.5 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 2.5 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 3 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 4 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, and a daily dose that is equivalent to a dose from 6 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone.
According to an embodiment, said NK1 -antagonist, in an amount per unit form of from 1 pg to 600 mg, is for use in the treatment of anhedonia in a patient in combination with a pramipexole, also in a pharmaceutical composition in dosage unit form comprising said pramipexole in an amount per unit form equivalent to 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 of pramipexole dihydrochloride monohydrate, to be administered to said patient at a daily dose equivalent to from 0.375 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 of pramipexole dihydrochloride monohydrate.
In particular, said NK1 -antagonist is selected from the group consisting of aprepitant or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from 10 mg to 250 mg of aprepitant; rolapitant or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from 15 mg to 270 mg of rolapitant; netupitant or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from 300 mg to 600 mg; and netupitant-300/palonosetron-0.5.
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.
Pramipexole, in said combination, may be formulated in a pharmaceutical composition in IR- or ER-form, in an amount per unit form as described herein and administered twice to three times per day in an IR-formulation or once a day in an ER-fonnulation, at the aforementioned daily doses, in combination with the NK1 -antagonist.
Use of a NKl-antagonist for the preparation of a medicament for the treatment of anhedonia
According to this aspect, the present invention provides the use of a NKl-antagonist for the preparation of a medicament for the treatment of anhedonia in a patient in need of said treatment, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof.
This aspect of the invention provides the use of said NKl-antagonist for the preparation of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said NKl-antagonist, in an amount of from 1 pg to 600 mg, in admixture with a pharmaceutical carrier or vehicle, for the treatment of anhedonia in a patient, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, at a daily dose, (in pramipexole dihydrochloride monohydrate) from up to 10 times, from up to 4.7 times, or from 1. 1 times to 10 times higher than the daily dose approved for the relief of the symptoms of PD (such as motor symptoms).
This aspect of the invention also provides the use of said NKl-antagonist for the preparation of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said NKl-antagonist, in an amount of from 1 pg to 600 mg, in admixture with a pharmaceutical carrier or vehicle, for the treatment of anhedonia in a patient, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof at a daily dose, (in pramipexole dihydrochloride monohydrate) from 1.1 times to 10 times higher than a maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone. Such a daily dose includes but is not limited to, a daily dose that is equivalent to a daily dose that is equivalent to a dose from 1.1 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a dose from 1.5 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 2.5 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 3 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 4 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, and a daily dose that is equivalent to a dose from 6 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone.
For this use, said NK1 -antagonist is fonnulated in a medicament consisting of or comprising a pharmaceutical composition in dosage unit form to be administered to a patient suffering from anhedonia in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, also in a pharmaceutical composition in dosage unit form.
The above medicament consisting of or comprising combinations of pharmaceutical compositions, for use for the treatment of anhedonia in a patient, normally are in dosage unit form, in an IR or ER formulation, and each of said compositions may comprise
(a) said NK1 -antagonist, in admixture with a pharmaceutical carrier or vehicle, and/or
(b) said pramipexole or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutical carrier or vehicle, or
(a/b) both said NK1 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof, in a fixed-dose combination comprising said NK1 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof in admixture with a phannaceutical carrier or vehicle.
Thus, this aspect of the invention provides the use of a NK1 -antagonist for the preparation of a pharmaceutical composition in dosage unit form comprising, as an active ingredient in admixture with a pharmaceutical carrier or vehicle, said NK1 -antagonist in an amount per unit form of form 1 pg to 600 mg (for use) for the treatment of anhedonia in a patient in need of said treatment, in combination with pramipexole, also in a pharmaceutical composition in dosage unit form comprising, in admixture with a pharmaceutical carrier or vehicle, said pramipexole in an amount per unit form equivalent to from 0. 125 mg to 45 mg of pramipexole dihydrochloride monohydrate, to be administered to said patient at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate.
As set forth above, the above pramipexole dose-range (daily and per unit form) includes low' doses to be used during the titration period.
In particular, in said pharmaceutical combination,
(a) said NK1 -antagonist is present in said composition in an amount per unit form of from 1 pg to 600 mg, to be administered at a daily dose of from 1 mg to 600 mg; and (b) said pramipexole is present in said composition in an amount per unit form equivalent to 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, to be administered at a daily dose equivalent to from 0.375 mg to 45 mg, preferably 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 of pramipexole dihydrochloride monohydrate.
According to an embodiment of this aspect, the invention provides a medicament consistingof or comprising a pharmaceutical combination comprising, as Components, an NK1 -antagonist, in a pharmaceutical composition in dosage unit form comprising, as an active ingredient, said NK1 -antagonist, in an amount per unit form of from 1 mg to 600 mg, in admixture with a pharmaceutical carrier or vehicle; and pramipexole or a pharmaceutically acceptable salt or solvate thereof, in a pharmaceutical composition in dosage unit form comprising, as an active ingredient, said pramipexole or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from 0. 125 mg to 21 mg of pramipexole dihydrochloride monohydrate, in admixture with a pharmaceutical carrier or vehicle.
The pharmaceutical combination according to this aspect of the invention may be administered to patients suffering from anhedonia with the intent of finding and adopting a safe and effective pramipexole daily dose with higher therapeutic efficacy than is used or known in the art, for the heretofore unachieved treatment or alleviation of symptoms of said anhedonia in each patient. Normally, an NK1 -antagonist and pramipexole or a pharmaceutically acceptable salt or solvate thereof are concurrently or sequentially administered to said patient suffering from anhedonia.
Any of the aforementioned NK1 -antagonists may be used as an active ingredient of the pharmaceutical composition of the combination according to this aspect of the invention. Preferably, said NK1 -antagonist 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 may also comprise, as a second active ingredient, palonosetron or a pharmaceutically acceptable salt or solvate thereof, in an amount per unit form equivalent to from 0. 1 mg to 0.5 mg of palonosetron base. In the pharmaceutical composition pramipexole or a pharmaceutically acceptable salt or solvate thereof, is in an amount per unit form equivalent to from 0.125 mg to 45 mg, in particular 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 of pramipexole dihydrochloride monohydrate.
In particular, the dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof per IR-unit form, for the treatment of anhedonia will range from an amount equivalent to from 0.125 mg to 22.5 mg, from 1.5 to 22.5 mg, from more than 3 mg to 22.5 mg, from 5 mg to 22.5 mg, from 6.5 mg to 22.5 mg, or from 10 mg to 22.5 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with the NK1 -antagonist).
The dose per unit form of pramipexole or a pharmaceutically acceptable salt or solvate thereof in an ER formulation, including slow-release compositions and transdermal therapeutic systems such as transdermal patches, for the treatment of anhedonia will range from an amount that is equivalent to from 0.375 mg to 45 mg, from 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 of pramipexole dihydrochloride monohydrate, depending on the tolerability (in combination with said NK1- antagonist).
According to an embodiment, in the pharmaceutical composition, pramipexole or a pharmaceutically acceptable salt or solvate thereof, is in an amount per unit form equivalent to from 0.125 mg to 21 mg, in particular from 0.125 mg to less than 1.6 mg, from 1.6 mg to 21 mg, from more than 4.5 mg to 21 mg or from more than 6 mg to 21 mg of pramipexole dihydrochloride monohydrate.
In particular, according to this embodiment the dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof per IR-unit form, for the treatment of anhedonia will range from an amount equivalent to from 1.6 mg to 10.5 mg, from 1.8 to 10.5 mg, from 2.4 mg to 10.5 mg or from 3 mg to 10.5 mg of pramipexole dihydrochloride monohydrate, depending on safety and tolerability (in combination with the NK1 -antagonist).
The dose per unit form of pramipexole or a pharmaceutically acceptable salt or solvate thereof in an ER formulation, including slow-release compositions and transdermal therapeutic systems such as transdermal patches, for the treatment of anhedonia according to this embodiment, will range from an amount that is equivalent to from more than 4.5 mg to 30 mg, more than 4.5 mg to 21 mg, in particular from 6 mg to 21 mg, or from more than 6 mg to 21 mg of pramipexole dihydrochloride monohydrate, depending on the tolerability (in combination with said NK1 -antagonist).
In the case of separate (concurrent or sequential) administration of said 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 NK1 -antagonist, in admixture with a pharmaceutical carrier or vehicle, in a container; and said pramipexole, in admixture with a pharmaceutical carrier or vehicle, in another, separate container.
For the intended use in the treatment of anhedonia in combination with pramipexole, the NK1 -antagonist is formulated in a pharmaceutical composition, wherein said NK1- antagonist is in admixture with a pharmaceutical carrier or vehicle.
For their concurrent administration for the treatment of anhedonia said NK1 -antagonist and said pramipexole may also be formulated together and with a pharmaceutical carrier or vehicle, in a pharmaceutical composition (fixed-dose combination).
Methods for treating anhedonia with compositions comprising pramipexole and an NKl-antagonist
According to a first aspect, the present invention includes a method for safely treating anhedonia in patients suffering from anhedonia, with pramipexole by concurrently administering to said patients a NKl-antagonist.
More particularly, the invention provides a method for treating a patient suffering from anhedonia which comprises administering to a patient in need of said treatment an effective dose of said NKl-antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
According to a preferred embodiment, said NKl-antagonist is selected from the group consisting of aprepitant or a pharmaceutically acceptable salt or solvate thereof, fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, rolapitant or a pharmaceutically acceptable salt or solvate thereof, netupitant or a pharmaceutically acceptable salt or solvate thereof, and netupitant- 300/palonosetron-0.5; each at a daily dose described herein, except for netupitant- 300/palonosetron-0.5 which is provided once a day or every 2-4 days; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose as described herein.
According to an advantageous embodiment, in the method of the present invention the NKl-antagonist is aprepitant, fosaprepitant meglumine, or rolapitant and the pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate, each at the daily doses described in the respective sections.
In carrying out the method of the present invention, the daily dose of these NK1- antagonists is at least as high as that for preventing or treating nausea and vomiting in patients undergoing a surgical operation or cancer chemotherapy according to the current protocols for said treatment or prevention. Said daily dose is from 1 pg to 600 mg, normally from 1 mg to 600 mg, or from 1 mg to 300 mg.
The pramipexole or a pharmaceutically acceptable salt or solvate thereof daily dose is equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate, including daily doses used during the titration period.
A NKl-antagonist selected from the group consisting of aprepitant or a pharmaceutically acceptable salt or solvate thereof and rolapitant or a pharmaceutically acceptable salt or solvate thereof is a particularly advantageous NK1 -antagonist.
Preferably, in said combination, said NKl-antagonist is aprepitant and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate.
In particular, said NKl-antagonist in said combination is aprepitant, at an effective daily dose of from 10 mg to 250 mg and said pramipexole or a pharmaceutically acceptable salt or solvate thereof in said combination is pramipexole dihydrochloride monohydrate, at an effective daily dose in a range selected from the group consisting of from more than 4.5 mg to 45 mg, from 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.
In carrying out the method (or use) of the present invention, said NKl-antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are each formulated in a pharmaceutical composition in dosage unit form comprising, respectively, said NKl- antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof, each in admixture with a pharmaceutical carrier or vehicle.
Said NKl-antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof may also be in a fixed-dose combination, co-formulated in a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said NKl- antagonist, and an effective amount per unit form of said pramipexole or pharmaceutically acceptable salts and solvates thereof, in admixture with a pharmaceutical carrier or vehicle. This fixed dose combination will be described herein below in the fourth aspect of the invention.
The doses per unit form of said NK1 -antagonist and of said pramipexole are described above.
In particular, in said composition, said NK1 -antagonist is present in an amount per unit form of from 1 pg to 600 mg or from 1 mg to 600 mg.
In said composition said pramipexole or a pharmaceutically acceptable salt or solvate thereof is present in an amount per unit form equivalent to from 0.125 mg to 45 mg or from 0.125 mg to 21 mg of pramipexole dihydrochloride monohydrate.
In particular, said NK1 -antagonist active ingredient of said pharmaceutical composition is selected from the group consisting of aprepitant or a pharmaceutically acceptable salt or solvate thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; rolapitant or a pharmaceutically acceptable salt or solvate thereof, in an amount, per unit form, equivalent to from 15 mg to 270 mg of rolapitant; netupitant or a pharmaceutically acceptable salt or solvate thereof, in an amount, per unit form, equivalent to from 300 mg to 600 mg; and netupitant-300/palonosetron- 0.5. 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 fomr of from 15 mg to 270 mg or from 30 mg to 270 mg.
Said pramipexole dose per unit form consists of or includes an amount per unit form equivalent to a range selected from the group consisting of from 0.125 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, from 10 mg to 45 mg, from 13 mg to 45 mg, and from 15 mg to 45 mg of pramipexole dihydrochloride monohydrate.
According to an embodiment, in the method of the present invention the NK1- antagonist is aprepitant or rolapitant, and pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose that is equivalent to from up to 10 times, from up to 4.7 times, or from 1.1 times to 10 times higher than the maximum recommended pramipexole dihydrochloride monohydrate dose approved for the relief of the symptoms of PD (such as motor symptoms).
According to another embodiment, in the method of the present invention the NK1- antagonist is aprepitant or rolapitant. and pramipexole or a pharmaceutically acceptable salt or solvate thereof is administered at a daily dose that is equivalent to a dose from 1.1 times to 10 times higher than a maximal tolerated dose of pramipexole dihydrochlonde monohydrate dose for the treatment of anhedonia when administered alone. Such a daily dose, includes but is not limited to, a daily dose that is equivalent to a dose from 1. 1 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a dose from 1.5 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 2.5 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 3 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, a daily dose that is equivalent to a dose from 4 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone, and a daily dose that is equivalent to a dose from 6 to 10 times higher than the maximal tolerated dose of pramipexole dihydrochloride monohydrate dose for the treatment of anhedonia when administered alone.
According to this embodiment, in said method (or use), said NK1 -antagonist, at the aforementioned effective daily dose, is administered to said patient, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof administered to said patient at a daily dose equivalent to from more than 4.5 mg to 21 mg, normally from more than 6 mg to 21 mg, from 10 mg to 21 mg, from 13 mg to 21 mg or from 15 mg to 21 mg of pramipexole dihydrochloride monohydrate.
Preferably, according to this embodiment, in the method for treating anhedonia in an adult patient according to the present invention, said NK1 -antagonist is aprepitant, at a daily oral dose of from 10 mg to 250 mg; or rolapitant, at a daily oral dose of from 30 mg to 270 mg, in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, at an effective daily oral dose corresponding to from more than 4.5 mg to 21 mg, normally from more than 6 mg to 21 mg, from 10 mg to 21 mg, from 13 mg to 21 mg, or from 15 mg to 21 mg of .pramipexole dihydrochloride monohydrate.
Formulations
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, in admixture with the classic phannaceutical carriers or vehicles.
The pharmaceutical compositions may be formulated in oral forms, such as tablets, gelatin capsules, and sublingual and buccal formulations, wherein the 5HT3-antagonist, NK1- antagonist or pramipexole or all of the active ingredients are 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.
Said oral fonns 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 activity7 by progressively releasing a predetermined quantity of 5HT3-antagonist or of pramipexole (or of a a pharmaceutically acceptable salt or solvate thereof), or of both the active ingredients. The oral formulations can also be in the form of capsules allowing the extended release the pramipexole (or a pharmaceutically acceptable salt or solvate thereof), or of 5HT3-antagonist or NK1 -antagonist, or of both the active ingredients. Sublingual or buccal formulations may be in the forms of tablets, films and sprays.
The pharmaceutical compositions may also be formulated as a transdermal therapeutic system (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.
The pharmaceutical compositions may be 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. EXAMPLE 1
CTC-501 (Pramipexole IR + Ondansetron) Phase 1 Study in Healthy Volunteers
The ability of the 5HT3 -antagonists to prevent the gastro-intestinal (GI) adverse effects (AEs) of pramipexole in humans was tested. This study was a single center phase I, multiple ascending dose study in a single group of healthy subjects.
To be enrolled in the study, participants were subject to the following inclusion/ exclusion key criteria:
Key Inclusion Criteria:
1. Male and female subjects aged 20-45 years old both ages included.
2. Females of childbearing potential must agree to be abstinent or else use any two of the following medically acceptable forms of contraception from the Screening Period through 14 days after the study Exit Visit: condom with spermicidal jelly, diaphragm or cervical cap with spermicidal jelly, or intrauterine device (IUD). A female whose male partner has had a vasectomy must agree to use one additional form of medically acceptable contraception. Subjects must agree to practice the above birth control methods for 14 days after the final visit as a safety precaution.
3. Females of non-childbearing potential, defined as surgically sterile (status posthysterectomy. bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months, do not require contraception during the study. The reason must be documented in the source documents.
4. Males with female partners of childbearing potential must agree to use a highly effective, medically acceptable form of contraception from the Screening Period through 14 days after the study Exit Visit. Males with female partners of childbearing potential who themselves are surgically sterile (status post vasectomy) must agree to use condoms with spermicide over the same period of time. Male subjects must agree to practice the above birth control methods for 14 days after the final visit as a safety precaution.
5. Subjects must be in good health as determined by their medical history including personal and family psychiatric history and results of physical examination, electrocardiogram (ECG), vital signs, and laboratory tests. A subject with a medical abnormality may be included only if the investigator or designee considers that the abnormality will not introduce significant additional risk to the subject's health or interfere with study objectives.6. Subjects must be able to clearly and reliably communicate changes in their medical condition.
7. Subjects with a body mass index (BMI) between 19.0 and 32.0 kg/m2 (both inclusive). 8. Subjects able to swallow multiple pills or capsules simultaneously.
9. Subjects must have signed an informed consent form indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study and comply with the study procedures and restrictions.
Key exclusion criteria:
The criteria for exclusion of a subject from enrollment in the study were as follows:
1. Any clinically relevant acute or chronic diseases which could interfere with the subjects’ safety during the trial, expose them to undue risk, or interfere with the study objectives.
2. History or presence of gastrointestinal, hepatic, or renal disease or other condition known to interfere with the absorption, distribution, metabolism or excretion of the study drugs.
3. History of substance abuse, known drug addiction, or positive test for drugs of abuse or alcohol.
4. History of drug or other significant allergy.
5. Known hypersensitivity' to pramipexole, or to ondansetron or similar serotonin receptor antagonists, or to aprepitant or similar Substance P/NK1 receptor antagonists.
5. History of and/or current QT interval prolongation, congenital long QT syndrome, electrolyse abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias or other medicinal products that lead to QT prolongation or 1st degree AV block at Screening, Day -1, or pre-dose, > 450 QTcF formales and > 470 QTcF for females..
7. Treatment with centrally active drugs or antiemetics, within 1 months of study entry.
8. Tobacco or nicotine users (except subjects who stopped using tobacco or nicotine 1 year or more before enrollment in the study).
9. Excessive daily consumption of xanthines containing drinks (i.e. > 500 mg/day of caffeine).
10. Subjects unwilling to curtail prolonged intensive physical exercise during the study conduct (from the Screening visit until the last dose of study drug).
11. Positive test result for hepatitis B surface antigen, hepatitis C antibody.
12. Positive test result for HIV 1 or 2 serology.
13. Likely to need any medical or dental treatment during the study period.
14. Use of any prescription or over-the-counter medication within 14 days prior to admission on Day-1. In addition any medications with central effects are prohibited for a period equal to 5 times the drug half-life prior to admission (Day -1), should this period be longer than 14 days.
15. Subjects unlikely to co-operate during the study, and/or be questionably compliant in the opinion of the investigator.
16. Subjects unable to be contacted in case of an emergency.
17. Intake of an investigational drug within 30 days of study entry.
18. Show evidence of suicidal ideation within the last 6 months as assessed by the C-SSRS (Columbia Suicide Severity Rating Scale) at Screening.
Five subjects were enrolled in the study. The following Table 1 summarizes the demographic characteristics of the subjects.
Table 1. Demographic Characteristics of Subjects Enrolled in the Study
Figure imgf000063_0001
All participants were first admitted to Period 1 , in which rising single daily doses of pramipexole IR up to the first intolerable dose (FID1) or maximum allowed dose (6 mg/day) were administered once a day in the morning. The starting dose of pramipexole was 0.5 mg and the dose was increased daily by 0.5 mg increments. Once a subject had reached his/her first intolerable dose (FID-1), upward dose escalation was discontinued. Participants completed Period 1 on the day they reached the FID1 or maximum allow ed dose (6 mg/day).
FID was defined as:
- one (1) episode of vomiting; or
- Two (2) episodes of retching, or
- 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
- 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
- One (1) episode of moderate diarrhea (Grade 2; defined as 4-6 stools more than at baseline).
Following a 5-20 day washout, participants entered Period 2. During this period, the same schedule of rising-doses of pramipexole IR. as given in Period 1, were administered up to the first intolerable dose (FID2) or the maximum allowed dose (6 mg/day), but this time together with a single ondansetron 8 mg tablet at the same time as the pramipexole IR dose.
The primary objective of this study was to evaluate if treatment with oral ondansetron in combination with pramipexole would facilitate an increase in the maximum tolerated dose (MTD) of pramipexole. The primary endpoint of the study was the change in pramipexole MTD for each subject between Period 1 (pramipexole alone) and Period 2 (pramipexole + ondansetron). A total of 5 subjects completed both Period 1 and Period 2.
Table 2 summarizes the FID and MTD values for pramipexole when administered alone (FID1 and MTD1) and when administered with ondansetron (FID2 and MTD2) by subject number.
Table 2. FID and MTD of Pramipexole IR Given Alone (FID1; MTD1) or with Ondansetron (FID2; MTD2) by Subject Number
Figure imgf000064_0001
*: #1005 reached FID2 at 1.5 mg pramipexole IR with 8 mg ondansetron by moderate nausea and continued with 16 mg ondansetron and reached FID2+ at 3.0 mg pramipexole IR with 16 mg.
FID=first intolerable dose; MTD=maximum tolerated dose; SD=standard deviation; NA=not available
The data in Table 2 reveals a clinically relevant increase in the mean MTD of pramipexole IR when coadministered with ondansetron as evidenced by a 2.6-fold or more increase in the mean MTD2 to MTD1 ratio.
Table 3 summarizes the plasma concentrations of pramipexole at MTD1 (pramipexole IR alone) and at MTD2 (pramipexole IR with ondansetron) by subject number. Table 3. Plasma Concentrations of Pramipexole at MTD1 (Pramipexole IR Alone) and MTD2 (Pramipexole IR with Ondansetron) by Subject Number
Figure imgf000065_0001
MTD=maximum tolerated dose; SD=standard deviation
As shown in Table 3 and in keeping with the increase in dose (Table 2), mean peak (at 2 hours post dose) plasma concentrations of pramipexole increased from 2468.1 ± 1729.4 pg/mL (pramipexole IR given alone) to 6702.8 ± 5820.5 pg/mL (pramipexole IR + ondansetron). This increase was dose proportional and not affected by ondansetron coadministration.
Table 4 presents the dose limiting side effects reported at the FID1 (pramipexole IR alone) and at FID2 (pramipexole IR + ondansetron) for each subject.
Table 4. Comparison of Pramipexole Dose Limiting Side Effects at FID1 (Pramipexole Alone) and FID2 (Pramipexole + Ondansetron) by Subject Number
Figure imgf000065_0002
1) with 8 mg ondansetron, 2) with 16 mg ondansetron. 3) Pi’s decision by several AEs (Vaginal Spotting, Insomnia, Chills, Slowed Thoughts/Percepti on, and Tremors) FID= first intolerable dose.
In conclusion, coadministration of the 5-HT? antagonist ondansetron with pramipexole in healthy volunteers resulted in at least 2.6-fold 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. Three of five (60%) subjects who completed Period 2 safely tolerated the maximum protocol allowed pramipexole dose of 6 mg. There was no evidence, based on plasma concentrations, of a PK interaction between pramipexole and ondansetron. The pramipexole plasma concentration increases were dose proportional and not affected by ondansetron coadministration. Ondansetron coadministration reduced GI side effects and did not cause new unexpected AEs.
EXAMPLE 2
CTC-501 (Pramipexole IR + Ondansetron) for the Treatment of Anhedonia
The efficacy of CTC-501 (a fixed dose combination of pramipexole IR and ondansetron) for the treatment of anhedonia was studied in a single-center, randomized, blind, placebo controlled, clinical trial (CTC-003) in patients suffering from a Major Depressive Disorder (MDD). Inclusion was based on the HAMD 17-item scale (total score > 18 and a score of > 2 on the depressed mood item); efficacy was judged on the Montgomery and Asberg Depression Rating Scale (MADRS). A total of 32 patients with MDD were enrolled in the study and randomized in a 1:1 ratio to CTC-501 (pramipexole + ondansetron) or to placebo.
CTC-501 or placebo were administered orally, twice per day (once in the morning and once in the evening). Treatments were allocated according to a pre-determined, computergenerated, randomization schedule. Upon initiation of treatment, participants were hospitalized for the pramipexole upward dose titration. The starting dose of pramipexole was 0.5 mg in the morning and 0.5 mg in the evening, The dose of pramipexole was titrated upward by 1 mg increments daily or every other day depending on each participant’s tolerability according to the investigator’s judgement, until patients reached their first intolerable dose (FID) or the maximum protocol-allowed dose of 5 mg per day of pramipexole (i.e., 2.5 mg in the morning and 2.5 mg in the evening). The most commonly reported dose-limiting side effects of pramipexole typically consist of nausea and vomiting. The dose of ondansetron was fixed at 16 mg per day (8 mg in the morning and 8 mg in the evening co-admimstered with pramipexole). Participants w ere discharged from the hospital on the day following MTD or the day they reached 5 mg/day of pramipexole and continued the trial as out-patients.
Once participants had reached their MTD or the maximum protocol-allowed dose of 5 mg/day they entered the Maintenance Period and were treated at their MTD (as reached during the titration period) or at the maximum protocol -al lowed dose of 5 mg/day for the remainder of the 8-week treatment. If at any time during the maintenance phase, intolerance developed (moderate to severe possibly or probably drug related AEs), the dose of study drug could be decreased.
Efficacy was judged on the MADRS anhedonia subscale, as well as on the Clinical Global Impression Severity' (CGI-S).
Up to 32 healthy males and females with a diagnosis of MDD according to the DSM- R criteria and a total score >18 on the 17-item HAM-D, who were not on antidepressants, not taking pramipexole or ondansetron, did not have a history of a serious suicidal attempt in the past 12 months, or a history of hypomania/mania, psychotic disorder, dementia and borderline or antisocial personality7 disorders were to be enrolled in this study.
Results
A total of 32 patients were enrolled in Study CTC-003; 16 were randomized to CTC- 501 (pramipexole + ondansetron) and 16 were randomized to placebo. Baseline demographic and illness characteristics were similar in both groups.
A total of 13 of the 16 participants randomized to CTC-501 completed the initial upward doe titration period, and 10 of 16 (62%) participants randomized to CTC-501 reached and tolerated the highest protocol-allowed dose of 5 mg/day. Interestingly, all participants who completed the study were on the same dose at the end of the study as they had been at the end of the upward dose titration period of the study.
Antianhedonic efficacy was evaluated on the MADRS anhedonia subscale. Efficacy was also evaluated on the CGI-S.
Mean changed total scores on the MADRS at Week 8 (end of study) showed statistically significant greater improvement in the CTC-501 group than in the placebo group (p=0.0037). Analysis of the MADRS anhedonia subscale, showed a significant (p=<0.02) improvement at Week 8 in the CTC-501 group. See Figure 1.
On the CGI-S participants randomized to CTC-501 moved from moderate se 'erity to mild severity7. By contrast, participants randomized to placebo remained in the moderate severity7 group. See Figure 2. These results indicate the anti-anhedonia efficacy of CTC-501.
In conclusion, in this study, compared to placebo, CTC-501 was an efficacious antidepressant and had a remarkable effect on anhedonia.
EXAMPLE 3
CTC-413 (Pramipexole IR and Aprepitant) Phase 1 Study in Healthy Volunteers
A Phase I study was conducted in subjects receiving a single oral dose of pramipexole dihydrochloride monohydrate (“pramipexole”) with or without a single oral dose of aprepitant. This study was a single center, multiple ascending dose study in a single group of healthy subjects. The objective of the study was to demonstrate that aprepitant could safely attenuate the gastro-intestinal side effects of pramipexole given in doses equivalent or higher than those approved in the treatment of Parkinson’s Disease or show n in clinical trials to be effective in the treatment of anhedonia.
The primary objective of this study was to evaluate if treatment with oral aprepitant in combination with pramipexole would facilitate a safe increase in the MTD of pramipexole. The primary endpoint of the study w as the measurement of the change in pramipexole MTD in the 4 subjects who completed the pramipexole + aprepitant; prtiod compared to the MTD in the same 4 subjects receiving pramipexole IR alone in Period 1 (MTD1).
The primary endpoint of the study was the difference in the individually determined MTD (defined as one dose below' the FID) of pramipexole when given alone or with aprepitant.
To be enrolled in the study, participants the following inclusion/exclusion key criteria:
Key Inclusion Criteria
1. Male and female subjects aged 20-45 years old both ages included.
2. Females of childbearing potential must agree to be abstinent or else use any two of the following medically acceptable forms of contraception from the Screening Period through 14 days after the study Exit Visit: condom with spermi ci dal jelly, diaphragm or cervical cap with spermicidal jelly, or intrauterine device (IUD). A female whose male partner has had a vasectomy must agree to use one additional form of medically acceptable contraception. Subjects must agree to practice the above birth control methods for 14 days after the final visit as a safety precaution.
3. Females of non-childbearing potential, defined as surgically sterile (status posthysterectomy. bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months, do not require contraception during the study. The reason must be documented in the source documents.
4. Males with female partners of childbearing potential must agree to use a highly effective, medically acceptable form of contraception from the Screening Period through 14 days after the study Exit Visit. Males with female partners of childbearing potential who themselves are surgically sterile (status post vasectomy) must agree to use condoms with spermicide over the same period of time. Male subjects must agree to practice the above birth control methods for 14 days after the final visit as a safety precaution.
5. Subjects must be in good health as determined by their medical history including personal and family psychiatric history and results of physical examination, electrocardiogram (ECG), vital signs, and laboratory tests. A subject with a medical abnormality may be included only if the investigator or designee considers that the abnormality will not introduce significant additional risk to the subject's health or interfere with study objectives.
6. Subjects must be able to clearly and reliably communicate changes in their medical condition.
7. Subjects with a body mass index (BMI) between 19.0 and 32.0 kg/m2 (both inclusive).
8. Subjects able to swallow multiple pills or capsules simultaneously.
9. Subjects must have signed an informed consent form indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study and comply with the study procedures and restrictions.
Key exclusion criteria:
The criteria for exclusion of a subject from enrollment in the study were as follows:
1. Any clinically relevant acute or chronic diseases which could interfere with the subjects’ safety during the trial, expose them to undue risk, or interfere with the study objectives.
2. History or presence of gastrointestinal, hepatic, or renal disease or other condition known to interfere with the absorption, distribution, metabolism or excretion of the study drugs.
3. History' of substance abuse, known drug addiction, or positive test for drugs of abuse or alcohol.
4. History of drug or other significant allergy.
5. Known hypersensitivity to pramipexole, or to ondansetron or similar serotonin receptor antagonists, or to aprepitant or similar Substance P/NK1 receptor antagonists.
5. History of and/or current QT interval prolongation, congenital long QT syndrome, electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias or other medicinal products that lead to QT prolongation or 1 st degree AV block at Screening, Day -1, or pre-dose, > 450 QTcF formales and > 470 QTcF for females..
7. Treatment with centrally active drugs or antiemetics, within 1 months of study entry.
8. Tobacco or nicotine users (except subjects who stopped using tobacco or nicotine 1 year or more before enrollment in the study).
9. Excessive daily consumption of xanthines containing drinks (i.e. > 500 mg/day of caffeine).
10. Subjects unwilling to curtail prolonged intensive physical exercise during the study conduct (from the Screening visit until the last dose of study drug).
11. Positive test result for hepatitis B surface antigen, hepatitis C antibody.
12. Positive test result for HIV 1 or 2 serology.
13. Likely to need any medical or dental treatment during the study period.
14. Use of any prescription or over-the-counter medication within 14 days prior to admission on Day-1. In addition any medications with central effects are prohibited for a period equal to 5 times the drug half-life prior to admission (Day -1), should this period be longer than 14 days.
15. Subjects unlikely to co-operate during the study, and/or be questionably compliant in the opinion of the investigator.
16. Subjects unable to be contacted in case of an emergency.
17. Intake of an investigational drug within 30 days of study entry.
18. Show evidence of suicidal ideation within the last 6 months as assessed by the C-SSRS (Columbia Suicide Severity Rating Scale) at Screening.
Following enrollment in the study, participants received single increasing oral doses of pramipexole given once daily in the morning (Period 1 of the study). The starting dose of pramipexole was 0.5 mg and the dose was increased daily by 0.5 mg increments. Once a subject had reached his/her first intolerable dose (FID-1), upward dose escalation was discontinued. First intolerable dose (FID) was defined as:
- One (1) episode of vomiting; or
- Two (2) episodes of retching, or
- 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
- 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
- One (1) episode of moderate diarrhea (Grade 2; defined as 4-6 stools more than at baseline).
Four subjects were enrolled in the study. The following Table 5 summarizes the demographic characteristics of the subjects. Table 5. Demographic Characteristics of Subjects Enrolled in the Study
Figure imgf000071_0001
All participants were first admitted to Period 1, in which rising single daily doses of pramipexole IR up to the first intolerable dose (FID1) or maximum allowed dose (6 mg/day) were administered once a day in the morning. Participants completed Period 1 on the day they reached the FID1 or maximum allowed dose (6 mg/day).
Following a washout of several days, participants entered Period 2 of the study during which pramipexole IR and aprepitant) were co-administered. The same schedule of rising doses of pramipexole IR as given in Period 1 up to the first intolerable dose (FID3) or the maximum allowed dose (6 mg/day) was administered, but this time together with 80 mg aprepitant tablets given once a day in the morning. Assessments were the same as those planned for the dose escalation day.
Table 6. FID and MTD of Pramipexole Given Alone or with Aprepitant by Subject Number - Phase 1 Study CTC-001
Figure imgf000071_0002
FID=first intolerable dose; MTD=maximum tolerated dose; SD=standard deviation;
NA=not available
The data in Table 6 reveals a clinically relevant increase in the mean MTD of pramipexole IR when coadministered with aprepitant as evidenced by a > 5.6-fold increase in the mean MTD3 to MTD1 ratio (paired t-test p=0.013).
Table 7 summarizes the plasma concentrations of pramipexole at MTD1 (pramipexole alone) and at MTD3 (pramipexole + aprepitant) by subject number. Table 7. Plasma Concentrations of Pramipexole Alone at MTD and Pramipexole + Aprepitant at MTD by Subject Number - Phase 1 Study CTC-001
Figure imgf000072_0001
MTD=maximum tolerated dose; SD=standard deviation
As shown in Table 7, the mean plasma concentrations of pramipexole at 2 hours post dose increased with increasing does of pramipexole, demonstrating that the increase in MTD with aprepitant was not due to a decrease in pramipexole plasma concentration. The increase in pramipexole plasma concentrations was dose proportional. There was no evidence of a PK interaction between pramipexole and aprepitant.
Table 8 presents by subject the pramipexole dose limiting side effect reported at FID1 (pramipexole alone) and FID3 (pramipexole + aprepitant).
Table 8. Comparison of Pramipexole Dose Limiting Side Effects at FID with Pramipexole Alone and with Pramipexole + Aprepitant by Subject Number - Phase 1 Study CTC-001
Figure imgf000072_0002
FID=first intolerable dose
In summary, the coadministration of the NK1 -antagonist aprepitant with pramipexole in healthy volunteers was associated with a 5.6-fold increase in MTD associated with a 3.1 - fold increase in the pramipexole plasma concentration 2 hours post MTD dosing. All subjects who completed Period 3, safely tolerated the maximum protocol allowed pramipexole dose of 6mg. The MTD of pramipexole + aprepitant was therefore not determined, but was higher than 6 mg. There was no evidence of a PK interaction between pramipexole and aprepitant. The pramipexole plasma concentration increases were dose proportional.
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Claims

What is claimed is:
1. A method for treating a patient suffering from anhedonia, which comprises treating said patient with a 5HT3 -antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
2. The method of claim 1, wherein said 5HT3-antagonist is administered at a daily dose of from 1 pg to 300 mg.
3. The method of claim 1, wherein said 5HT3-antagonist is selected from the group consisting of azasetron or a pharmaceutically acceptable salt or solvate thereof, dolasetron or a pharmaceutically acceptable salt or solvate thereof, granisetron or a pharmaceutically acceptable salt or solvate thereof, ondansetron or a pharmaceutically acceptable salt or solvate thereof, palonosetron or a phannaceutically acceptable salt or solvate thereof, ramosetron or a pharmaceutically acceptable salt or solvate thereof, and tropisetron or a pharmaceutically acceptable salt or solvate thereof.
4. The method of claim 1, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate.
5. The method of claim 1, wherein, in said combination, said 5HT3-antagonist is selected from the group consisting of ondansetron or a pharmaceutically acceptable salt or solvate thereof at a daily dose equivalent to from 2 mg to 32 mg of ondansetron base, and dolasetron or a pharmaceutically acceptable salt or solvate thereof 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 at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate.
6. The method of claim 5, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
7. The method of claim 5, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
8. The method of claim 5, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
9. The method of claim 1, wherein said 5HT3 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are each formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
10. The method of claim 1, wherein 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 separate pharmaceutical composition in dosage unit form comprising an effective amount per unit fonn of 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 claim 10, wherein said 5HT3 -antagonist is selected from the group consisting of ondansetron or 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 or a pharmaceutically acceptable salt or solvate thereof in an amount per unit form equivalent to from 25 mg to 200 mg of dolasetron mesylate; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
12. The method of claim 11, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
13. The method of claim 11, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
14. The method of claim 11, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is 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 anhedonia 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 anhedonia in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
17. The use of claim 16, wherein said medicament comprises a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said 5HT3- antagonist in admixture with a pharmaceutical carrier or vehicle, and another pharmaceutical composition in dosage unit form comprising 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.
18. The use of claim 17, wherein said medicament comprises a fixed-dose combination of an effective amount per unit form 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.
19. A method for treating a patient suffering from anhedonia. which comprises treating said patient with a combination of a 5HT3-antagonist with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof, wherein the combination does not contain any additional active compounds having an antidepressant efficacy.
20. A method for treating a patient suffering from anhedonia, which comprises treating said patient with a combination of a 5HT3-antagonist with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof, wherein another active compound with an antidepressant efficacy is not concurrently administered.
21. A 5HT3-antagonist for use in the treatment of anhedonia 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, wherein another active compound with an antidepressant efficacy is not concurrently administered.
22. A fixed dose combination for the treatment of anhedonia in a patient in need thereof, wherein the fixed dose combination contains active ingredients and inactive ingredients, and the active ingredients consist of pramipexole or a pharmaceutically acceptable salt or solvate thereof and a 5HT3-antagonist.
23. A pharmaceutical composition for the treatment of anhedonia in a patient in need thereof, wherein the pharmaceutical composition contains active ingredients and inactive ingredients, and the active ingredients consist of pramipexole or a pharmaceutically acceptable salt or solvate thereof and a 5HT3-antagonist.
24. The method of claim 1, wherein anhedonia is a symptom of a depressive disorder.
25. The method of claim 1, wherein anhedonia is a symptom of a major depressive disorder.
26. The method of claim 1, wherein the patient does not have a depressive disorder.
27. The method of claim 1, wherein anhedonia is due to or is a symptom of a neuroinflammatory disease.
28. The method of claim 1, wherein anhedonia is associated with a neurodegenerative disorder which is one or more selected from the group consisting of Parkinson’s disease, Alzheimer’s disease, post-traumatic stress disorder, and a substance abuse disorder.
29. The method of claim 28, wherein anhedonia is due to neurodegeneration of dopaminergic nigral neurons.
30. The method of claim 28, wherein anhedonia is due to Alzheimer’s disease.
31. The method of claim 28, wherein anhedonia is due to Parkinson’s Disease.
32. The method of claim 28, wherein anhedonia is due to post-traumatic stress disorder.
33. The method of claim 28, wherein anhedonia is due to substance abuse disorder.
34. The method of claim 1, wherein anhedonia is due to a synucleinopathy.
35. The method of claim 1 , wherein anhedonia is a symptom of or is associated with one or more selected from the group consisting of bipolar disorder, schizophrenia, schizoaffective disorder, personality disorder, mild cognitive impairment, an autoimmune disorder, rheumatoid arthritis, psoriasis, multiple sclerosis, and anticancer treatment.
36. A method for enabling the use of a dose of pramipexole sufficient for the effective treatment of anhedonia in humans comprising administering a dose of a 5-HT3 antagonist in combination with the dose of pramipexole, wherein the dose of the 5-HT3 antagonist is selected to reduce to tolerable levels the dose limiting adverse effects of the dose of pramipexole.
37. A method for treating a patient suffering from anhedonia, which comprises treating said patient with an NK1 -antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
38. The method of claim 37, wherein said NK1 -antagonist is administered at a daily dose of from 1 pg to 600 mg.
39. The method of claim 37, wherein said NK1 -antagonist is selected from the group consisting of aprepitant or a pharmaceutically acceptable salt or solvate thereof, fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, casopitant or a pharmaceutically acceptable salt or solvate thereof, maropitant or a pharmaceutically acceptable salt or solvate thereof, eziopitant or a pharmaceutically acceptable salt or solvate thereof, lanepitant or a pharmaceutically acceptable salt or solvate thereof, netupitant or a pharmaceutically acceptable salt or solvate thereof, orvapitant or a pharmaceutically acceptable salt or solvate thereof, rolapitant or a pharmaceutically acceptable salt or solvate thereof, serlopitant or a pharmaceutically acceptable salt or solvate thereof, vestipitant or a pharmaceutically acceptable salt or solvate thereof, vofopitant or a pharmaceutically acceptable salt or solvate thereof, and netupitant-300/palonosetron-0.5.
40. The method of claim 37, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is pramipexole dihydrochloride monohydrate.
41. The method of claim 37, wherein said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof at a daily dose of from 10 mg to 250 mg; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate.
42. The method of claim 41, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
43. The method of claim 41, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
44. The method of claim 41, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is at a daily dose equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
45. The method of claim 37, wherein said NK1 -antagonist and said pramipexole or a pharmaceutically acceptable salt or solvate thereof are each formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
46. The method of claim 37, wherein said NK1 -antagonist is formulated in a pharmaceutical composition in dosage unit form comprising said NK1 -antagonist in an amount per unit fonn of from 1 pg to 600 mg, in admixture with a pharmaceutical carrier or vehicle; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is formulated in a separate pharmaceutical composition in dosage unit form comprising an effective amount per unit fonn of 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.
47. The method of claim 45, wherein said NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof in an amount per unit form equivalent to from 10 mg to 250 mg of aprepitant, or rolapitant or a pharmaceutically acceptable salt or solvate thereof in an amount per unit form equivalent to from 15 mg to 270 mg of rolapitant; and said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
48. The method of claim 46, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
49. The method of claim 46, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 6.5 mg to 45 mg of pramipexole dihydrochloride monohydrate.
50. The method of claim 46, wherein said pramipexole or a pharmaceutically acceptable salt or solvate thereof is in an amount per unit form equivalent to from 6.5 mg to 20 mg of pramipexole dihydrochloride monohydrate.
51. An NK1 -antagonist for use in the treatment of anhedonia 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.
52. Use of an NK1 -antagonist for the preparation of a medicament for the treatment of anhedonia in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof.
53. The use of claim 52, wherein said medicament comprises a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said NK1- antagonist in admixture with a pharmaceutical carrier or vehicle and another pharmaceutical composition in dosage unit form comprising 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.
54. The use of claim 52, wherein said medicament comprises a fixed-dose combination of an effective amount per unit form of said NK1 -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.
55. A method for treating a patient suffering from anhedonia. which comprises treating said patient with a combination of an NK1 -antagonist with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof, wherein the combination does not contain any additional active compounds having an antidepressant efficacy.
56. A method for treating a patient suffering from anhedonia, which comprises treating said patient with a combination of a NK1 -antagonist with an effective daily dose of pramipexole or a pharmaceutically acceptable salt or solvate thereof, wherein another active compound with an antidepressant efficacy is not concurrently administered.
57. A NK1 -antagonist for use in the treatment of anhedonia 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, wherein another active compound with an antidepressant efficacy is not concurrently administered.
58. A fixed dose combination for the treatment of anhedonia in a patient in need thereof, wherein the fixed dose combination contains active ingredients and inactive ingredients, and the active ingredients consist of pramipexole or a pharmaceutically acceptable salt or solvate thereof and an NK1 -antagonist.
59. A pharmaceutical composition for the treatment of anhedonia in a patient in need thereof, wherein the pharmaceutical composition contains active ingredients and inactive ingredients, and the active ingredients consist of pramipexole or a pharmaceutically acceptable salt or solvate thereof and an NK1 -antagonist.
60. The method of claim 38, wherein anhedonia is a symptom of a depressive disorder.
61. The method of claim 38, wherein anhedonia is a symptom of a maj or depressive disorder.
62. The method of claim 38, wherein the patient does not have a depressive disorder.
63. The method of claim 38, wherein anhedonia is due to or is a symptom of a neuroin flammatory disease.
64. The method of claim 38, wherein anhedonia is associated with a neurodegenerative disorder which is one or more selected from the group consisting of Parkinson’s disease, Alzheimer’s disease, post-traumatic stress disorder, and a substance abuse disorder.
65. The method of claim 64, wherein anhedonia is due to neurodegeneration of dopaminergic nigral neurons.
66. The method of claim 64, wherein anhedonia is due to Alzheimer’s disease.
67. The method of claim 64, wherein anhedonia is due to Parkinson's Disease.
68. The method of claim 64, wherein anhedonia is due to post-traumatic stress disorder.
69. The method of claim 64, wherein anhedonia is due to substance abuse disorder.
70. The method of claim 37, wherein anhedonia is due to a synucleinopathy.
71. The method of claim 37. wherein anhedonia is a symptom of or is associated with one or more selected from the group consisting of bipolar disorder, schizophrenia, schizoaffective disorder, personalia disorder, mild cognitive impairment, an autoimmune disorder, rheumatoid arthritis, psoriasis, multiple sclerosis, and anticancer treatment.
72. A method for enabling the use of a dose of pramipexole sufficient for the effective treatment of anhedonia in humans comprising administering a dose of an NK1- antagonist in combination with the dose of pramipexole, wherein the dose of the NK1- antagonist is selected to reduce to tolerable levels the dose limiting adverse effects of the dose of pramipexole.
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