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WO2025145022A1 - Compositions et méthodes de traitement de l'anhédonie - Google Patents

Compositions et méthodes de traitement de l'anhédonie 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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Prior art keywords
pramipexole
solvate
acceptable salt
pharmaceutically acceptable
antagonist
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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

La présente invention décrit la combinaison d'un antagoniste de 5HT3 et/ou d'un antagoniste de NK1 avec le pramipexole pour réduire ou éliminer les effets indésirables associés à l'utilisation du pramipexole et pour permettre l'utilisation de doses élevées de pramipexole afin de traiter l'anhédonie.
PCT/US2024/062080 2023-12-28 2024-12-27 Compositions et méthodes de traitement de l'anhédonie Pending WO2025145022A1 (fr)

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