WO2018039159A1 - Muscarinic m2-antagonist combination - Google Patents

Muscarinic m2-antagonist combination Download PDF

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WO2018039159A1
WO2018039159A1 PCT/US2017/047897 US2017047897W WO2018039159A1 WO 2018039159 A1 WO2018039159 A1 WO 2018039159A1 US 2017047897 W US2017047897 W US 2017047897W WO 2018039159 A1 WO2018039159 A1 WO 2018039159A1
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pharmaceutically acceptable
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hydrochloride
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Thomas N. Chase
Kathleen E. Clarence-Smith
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Chase Pharmaceuticals Corporation
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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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the invention pertains to the field of treating hypocholinergic disorders of the central nervous system, in particular of Alzheimer's type dementias, AD-type dementia, schizophrenia, schizophrenia associated dementia, Parkinson's dementia, Lewy body diseases, Down Syndrome, and chronic neuropathic pain, and provides a new combination of a cholinergic M 2 -receptor antagonist agent and an antiemetic agent, which optionally further includes an acetylcholinesterase inhibitor.
  • the present invention relates to a new combination of a centrally active, selective-muscarinic M 2 -receptor antagonist herein below also referred to as "M 2 -antagonist”or “M2-antagonist”, with an antiemetic agent substantially devoid of anticholinergic activity herein below also referred to as “non-anticholinergic Antiemetic Agent” (“naAEA”), as well as the optional addition of an acetyl choline esterase inhibitor (AChEI) to said M 2 -antagonist/naAEA combination.
  • naAEA non-anticholinergic Antiemetic Agent
  • This combination provides pro-cognitive activity by enabling safe administration of a M2- antagonist without inducing peripheral, dose-limiting adverse effects.
  • AD Alzheimer's disease
  • Ml through M5 Five subtypes of muscarinic receptors, Ml through M5, have been identified.
  • ACh refers to the neurotransmitter acetylcholine.
  • naAEA(s) non-anticholinergic Anti -Emetic Agent(s).
  • Non-anticholinergic refers to antiemetic medications not primarily regarded as anticholinergic agents; they are entirely devoid of anticholinergic activity or have an extremely low ability to prevent acetylcholine from acting at its cholinergic receptor sites.
  • Selective refers to M 2 -antagonists, and applies to antagonists of the mAChR sharing an affinity for the M 2 receptor subtype higher than that for the Mi and M 3 -M 5 receptor subtypes, i.e. a muscarinic antagonist having a ratio of (Ki for Mi and, respectively, M 3 -M 5 /Ki for M 2 ) greater than 1.
  • hypercholinergic disorder means a pathologic condition of the CNS due to or derived from a decrease in cholinergic transmission typically associated with events or diseases including but not limited to: Alzheimer disease, Alzheimer-type dementia, mild cognitive impairment, Lewy body disease dementia, Parkinson's disease dementia, post-stroke dementia, vascular dementia, traumatic brain injury, Down syndrome, anorexia nervosa, Tourette disease, tardive dyskinesia, Pick's disease, Huntington's chorea, Friedrich's ataxia, chronic neuropathic pain, falls, post-operative delirium, schizophrenia, schizophrenia associated dementia, and schizoaffective disorders.
  • CSF Cerebrospinal Fluid
  • Extended Release including sustained release, controlled release and slow release of the active ingredient from a composition by any administration route, in particular, but not limited to oral and parenteral (including transcutaneous, transdermal, intramuscular, intravenous, and subcutaneous) routes.
  • Transdermal delivery administration of drug via the skin which targets, without limitation, skin tissues just under the skin, other tissues or organs under the skin, systemic circulation, and/or the central nervous system.
  • Transdermal Therapeutic System administration of drug via transdermal delivery using transdermal drug formulations and transdermal patches incorporating such transdermal drug formulations.
  • maximum tolerated dose refers to the highest dose of a drug or treatment that does not cause unacceptable side effects. 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.
  • compositions and methods include the recited elements, but do not exclude others, “comprising” is inclusive of the terms “consisting of and “consisting essentially of .
  • consisting essentially of means that the methods and compositions may include additional steps, components or ingredients, but only if the additional steps, components or ingredients do not materially alter the basic and novel characteristics of the claimed methods and compositions.
  • compositions and methods consisting essentially of means that the subsequently named component(s) is necessarily included but that another unlisted ingredient(s) that does not materially affect the basic and novel properties can also be present.
  • compositions and methods when used to define compositions and methods, “consisting essentially of means excluding other elements of any essential significance to the combination for the intended use. Thus, for example, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants and pharmaceutically acceptable carriers.
  • pharmaceutically acceptable salt means either a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.
  • hypercholinergic disorder means a pathologic condition of the CNS due to or derived from a decrease in cholinergic transmission typically associated with events or diseases including but not limited to: Alzheimer disease, Alzheimer-type dementia, mild cognitive impairment, Lewy body disease dementia, Parkinson's disease dementia, post-stroke dementia, vascular dementia, traumatic brain injury, Down syndrome, anorexia nervosa, Tourette disease, tardive dyskinesia, Pick's disease, Huntington's chorea, Friedrich's ataxia, chronic neuropathic pain, falls, post-operative delirium, schizophrenia, schizophrenia associated dementia, and schizoaffective disorders.
  • Combination therapy means treating a patient with a combination of a selective- muscarinic M 2 -receptor antagonist that crosses the blood-brain barrier, with a non- anticholinergic antiemetic agent and/or a non-selective peripheral muscarinic receptor antagonist, and optionally further including an acetylcholinesterase inhibitor, as a therapeutic platform in a rotating, an alternating and/or a simultaneous treatment schedule or regimen.
  • Combination therapy may include a temporal overlap of other therapeutic agents, depending on the clinical course of a given hypocholinergic disease in a subject.
  • Acetylcholinesterase inhibitors currently constitute the major drug class used to treat AD type dementias. Medications of this type serve not only as part of the standard of care for patients suffering from a dementia of the AD type, but are also used off-label for various other, generally chronic and progressive, hypocholinergic CNS disorders.
  • AChEIs have the enhancement of ACh-mediated neurotransmission as a general mechanism of action. All work to increase and prolong the availability of ACh in the brain by inhibiting its degradatory enzyme acetylcholinesterase.
  • Four AChEIs have been approved by the U.S. F.D.A.
  • Rivastigmine has also been approved for the treatment of Parkinson's disease dementia.
  • AChEIs are available in various formulations including immediate release forms such as tablets, capsules and solutions as well as rapid dissolving and extended release forms for oral administration as well as those for parenteral (e.g. transdermal) administration.
  • AD type dementias Unfortunately, none of the AChEIs approved for use for AD type dementias provide more than modest symptomatic benefit to any of these disorders. A critical medical need thus exists to improve the efficacy of these cholinergic replacement therapies.
  • M 2 muscarinic receptors are generously expressed on the presynaptic terminals of cholinergic neurons projecting to the hippocampus and cerebral cortex as well as in most other brain regions involved in learning and memory processes (Alcantara AA et al. 2001; and Rouse ST et al. 2000; the disclosures of which are incorporated herein in their entirety by reference).
  • these autoreceptors act to inhibit further ACh synthesis and release, thus attenuating cholinergic transmission (Tzavara ET et al.
  • M 2 receptor knockout mice showed an impaired performance in passive avoidance testing that suggests a crucial role for these muscarinic receptors in the regulation not only of acetylcholine efflux but also of cognitive function (Tzavara ET et al. 2003).
  • drugs that block M 2 receptors increase ACh release and stimulate cholinergic transmission.
  • M 2 muscarinic receptor antagonists have been proposed as a potential cholinomimetic treatment of AD type dementia (Stoll C et al. 2009; the disclosure of which is incorporated herein in its entirety by reference).
  • BIBN-99 also improves scopolamine-induced amnesia in young animals (Quirion R et al. 1995; the disclosure of which is incorporated herein in its entirety by reference). In traumatic brain-injured rats, BIBN 99 has been found to attenuate cognitive deficits (Pike BR et al. 1995; the disclosure of which is incorporated herein in its entirety by reference). The efficacy of BIBN-99 in these studies is presumed to relate to its antagonistic properties on negative muscarinic M 2 autoreceptors. Taken together, the forgoing observations could have implications for the treatment of degenerative disorders associated with impaired cholinergic function such as the AD type dementias (Rowe WB et al. 2003; the disclosure of which is incorporated herein in its entirety by reference).
  • Piperazine, piperazinyl-piperidine and piperidinyl-piperidine derivatives form a series of muscarinic M 2 -antagonists studied for their pro-cognitive properties.
  • the muscarinic M 2 receptor antagonist 4-cyclohexyl-alpha-[4[[4- methoxyphenyl]sulphinyl]-phenyl]-l-piperazineacetonitrile (SCH 57790) produces a dose-related increase in brain acetylcholine release and enhances cognitive performance in rodents and nonhuman primates, effects that were qualitatively similar to those produced by the AChEI donepezil.
  • the forgoing results support the view that blockade of muscarinic M 2 receptors is a viable approach to enhancing cognitive performance (Carey GJ et al. 2001; the disclosure of which is incorporated herein in its entirety by reference).
  • the piperidinyl-piperidine derivative SCH-217443 shows activity in a rat model of cognition (Greenlee W et al. 2001; the disclosure of which is incorporated herein in its entirety by reference).
  • Methoctramine a polym ethyl enetetraamine, acts as a muscarinic antagonist that binds preferently to the pre-synaptic M 2 receptor.
  • the bilateral intrastriatal infusion of methoctramine improves procedural memory performance presumably by enhancing the release of acetylcholine (Lazaris A et al. 2003; the disclosure of which is incorporated herein in its entirety by reference).
  • drugs identified as having relatively selective M 2 muscarinic receptor antagonist activity but receiving little or no investigative attention in preclinical cognitive models, include: otenzepad (AF-DX 116), its (+)-enantiomer (AF-DX 250) and its analog AF-DX 384, ( ⁇ )-5, l 1-dihydro-l l-([(2-[(dipropylamino)methyl]-l- piperidinyl)ethyl)amino]carbonyl)-6H-pyrido(2,3-b)(l,4)benzodiazepine-6-one;
  • caproctamine and benextramine.
  • - may be orally administered to a human being at a dose of 120 mg bid or 240 mg bid; - does not induce manifest muscarinic adverse effects after single oral doses of 120, 240 and 480 mg; and - gives mild and tolerable adverse events, including palpitations, dry mouth and headache in about 20% of the subjects, when administered at 270 to 810 mg/day, but no other information of a clinical nature concerning otenzepad appears in the subsequent literature, specifically, no information concerning the adequacy of its cognitive efficacy at the doses administered to patients with hypocholinergic type dementias is found in the literature.
  • AD type dementia In a clinical study (Sramek JJ et al. 1998), the fixed-dose Maximum Tolerated Dose of LU-25-109 was established to be 150 mg t.i.d. In binding assays, alvameline acts as a partial Mi agonist and as a M 3 and mainly M 2 antagonist with low affinities for other receptor types but is extensively metabolized in rodents and humans (Christensen EB et al. 1999). To evaluate the therapeutic effect of LU 25- 109, a 6-month, randomized, double-blind, placebo-controlled trial comparing three doses of Lu25-109 with placebo was carried out in 496 patients with probable AD.
  • Dimethindene also known as dimetindene (trade name Fenistil)
  • dimetindene is N,N-Dimethyl-3- [l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine, CAS 0005636-83-9. It can be prepared as described by Huebner et al, in US 2,970,149, which also describes the optically active form of 2-(2-dimethylamino-ethyl))-3-[l-(2-pyridyl)-ethyl]-indene with an [a] D 25° of +70, or in J Am Chem Soc 1960, 87, 2077; the disclosure of which is incorporated herein in its entirety by reference.
  • Dimet(h)indene is sold OTC in a number of countries worldwide as orally or locally administered antipruritic. Dimethindene for oral administration is available for example in IR coated tablets containing 1 mg dimet(h)indene or in ER unit forms containing 4 mg dimet(h)indene and the daily recommended dose is from 3 to 6 mg.
  • the ( S)-(+)-dimethindene, N,N- Dimethyl-3-[(l,S)-l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine is a potent M 2 - selective muscarinic receptor antagonist (Pfaff et al. 1995; the disclosure of which is incorporated herein in its entirety by reference).
  • the (R)-(-)-enantiomer is the eutomer (responsible for bioactivity) for histamine Hi receptor binding (Histamine 3 ⁇ 4 -receptor antagonist).
  • Binding selectivity results indicate that it binds to the muscarinic M 2 receptor with a 3 ⁇ 4 value of 0.27 +/- 0.02 nM (Maggio R et al. 1994; the disclosure of which is incorporated herein in its entirety by reference).
  • Tripitramine can be prepared as described by Melchiorre et al. 1993; the disclosure of which is incorporated herein in its entirety by reference).
  • 3-methyldecahydronaphtho[2,3-c]furan-l(3H)-one is a potent muscarinic receptor antagonist that displays selectivity for the M 2 and M 4 receptors but failed in clinical development.
  • WO0000488 discloses di-N-substituted piperazines and 1,4-di-substituted piperidines linked to a pyridine, pyrazine or thiophene group via a substituted methyl group. These compounds are muscarinic agonists useful in the treatment of cognitive disorders, pharmaceutical compositions containing the compounds, methods of treatment using the compounds, and to the use of said compounds in combination with acetylcholinesterase inhibitors.
  • a selective M 2 receptor antagonist with a bipiperidine moiety, showing superior M 2 receptor selectivity profile over SCH 211803, is "Compound 30" of formula
  • Wang Compound 30 disclosed by Y. Wang et al in Bioorg Med Chem Lett. 2002, 12, Pages 1087-1099 ("Sulfide analogues as potent and selective M2 muscarinic receptor antagonist”), the disclosure of which is incorporated herein in its entirety by reference.
  • Palani Compound 31 disclosed by A. Palani et al., Bioorg. Med. Chem Lett, 2004, 14(7) 1791-1794 (“Isopropyl amide derivatives of potent and selective muscarinic M2 receptor antagonists”), the disclosure of which is incorporated herein in their entirety by reference.
  • WO 03/031412 discloses piperidine compounds as muscarinic receptor antagonists, as well as methods for preparing such compounds.
  • this document discloses pharmaceutical compositions comprising such muscarinic receptor antagonists as well as methods for using them to treat cognitive disorders such as Alzheimer's disease.
  • An improvement in the treatment of the cognitive disorders globally designated as hypocholinergic disorders of the CNS including dementias of Alzheimer's type, is possible by combining an AChEI with a nsPAChA (US 8,404,701, the disclosure of which is incorporated herein in its entirety by reference) or with a non-anticholinergic antiemetic agent (US 8,877,768, the disclosure of which is incorporated herein in its entirety by reference).
  • the present inventors recognized the critical need to take advantage of the potent activity of a M2 muscarinic antagonist for the treatment of hypocholinergic disorders as defined above, in particular AD type dementia, schizophrenia, and schizophrenia associated dementia.
  • the present invention relates to a pharmaceutical combination comprising:
  • a muscarinic receptor antagonist selected from the group consisting of centrally active, selective M 2 -muscarinic cholinergic receptor antagonists (M 2 -antagonist); and
  • naAEA non-anticholinergic antiemetic agent
  • the M 2 -antagonist Component (a) in the combination of the present invention may be selected from the group consisting of:
  • Component (a) is present in an amount from 0.5 mg to 1500 mg.
  • the naAEA Component (b) in the combination of the present invention may be any antiemetic agent currently used for suppress vomiting of any origin and is normally selected from the group consisting of (bl) 5-hydroxytryptamine -3 antagonists ("5-HT3- antagonists”); (b2) dopamine antagonists (DA-antagonists”); (b3) HI -histamine antagonists (HI -antagonists); (b4) cannabinoid agonists ("cannabinoids”); and (b5)
  • Neurokinine-1 antagonists (" K1 -antagonists").
  • the present inventors found that, in order to assure a safe treatment of hypocholinergic disorders, the non-anticholinergic antiemetic agent Component (b) must be administered in combination with the M 2 -antagonist Component (a) from the start of the treatment of a patient with this combination and that said combination is essential for the continuation of said therapeutic treatment.
  • the invention provides a combination wherein said naAEA Component (b) and said M 2 -antagonist Component (a) are present in a fixed-dose combination as a pharmaceutical composition in dosage unit form comprising said naAEA and said M 2 -antagonist in admixture with a pharmaceutical carrier.
  • said the M 2 -antagonist/naAEA fixed-dose combination will also be referred to as "Component (a/b)".
  • the novel pharmaceutical composition in dosage unit form comprising, as active ingredients, (a) a M 2 -antagonist; and (b) a naAEA, in admixture with a pharmaceutical carrier or vehicle, is a particularly advantageous embodiment of the present invention.
  • the present invention also provides the addition of an AChEI to the above M 2 - antagonist/naAEA combination, thus assuring a maximum supply of acetylcholine to the CNS by the administration of a combination of the three components.
  • the third AChEI component will also be designated as “Component (c)”.
  • Components (b) and Component (c) are formulated in the same unit form, said fixed- dose combination will also be designated as "Component (b/c)".
  • the combination of the present invention allows the administration of a M2- antagonist at even high doses, never previously administered to a human being, without any sign of dose-limiting adverse effects thus, on one side, eliminating the dose-limit that heretofore did not permit the full expression of the M 2 -antagonists' potency and, on the other side, allowing the treatment with said M 2 -antagonists of patients suffering from hypocholinergic disorders such as Alzheimer type dementia.
  • the present invention also relates to a method of treating a hypocholinergic disorder comprising administering a pharmaceutical combination as described herein, to a mammalian, preferably human, subject in need thereof.
  • the method or the use according to the present invention involves administering to a patient in need thereof, an effective dose of a M 2 -antagonist, in combination with a non-anticholinergic antiemetic agent (naAEA)
  • naAEA non-anticholinergic antiemetic agent
  • the hypocholinergic disorder is selected from the group consisting of schizophrenia, schizophrenia associated dementia, and schizoaffective disorders.
  • hypocholinergic disorder is Alzheimer type dementia.
  • acetylcholine reduces levels of neurotransmitters including acetylcholine occur in dementias such as the Alzheimer disease (AD) type, and reduced cholinergic transmission is thought to attend the cognitive deficits observed in schizophrenia, and schizophrenia associated dementia.
  • AD Alzheimer disease
  • ACh acetylcholine
  • drugs known to augment cholinergic transmission in the Central Nervous System (CNS) are the mainstay of current therapy.
  • other diseases of the nervous system also involve decreased cholinergic transmission and are also known as hypocholinergic syndromes and disorders of the central nervous system, herein above referred to as "hypocholinergic disorders”.
  • the present invention provides a combination of a muscarinic antagonist that is a M2-antagonist and a non-anticholinergic antiemetic agent.
  • the present invention provides a treatment based on selective M 2 antagonism at doses that could not previously be achieved due to adverse effects.
  • selective M 2 muscarinic antagonists to treat hypocholinergic disorders of the CNS such as dementia of the AD type and schizophrenia or schizophrenia associated dementia.
  • a major deterrent to such clinical investigations, as described above, is that the treatment with muscarinic agonists and/or antagonists has been limited by dose-limiting side effects, especially those reflecting hyperstimulation of peripheral muscarinic receptors.
  • the present inventors discovered that the lack of efficacy of the tested M2- antagonists was not due to an intrinsic inactivity of said compounds in humans but to an insufficient M 2 -antagonist action in the CNS and that, as a consequence, a major cause of failure of such clinical investigations, as described above, was that the treatment with muscarinic agonists or antagonists has been limited by dose-limiting side effects, especially those reflecting hyperstimulation of peripheral muscarinic receptors.
  • M 2 antagonists do not mention a possible combination of M 2 antagonists with non-anticholinergic antiemetic agents, nor that the administration of such a combination can enable the safe and tolerable administration of doses of M 2 -antagonists capable of potentiating central cholinergic transmission so as to achieve efficacy in those suffering from hypocholinergic disorders, such as AD type dementias and schizophrenia or schizophrenia associated dementia, as provided in the present invention.
  • the present invention provides the combination of a centrally acting, selective muscarinic-M 2 -antagonist drug and a non-anticholinergic antiemetic agent for the safe treatment of hypocholinergic disorders such as Alzheimer, dementia of Alzheimer type, schizophrenia, schizophrenia associated dementia, and other hypocholinergic type cognitive or behavioral disorders.
  • the present invention thus enables the heretofore inapplicable, safe and tolerable use of a presynaptic M 2 muscarinic receptor antagonist in the treatment of hypocholinergic disorders such as Alzheimer, dementia of Alzheimer type, schizophrenia, schizophrenia associated dementia, and other hypocholinergic type cognitive or behavioral disorders, such as those described above, by combining said M 2 - antagonist with a non-anticholinergic antiemetic agent.
  • hypocholinergic disorders such as Alzheimer, dementia of Alzheimer type, schizophrenia, schizophrenia associated dementia, and other hypocholinergic type cognitive or behavioral disorders, such as those described above
  • This combination allows M 2 - antagonists to be safely used at high doses, thus allowing therapeutically adequate blockade of M 2 -receptor with attending increase in acetylcholine presynaptic release.
  • the finding of the present invention eliminates the dose-limit that, in the past, caused the failure of all clinical trials to demonstrate efficacy, thus providing a method for treating Alzheimer type dementia as well as central hypocholinergic disorders of the CNS by enabling the full efficacy of M 2 -antagonists.
  • the present invention provides a composition useful for treating a patient with a hypocholinergic disorder as described herein, which comprises a non-anticholinergic antiemetic agent, in combination with a M 2 -antagonist.
  • the present invention provides said pharmaceutical combination or composition comprising a M 2 -antagonist and a naAEA for use in combating a hypocholinergic disorder in a patient.
  • the present invention also provides the addition of an AChEI to the above combination, thus assuring a maximum supply of acetylcholine to the CNS by the administration of a triple combination.
  • the present invention provides a method for treating a patient with a hypocholinergic disorder of the CNS as described herein, which comprises treating such patient in need of treatment with a non-anticholinergic antiemetic agent, in combination with a M 2 -antagonist.
  • the method of the present invention may further include administration of an AChEI.
  • the present invention provides a pharmaceutical combination comprising, as Components:
  • a muscarinic receptor antagonist selected from the group consisting of M 2 - muscarinic cholinergic receptor antagonists (M 2 -antagonists);
  • said pharmaceutical combination comprises, as Components:
  • said pharmaceutical combination comprises, as
  • a naAEA selected from the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, domperidone and pharmaceutically acceptable salts and solvates thereof, metoclopramide and pharmaceutically acceptable salts and solvates thereof, in an amount of from 50% to 300% the maximum amount contained in the commercial preparations of said naAEA at the time of this filing for the treatment of nausea/vomiting, in a pharmaceutical composition in admixture with a pharmaceutical carrier.
  • said pharmaceutical combination comprises as Components:
  • composition in dosage unit form comprising
  • said pharmaceutical combination comprises as Components:
  • composition in dosage unit form comprising
  • a preferred pharmaceutical combination comprises
  • a naAEA selected from the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, domperidone and pharmaceutically acceptable salts and solvates thereof and metoclopramide and pharmaceutically acceptable salts and solvates thereof, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and, optionally,
  • the present invention provides a method of using the above combinations for the treatment of hypocholinergic disorders in CNS, as described herein.
  • the AChEI Component (c) When the AChEI Component (c) is present in the combination, said Component (c) may be also present in a fixed-dose combination Component (b/c) in admixture with the naAEA Component (b) and with a pharmaceutical carrier or vehicle, as illustrated in US 9.192,591, the contents of which are incorporated herein in their entirety.
  • the present invention also provides a M 2 -antagonist/naAEA/AChEI combination as described herein wherein the naAEA Components (b) and the AChEI Component (c) are formulated in the same unit form.
  • the combinations of the invention may be used for the treatment of Alzheimer type dementia and more generally for hypocholinergic disorders of the central nervous system, including Parkinson's disease dementia, Lewy Body Dementia, Frontotemporal Lobar Dementia, Mild Cognitive Impairment (MCI), Vascular Dementia, Traumatic Brain Injury, falls, post-operative delirium, Down Syndrome, Anorexia nervosa, and Schizophrenia.
  • Parkinson's disease dementia Lewy Body Dementia
  • Frontotemporal Lobar Dementia Mild Cognitive Impairment (MCI)
  • Vascular Dementia Traumatic Brain Injury, falls, post-operative delirium, Down Syndrome, Anorexia nervosa, and Schizophrenia.
  • Any M 2 -antagonist which is able to cross the brain blood barrier of a human in order to block the presynaptic muscarinic M 2 -receptor thus allowing the increase of acetylcholine transmission in the CNS may be used as Component (a) according to the present invention.
  • the M 2 -antagonists used as Component (a) are muscarinic receptor antagonists that are selective - as herein above defined - for the M 2 -receptor subtype.
  • Preferred Component (a) is a M 2 -antagonist selected from the group consisting of
  • the M2-antagonists are formulated in a pharmaceutical composition in IR- form or in ER-form, including a TTS, in admixture with a pharmaceutical carrier or vehicle.
  • the compositions in dosage unit form contain said M 2 -antagonist at a dose which is dependent on the intrinsic potency of said M 2 -antagonist and is from 0.5 mg to 1500 mg, normally from 0.5 mg to 1000 mg, when included in a pharmaceutical composition in dosage unit form, as set forth above, wherein said M 2 -antagonist is present alone or in combination with a naAEA in a fixed-dose combination in said unit form, generally in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
  • said M2-antagonists are administered to patients in need of said treatment at a daily dose of from 1.5 mg to 3000 mg, or from 1.5 mg to 1500 mg by any administration route.
  • the pharmaceutical composition comprising the M 2 -antagonist may be used, in combination with Component (b) and, optionally, with an AChEI Component (c), for the treatment of a patient suffering from any of the hypocholinergic disorders described herein with a dose of M 2 -antagonist heretofore never tested for the adverse effects exhaustively illustrated herein above and in the literature.
  • compositions are preferably formulated in dosage unit forms for oral, including buccal (as orodispersible or orosoluble preparations), topical, transmucosal or parenteral, in particular, transdermal, administration, wherein the active ingredient is mixed with a pharmaceutical carrier or vehicle.
  • alvameline as free base or a salt or solvate thereof, especially as its tartrate, may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg;
  • - tripitramine as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, may be present in an amount of from 10 mg to 200 mg, preferably from 25 mg to 100 mg;
  • - dimethindene preferably as the maleate thereof, is present as racemate or as its S(+) enantiomer, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg, from 1.5 mg to 8 mg, from 1.5 to 6 mg or from 1.5 to 4 mg in a IR-form or, as the free base or the maleate thereof, in an amount of from 3 mg to 32mg, preferably from 4 mg to 32 mg , from 4.4 to 32 mg, from 6 mg to 32 mg, from 6 mg to 16 mg or from 3 mg to 10 mg, in an ER-form, including a TTS;
  • - otenzepad as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate (INN: monomesilate, US AN: monomesylate) thereof, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg in a IR unit form or as the free base or as one of the aforementioned salts, in an amount of from 200mg to 500 mg, preferably from 300 mg 500 mg, in an ER-form, including a TTS;
  • - AQ-RX 741 as free base or as a salt or solvate thereof, especially as its monomethanesulfonate salt, may be present in an amount of from 10 mg to 500 mg, preferably from 10 mg to 250 mg in a IR-form or, as the free base or the methanesulfonate salt thereof, in an amount of from 20 mg to 500 mg, preferably from 50 mg to 500 mg, in an ER-form, including a TTS.
  • compositions are destined for their use in the treatment of hypocholinergic disorders such as AD type dementia by administering said compositions once, twice or three times per day.
  • the pharmaceutical compositions prepared by using the M 2 -antagonist Component (a), which acts as cholinergic agent in the CNS to improve the symptoms of Alzheimer type dementia, in a quantity sufficient to maximally alleviate disease-associated neurobehavioral symptoms are present in unit forms also containing other active ingredients, in particular the naAEA Component (b) to form a fixed-dose combination assuring a minimum of treatment-associated adverse effect according to the present invention.
  • Said fixed dose combination may be concurrently or sequentially administered in combination with a pharmaceutical composition in dosage unit form comprising an AChEI in admixture with a pharmaceutical carrier.
  • Antiemetic medications commonly used to treat emesis, and not primarily regarded as anticholinergic agents, that are entirely devoid of anticholinergic activity or have an extremely low ability to prevent acetylcholine from acting at its cholinergic receptor sites in the brain may be used as Component (b) of the pharmaceutical combination of the present invention.
  • said Component (b) is a non-anticholinergic antiemetic agent selected from the group consisting of (bl) 5HT3 -antagonists, (b2) DA-antagonists, (b3) HI -antagonists, (b4) cannabinoids, (b5) K1 -antagonists.
  • Typical non-anticholinergic antiemetic agents are
  • 5HT3 -antagonists such as 9-methyl-3-[(2-methyl-lH- imidazol-l-yl)methyl]-l,2,3,9-tetrahydrocarbazol-4-one (ondansetron) and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride dihydrate, described in EP 191562; 3S-ondansetron; 3R-onsdansetron; (3R)-10-oxo-8- azatricyclo[5.3.1.03,8]undec-5-yl lH-indole-3-carboxylate (dolasetron) and pharmaceutically acceptable salts and solvates thereof, in particular its monomethanesulfonate (mesylate or mesilate) monohydrate, described in EP 266730; 1 -methyl -N-(9-methyl-9-azabicyclo[3.3. l]non-3-yl)-indazole-3-carboxamide
  • DA-antagonists such as 5-chloro-l-(l-[3-(2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)propyl]piperidin-4-yl)-lH-benzo[d]imidazol- 2(3H)-one (domperidone) and pharmaceutically acceptable salts and solvates thereof, particularly its maleate; l-[l-[4-(4-fluorophenyl)-4-oxo-butyl]-3,6-dihydro-2H- pyridin-4-yl]-3H-benzoimidazol-2-one (droperidol); 4-[4-(4-chlorophenyl)-4-hydroxy- 1 -piperidyl]- 1 -(4-fluorophenyl)-butan- 1 -one (haloperidol); 3 -(2-chloro- 10H- pheno
  • HI histamine receptor antagonists such as l-[(4-chlorophenyl)- phenyl-methyl]-4-[(3-methylphenyl)methyl]piperazine (meclizine or meclozine) and pharmaceutically acceptable salts and solvates thereof, particularly its dihydrochloride monohydrate; dimethyl [ 1 -( 1 OH-phenothiazin- 10-yl)propan-2-yl]amine (promethazine) and pharmaceutically acceptable salts and solvates thereof, particularly its hydrochloride; 3 -(2-chloro-l OH-phenothiazin- 10-yl)-N,N-dimethyl-propan-l -amine (chlorpromazine) or a salt thereof, particularly its hydrochloride; 2-chloro-10-[3-(4- methyl-l-piperazinyl)propyl]-10H-phenothiazine (prochlorperazine) and pharmaceutically acceptable salt
  • annabinoids such as cannabis; (6aR-trans)- 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-l-ol
  • K1 -antagonists such as 5-[[(2R,3S)-2- [(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4- mo holinyl]methyl]-l,2-dihydro-3H-l,2,4-triazol-3-one (aprepitant); (2S,4S)-4-(4- Acetyl- 1 -piperazinyl)-N- [( 1 R)- 1 - [3 , 5 -bi s(trifluoromethyl)phenyl] ethyl] -2-(4-fluoro-2- methylphenyl)-N-methyl-l-piperidinecarboxamide (casopitant); 2-[3,5- bis(trifluoromethyl)phenyl]-N,2-dim
  • naAEAs are the compounds available in drugs for the current antiemetic therapy, in particular,
  • alosetron hydrochloride available at the oral dose/unit form (in alosetron) of 0.5-1 mg;
  • dolasetron mesylate monohydrate available at the oral dose (in dolasetron) of 50-100 mg;
  • ondansetron hydrochloride dihydrate available at the oral dose (in ondansetron) of 4-8 mg;
  • - palonosetron hydrochloride available at a the oral dose (in palonosetron) of 0.5 mg and i.v. dose (in palonosetron) of 0.25 mg;
  • tropisetron hydrochloride available at the oral dose (in tropisetron) of 5 mg;
  • chlorpromazine hydrochloride available at the oral dose (in chlorpromazine) of 25-100 mg;
  • bromopride dihydrochloride monohydrate available at the oral dose (in bromopride) of 10 mg
  • clebopride malate (1 : 1) available at a oral dose (in clebopride) of 1 mg
  • trimethobenzamide hydrochloride available at the oral dose (in trimethobenzamide) of 100 mg
  • - meclizine also called meclozine
  • promethazine hydrochloride available at the oral dose (in promethazine) of 25 mg;
  • the non-anticholinergic antiemetic agent Component (b) is formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier to be administered with the M 2 -antagonist Component (a)
  • the pharmaceutical combination may further include, as Component (c), an AChEI.
  • Component (a) sufficient to maximally alleviate disease- associated cognitive and other neurobehavioral symptoms is illustrated in the above "The M 2 -antagonists" section.
  • the Component (b) is advantageously selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and pharmaceutically acceptable salts and solvates thereof,
  • the non-anticholinergic antiemetic agent, Component (b) is present, generally in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle, in an amount of from 50% to 600%, normally 50% to 300%, of the amount of the said non-anticholinergic antiemetic agent contained as a sole active ingredient in the aforementioned, currently used brand or generic drugs.
  • Each of said typical non-anticholinergic antiemetic agents is present in the pharmaceutical composition, as Component (b), in an amount ranging from 50% of the minimum amount to 600%, and in some cases beyond 600%, normally 300%, of the maximum amount of said typical non-anticholinergic antiemetic agent contained in the corresponding, currently used generic or brand drug for its antiemetic indication in IR form.
  • Advantageous Component (b) is selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 3 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 300 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 3 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 48 mg, up to 64 mg; palonosetron, and pharmaceutically acceptable salts and solvates thereof
  • Preferred Component (b) is selected from the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in ondansetron) of from 2 mg to 32 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in granisetron) of from 0.5 mg to 3 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in an amount (in metoclopramide) of from 5 mg to 30 mg; dronabinol, in an amount of from 1.25 mg to 30 mg; nabilone, in an amount of from 0.25 mg to 3 mg; aprepitant, in an amount of from 20 mg to 375 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 90 mg to 360 mg; and casopitant, in
  • the non-anticholinergic antiemetic agent is present, in an IR unit form, in an amount ranging from 50% to 200% of the maximum amount of said antiemetic agent contained in the currently administered IR dosage unit forms for the treatment of emesis or, in an ER unit form, in an amount ranging from 75%) to 300%) of the currently administered IR dosage unit forms for the treatment of emesis.
  • ondansetron or a pharmaceutically acceptable salt or solvate thereof, in particular its hydrochloride dihydrate is present in an amount (in ondansetron) of from 2 mg to 16 mg per dosage unit in an IR unit form or in an amount of from 3 mg to 24 mg, preferably from 8 mg to 24 mg in an ER unit form;
  • alosetron or a pharmaceutically acceptable salt thereof, in particular its hydrochloride is present in an amount (in alosetron) of from 0.25 mg to 2 mg per dosage unit in an IR unit form or in an amount of from 0.375 mg to 3 mg, preferably from 1 mg to 3 mg, in an ER unit form;
  • azasetron or a pharmaceutically acceptable salt thereof, in particular its hydrochloride is present in an amount of from 5 mg to 20 mg per dosage unit in an IR unit form or in an amount of from 7.5 mg to 30 mg, preferably from 10 mg to 30
  • Preferred Component (b) is a pharmaceutical composition in dosage unit form comprising a non-anticholinergic antiemetic agent selected from the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in ondansetron) of from 8 mg to 24 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in granisetron) of from 0.5 mg to 3 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 10 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in an amount (in metoclopramide) of from 105- mg to 30 mg; dronabinol, in an amount of from 10 mg to 30 mg; nabilone, in an amount of from 1 mg to 3 mg; aprepitant, in an amount of from 125 mg to 375 mg; netupitant, in an amount of from 300 mg to
  • compositions and methods for treating hypocholinergic disorders which comprises administering to a patient in need of said treatment the above-illustrated combination.
  • Component (a) and Component (b) of the combination may be administered simultaneously or sequentially to said patient, Component (a) being indifferently administered before or after Component (b).
  • Component (a) and Component (b) may also be administered by the same or a different administration route.
  • the invention may also include a third component, Component (c) that is an AChEI, also formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
  • Component (c) that is an AChEI, also formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
  • the present invention provides the combination of any M 2 -antagonist and any naAEA as exemplified in the respective sections herein, each formulated in pharmaceutical composition in admixture with a pharmaceutical carrier.
  • the combination of the present invention may be a combination comprising or consisting essentially of
  • M 2 -antagonists such as those described herein, each in a pharmaceutical composition in dosage unit form, in admixture with a pharmaceutical carrier, said M 2 -antagonist being preferably selected from the group consisting of 5-(2-ethyl- 2H-tetrazol-5-yl)-l-methyl-l,2, 3,6-tetrahydropyridine (alvameline) and pharmaceutically acceptable salts and solvates thereof), 5,l l-dihydro-8-chloro-l l- [[4-[3-[(2,2-dimethyl-l-oxopentyl)ethylamino]propyl]-l-piperidinyl]acetyl]-6H- pyrido[2,3-b][l,4]benzodiazepin-6-one (BIBN-99) and pharmaceutically acceptable salts and solvates thereof; racemic l l-[[2-(Diethylamino)methyl]-l-piperidinyl
  • each of the Components (a) and (b) is in pharmaceutical composition in dosage unit form wherein each of said components is in admixture with a pharmaceutical carrier or vehicle.
  • an advantageous combination may be a combination comprising or consisting essentially of
  • a M 2 -antagonist selected from the group consisting of alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tripitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; ( ⁇ )-dimethindene or ,S'(+)-dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount, in o
  • another advantageous combination may be a combination comprising or consisting essentially of
  • a M 2 -antagonist selected from the group consisting of alvameline, as free base or a salt or solvate thereof, especially as its tartrate, in an amount, in alvameline, of from 200 mg to 600 mg; tripitramine sesquifumarate in an amount, in tripitramine, of from 15 mg to 150 mg; ( ⁇ )-dimethindene or ,S'(+)-dimethindene maleate, in an amount of from 1.5 mg to 25 mg; otenzepad maleate (1 : 1), in an amount of from 200 mg to 400 mg; and AQ-RX 741 monomethanesulfonate, in an amount of from 15 mg to 300 mg, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
  • the pharmaceutical combinations of this first embodiment of the present invention are useful for the treatment of hypocholinergic disorders, and even high doses of a M 2 -antagonist Component (a), may be present to improve symptoms of AD type dementia or schizophrenia without adverse effects to a greater extent.
  • the present invention provides a method for treating hypocholinergic disorders, which comprises administering to a patient in need of said treatment the combinations described herein in one embodiment.
  • Component (a), and Component (b) of the combination may be administered simultaneously or sequentially to said patient, Component (a) being indifferently administered before or after Component (b).
  • Component (a) and Component (b) may also be administered by the same or a different administration route.
  • the present invention provides a pharmaceutical combination comprising or consisting essentially of, as Components: (a) a M 2 -antagonist, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
  • a naAEA selected from the group consisting of (bl) 5HT3 -antagonists, (b2) DA- antagonists, (b3) HI -antagonists, (b4) cannabinoids, (b5) K1 -antagonists, and the netupitant-palonosetron fixed-dose combination, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
  • a naAEA consisting of a 5HT3 -antagonist selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, azasetron and pharmaceutically acceptable salts and solvates thereof; ondansetron and pharmaceutically acceptable salts and solvates thereof; granisetron and pharmaceutically acceptable salts and solvates thereof; dolasetron and pharmaceutically acceptable salts and solvates thereof, ramosetron and pharmaceutically acceptable salts and solvates thereof; tropisetron and pharmaceutically acceptable salts and solvates thereof; and palonosetron and pharmaceutically acceptable salts and solvates thereof, alone or in combination with the K1 -antagonist netupitant, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
  • a 5HT3 -antagonist selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, azasetron and pharmaceutically acceptable salts and solvates thereof; ondansetron and pharmaceutically acceptable
  • another advantageous combination is a combination comprising or consisting essentially of:
  • a naAEA consisting of a 5HT3 -antagonist selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable
  • a further advantageous combination is a combination comprising or consisting essentially of:
  • a naAEA consisting of a DA-antagonist consisting of domperidone and pharmaceutically acceptable salts and solvates thereof such as the maleate; metoclopramide and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride monohydrate, bromopride and pharmaceutically acceptable salts and solvates thereof such as the monohydrochloride or the dihydrochloride monohydrate, alizapride and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride, and clebopride and pharmaceutically acceptable salts and solvates thereof such as the malate and the hydrochloride monohydrate; in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
  • a naAEA consisting of a DA-antagonist consisting of domperidone or a pharmaceutically acceptable salt thereof, in particular its maleate, in an amount (in domperidone) of from 5 mg to 20 mg per dosage unit in an IR unit form or in an amount of from 7.5 mg to 60 mg, preferably from 10 mg to 60 mg, in an ER unit form; metoclopramide or a pharmaceutically acceptable salt or solvate thereof, in particular its monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 20 mg per dosage unit in an IR unit form or in an amount of from 7.5 mg to 30 mg, preferably from 10 mg to 30 mg, in an ER unit form; alizapride or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, in an amount (in alizapride) of from 25 mg to 100 mg per dosage unit in an IR unit form or in an amount of from 37.5 mg to 300 mg, preferably from 100 mg to 300 mg,
  • a naAEA consisting of a histamine HI receptor antagonists selected from the group consisting of meclizine (meclozine) and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride monohydrate; promethazine and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride; chlorpromazine and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride, prochlorperazine and pharmaceutically acceptable salts and solvates thereof such as the dimaleate, the dimesylate or the 1,2-ethanedisulfonate (1 : 1) (edisilate); hydroxyzine and pharmaceutically acceptable salts and solvates thereof such as the dihydrochloride or the 1, 1 '-methylene bis(2-hydroxy-3- naphthalenecarboxylic acid (pamoate) salt; in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
  • meclizine meclozine
  • a further advantageous combination is a combination comprising or consisting essentially of the following Components:
  • a naAEA consisting of a histamine HI receptor antagonists selected from the group consisting of meclizine or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, in an amount (in meclizine) of from 6.25 mg to 100 mg per dosage unit in an IR unit form or in an amount of from 37.5 mg to 150 mg, preferably from 50 mg to 150 mg, in an ER unit form; chlorpromazine or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 200 mg per dosage unit in an IR unit form or in an amount of from 75 mg to 300 mg, preferably from 150 mg to 300 mg, in an ER unit form; prochlorperazine or a pharmaceutically acceptable salt thereof, in particular its maleate, in an amount (in prochlorperazine) of from 6.25 mg to 100 mg per dosage unit in an IR unit form or in an amount of from 37.5 mg to 150 mg, preferably from 50 mg to 150
  • the invention provides a specific M 2 - antagonist/naAEA combination comprising
  • a naAEA consisting of a fixed-dose combination comprising palonosetron, in an amount of from 0.25 mg to 3 mg of palonosetron or a pharmaceutically acceptable salt thereof such as its hydrochloride and from 150 mg to 600 mg of netupitant, in admixture with a pharmaceutical carrier formulated in an oral IR formulation.
  • an advantageous combination may be a combination comprising or consisting essentially of (a) a pharmaceutical composition comprising alvameline or a pharmaceutically acceptable salt or solvate thereof, an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg,
  • a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, azasetron and pharmaceutically acceptable salts and solvates thereof; ondansetron and pharmaceutically acceptable salts and solvates thereof; granisetron and pharmaceutically acceptable salts and solvates thereof; dolasetron and pharmaceutically acceptable salts and solvates thereof, ramosetron and pharmaceutically acceptable salts and solvates thereof; tropisetron and pharmaceutically acceptable salts and solvates thereof; and palonosetron and pharmaceutically acceptable salts and solvates thereof, domperidone and pharmaceutically acceptable salts and solvates thereof such as the maleate; chlorpromazine and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride; prochlorperazine and its salts and solvates, particularly the dimaleate and the dimesylate; promethazine and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride; and 4-ami
  • An advantageous combination according to this fourth embodiment may be a combination comprising or consisting essentially of, as Components:
  • a pharmaceutical composition comprising alvameline tartrate, in an amount, in alvameline, of from 200 mg to 600 mg, in admixture with a pharmaceutical carrier; and a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof,
  • the pharmaceutical composition Component (a) comprises alvameline, as free base or as its tartrate, in an amount from 160 mg to 960 mg, in particular, from 160 mg to 480 mg in an IR- formulated oral composition or in an amount of from 240 mg to 960 mg in an ER- formulated composition or device, including a TTS, in admixture with a pharmaceutical carrier or vehicle.
  • an advantageous M 2 - antagonist/naAEA/nsPAChA combination according to the present invention may be a combination comprising or consisting essentially of
  • a pharmaceutical composition comprising dimethindene or S-(+)- dimethindene, or a pharmaceutically acceptable salt or solvate thereof, in an amount, in dimethindene or ,S'-(+)-dimethindene, of from 1.1 mg to 32 mg, normally from 1.5 mg to 32 mg, in admixture with a pharmaceutical carrier or vehicle; and
  • a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, azasetron and pharmaceutically acceptable salts and solvates thereof; ondansetron and pharmaceutically acceptable salts and solvates thereof; granisetron and pharmaceutically acceptable salts and solvates thereof; dolasetron and pharmaceutically acceptable salts and solvates thereof, ramosetron and pharmaceutically acceptable salts and solvates thereof; tropisetron and pharmaceutically acceptable salts and solvates thereof; and palonosetron and pharmaceutically acceptable salts and solvates thereof, domperidone and pharmaceutically acceptable salts and solvates thereof such as the maleate; chlorpromazine and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride; prochlorperazine and its salts and solvates, particularly the dimaleate and the dimesylate; promethazine and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride; and 4-ami
  • An advantageous combination according to this fifth embodiment may be a combination comprising or consisting essentially of, as Components:
  • a pharmaceutical composition comprising dimethindene or S-(+)- dimethindene, or a pharmaceutically acceptable salt or solvate thereof, in an amount, in dimethindene or ,S'-(+)-dimethindene, of from 1.1 mg to 32 mg, normally from 1.5 mg to 32 mg, in admixture with a pharmaceutical carrier or vehicle; and
  • a pharmaceutical composition comprising a naAEA selected from the group consisting of a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg;
  • the pharmaceutical composition Component (a) comprises a pharmaceutical composition comprising dimethindene or S- (+)-dimethindene, as free base or as maleate, in an amount, in dimethindene or S-(+)- dimethindene, of from 1.1 mg to 16 mg, normally from 1.5 mg to mg, in admixture with a pharmaceutical carrier in an IR-unit form or in an amount of from 4.1 mg to 32 mg, normally from 6 mg to 32 mg, preferably from 6 mg to 24 mg, in admixture with a pharmaceutical carrier or vehicle in a ER-unit form, including TTS forms.
  • a pharmaceutical composition comprising dimethindene or S- (+)-dimethindene, as free base or as maleate, in an amount, in dimethindene or S-(+)- dimethindene, of from 1.1 mg to 16 mg, normally from 1.5 mg to mg, in admixture with a pharmaceutical carrier in an IR-unit form or in an amount of from 4.1 mg to 32
  • the pharmaceutical composition Component (a) comprises a pharmaceutical composition comprising dimethindene or ,S'-(+)-dimethindene, as free base or as maleate, in an amount, in dimethindene or ,S'-(+)-dimethindene, selected from the groups ranges consisting of: from 3 mg to 32 mg; from 4 mg to 32 mg; from 4.4 to 32 mg; from 6 mg to 32 mg; from 6 mg to 16 mg; and from 3 mg to 10 mg, in admixture with a pharmaceutical carrier in an ER-form, including a TTS.
  • an advantageous M 2 - antagonist/naAEA/combi nation may be a combination comprising or consisting essentially of
  • composition comprising otenzepad or a pharmaceutically acceptable salt or solvate thereof, in an amount of 100 mg to 500 mg, normally from 150 mg to 350 mg, in admixture with a pharmaceutical carrier or vehicle;
  • a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and pharmaceutically acceptable salts
  • an advantageous M 2 - antagonist/naAEA/nsPAChA/combination may be a combination comprising or consisting essentially of
  • composition comprising otenzepad or a pharmaceutically acceptable salt or solvate thereof, in an amount of 100 mg to 500 mg, normally from 150 mg to 350 mg, in admixture with a pharmaceutical carrier or vehicle;
  • a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated
  • the pharmaceutical composition Component (a) comprises a pharmaceutical composition comprising otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate thereof, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg in a IR unit form or as the free base or as one of the aforementioned salts, in an amount of from 200 mg to 500 mg, preferably from 300 mg 500 mg, in an ER-form, including a TTS.
  • otenzepad as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate thereof, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg in a IR unit form or as the free base or as one of the aforementioned salts, in an
  • the present invention also provides a pharmaceutical combination comprises or consist essentially of, as Components:
  • a M 2 -antagonist selected from the group consisting of otenzepad and pharmaceutically acceptable salts thereof in an amount, in otenzepad, of from 100 mg to 500 mg, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle;
  • a naAEA essentially consisting of palonosetron hydrochloride, in an amount, in palonosetron, of 0.5 mg; and netupitant, in an amount of 300 mg, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
  • an advantageous M 2 -antagonist/naAEA combination according to the present invention is a combination comprising or consisting essentially of, as Components,
  • a pharmaceutical composition comprising AQ-RX 741 or a pharmaceutically acceptable salt or solvate thereof, in an amount of from 10 mg to 500 mg, normally from 10 mg to 250 mg, in admixture with a pharmaceutical carrier or vehicle;
  • a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and pharmaceutically acceptable salts
  • an advantageous M 2 -antagonist/naAEA/nsPAChA combination may be a combination comprising or consisting essentially of
  • a pharmaceutical composition comprising AQ-RX 741 or a pharmaceutically acceptable salt or solvate thereof, in an amount of from 10 mg to 500 mg, normally from 10 mg to 250 mg, in admixture with a pharmaceutical carrier or vehicle;
  • a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated
  • the pharmaceutical composition Component (a) comprises AQ-RX 741 as free base or as monomethanesulfonate, in an amount of from 10 mg to 500 mg, normally from 10 mg to 250 mg, in admixture with a pharmaceutical carrier formulated IR or ER administration.
  • Component (a) comprises AQ-RX 741 as free base or as monomethanesulfonate, in an amount of from 10 mg to 500 mg, preferably from 10 mg to 250 mg in a IR-form or, as the free base or the methanesulfonate salt thereof, in an amount of from 20 mg to 500 mg, preferably from 50 mg to 500 mg, in an ER-form, including a TTS.
  • AChEI may include, but is not limited to, 1,2,3,4- tetrahydro-9-acridinamine (tacrine) and pharmaceutically acceptable salts and solvates thereof, ( ⁇ )-2,3-dihydro-5,6-dimethoxy-2-[[l-(phenylmethyl)-4-piperidinyl]methyl]- lH-inden-l-one (donepezil) and pharmaceutically acceptable salt and solvates thereof, (,S)-N-Ethyl-N-methyl-3-[l-(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) and pharmaceutically acceptable salts and solvates thereof, or 4aS,6R,8aS-3-methoxy-l l- methyl-4a,5,9, 10,l l, 12-hexahydroxy-6H-benzofuro[3a,3,
  • Donepezil hydrochloride available in 5-mg, 10-mg and 23-mg tablets; rivastigmine, preferably as free base or as hydrogen tartrate, available in 1.5-mg, 3-mg and 6-mg, capsules, as a 2-mg/dose oral solution, and in form of a transdermal patch releasing rivastigmine at 4.6 mg/24 hours, 9.5 mg/24 hour or 13.3 mg/24h; and galantamine, preferably as hydrobromide, available as a 4-mg/ml oral solution, in 4- mg, 8-mg and 12-mg IR-tablets and in 8-mg, 16-mg and 24-mg ER-capsules; are particularly preferred AChEIs.
  • donepezil hydrochloride is present at a dose of from 5 mg to 98 mg, advantageously from 10 mg to 98 mg, preferably from 15 mg to 69 mg, normally from 15 mg to 60 mg; rivastigmine, as hydrogen tartrate, is present, in a composition for oral administration, at a dose, in rivastigmine, of from 1.5 mg to 30 mg, advantageously from 6 mg to 30 mg, preferably from 9 mg to 24 mg, normally from 9 mg to 18 mg; rivastigmine, as the free base, is present in patch releasing from 4.6mg/24h to 52mg/24h, advantageously from 9.6mg/24h to 39.9mg/24h, normally from 13.3mg/24h to 39.9mg/24h or from 4.6mg/24h to 13.3mg/24h nvastigmine; and galantamine, as hydrobromide, is present in an amount of from 4 mg to 98 mg, advantageously from 10 mg to 98 mg, preferably from
  • said AChEI Component (c) may be formulated, in admixture with a pharmaceutical carrier or vehicle, in a pharmaceutical composition or device in dosage unit form or also used as a brand preparation.
  • rivastigmine may be also used by orally administering EXELON ® immediate-release 6mg-capsules or by applying one or more EXELON ® patches releasing 4.6mg/24 hours, 9.5mg/24 hours, or 13.3 mg/24 hours on the subject's skin, to daily release rivastigmine at a dose/24h of from 4.6 mg to 53.2 mg or from 19.95 to 53.2 mg, normally from 14.1 mg to 46 m, in combination with the above-illustrated M 2 - antagonist /naAEA combination.
  • Donepezil hydrochloride may be also used by orally administering one or more ARICEPT ® immediate-release 5mg- or lOmg-tablets or the 23-mg tablets.
  • donepezil hydrochloride may be orally administered, in combination with the above- illustrated M 2 -antagonist /naAEA combination, at a daily dose of from 5 mg to 100 mg or from 15 mg to 70 mg.
  • galantamine may be also administered as a brand preparation, for example by orally administering RAZADYNE ® immediate-release 8mg- or 12mg-tablets or RAZADYNE ® ER 8mg-, 16mg- or 24mg-capsules.
  • galantamine hydrobromide may be orally administered, in combination with the above-illustrated M 2 -antagonist/naAEA combination, at a daily dose (in galantamine) of from 36 mg to 96 mg, normally at a daily dose or from 36 mg to 72 mg, preferably in an ER-form.
  • the AChEI Component (c) when included in the combination with Component (a) and Component (b) as described herein, may be present in an amount of from about 100% to about 1000% of a recommended dose of Component (c) contained in a unit form used for the treatment of Alzheimer type dementia.
  • kits or package containing a combination as described herein, accompanied by instructions for use are provided.
  • a kit of the present invention is a kit comprising a combination of medicaments for the treatment of hypocholinergic disorders of the CNS.
  • the kit allows for the maximal functional capacity and safety during the treatment of a patient with a combination wherein the components may be administered concurrently or sequentially.
  • Component (a) and Component (b) may be present in the kit all in IR or in ER form or one of the Components is in IR form and at least one of the others are in ER form, each in admixture with a pharmaceutical carrier in a composition formulated as illustrated in "The Formulations" section, according to known technologies.
  • kit according to the present invention may also comprise an AChEI Component (c), also in an IR or ER form, in admixture with a pharmaceutical carrier in a composition formulated as illustrated in "The Formulations" section below, according to known technologies.
  • AChEI Component (c) also in an IR or ER form, in admixture with a pharmaceutical carrier in a composition formulated as illustrated in "The Formulations" section below, according to known technologies.
  • the AChEI Component (c) When the AChEI Component (c) is present in the kit, it may be in a separate unit form wherein said AChEI is mixed with a pharmaceutical carrier in a pharmaceutical composition formulated in an IR or ER unit forrnr
  • kit of the present invention comprises
  • composition in IR or ER dosage unit form comprising or consisting essentially of a therapeutically effective amount of a M 2 -antagonist in admixture with a pharmaceutical carrier or vehicle;
  • composition in IR or ER dosage unit form comprising or consisting essentially of a therapeutically effective amount of a naAEA in admixture with a pharmaceutical carrie or vehicle,
  • compositions may be packaged in any manner suitable for administration to a patient suffering from a hypocholinergic disorder of the CNS dementia and the packaging is manufactured according to known technologies and completed with instructions for use clearly showing to the patient or to the caregiver how to take each of the units forms to be administered.
  • Said kit comprises a Component (a) selected among the M 2 -antagonists illustrated in the above section "The M 2 -antagonists", a Component (b) selected among the naAEAs illustrated in the above section "The naAEAs” and, optionally, a Component (c) selected among the AChEIs illustrated above.
  • the kit of the present invention comprises a M 2 -antagonist selected from the group consisting of 5-(2-ethyl-2H-tetrazol-5-yl)- l-methyl-1,2, 3,6-tetrahydropyridine (alvameline) and pharmaceutically salts and solvates thereof, 5,1 l-dihydro-8-chloro-l l-[[4-[3-[(2,2-dimethyl-l- oxopentyl)ethylamino]propyl]-l-piperidinyl]acetyl]-6H-pyrido[2,3- b][l,4]benzodiazepin-6-one (BIBN-99) and pharmaceutically acceptable salts and solvates thereof; racemic l l-[[2-(Diethylamino)methyl]-l-piperidinyl]-acetyl]- 5,l l-dihydro-6H-pyrido[2,3-b][
  • a naAEA selected from the group consisting of (bl) 5HT3 -antagonists, (b2) DA- antagonists, (b3) HI -antagonists, (b4) cannabinoids, and (b5) K1 -antagonists; said combination being in a fixed-dose combination formulated in admixture with a pharmaceutical carrier.
  • the fixed-dose (a/b) combination illustrated in the "The Fixed Combinations” section, is administered to a patient in need of the treatment as a single unite form at the doses illustrated in said section.
  • the invention provides a kit comprising
  • composition in dosage unit form comprising or consisting essentially of a M 2 -antagonist in admixture with a pharmaceutical carrier or vehicle;
  • composition comprising or consisting essentially of a naAEA, in admixture with a pharmaceutical carrier or vehicle.
  • kit according to this second embodiment may comprise:
  • a pharmaceutical composition in dosage unit form comprising or consisting essentially of a M 2 -antagonist selected from the group consisting of alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt, in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tnpitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tnpitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; ( ⁇ )-dimethindene or ,S'(+)-dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the
  • a pharmaceutical composition comprising or consisting essentially of a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and
  • a pharmaceutical composition in dosage unit form comprising or consisting essentially of a M 2 -antagonist selected from the group consisting of alvameline tartrate, in an amount, in alvameline, of from 200 mg to 600 mg; tripitramine sesquifumarate in an amount, in tripitramine, of from 15 mg to 150 mg; ( ⁇ )- dimetindene or ,S'(+)-dimethindene maleate, in an amount of from 1.5 mg to 25 mg; otenzepad maleate (1 : 1), in an amount of from 200 mg to 400 mg; and AQ-RX 741 monomethanesulfonate, in an amount of from 15 mg to 300 mg;
  • a M 2 -antagonist selected from the group consisting of alvameline tartrate, in an amount, in alvameline, of from 200 mg to 600 mg; tripitramine sesquifumarate in an amount, in tripitramine, of from 15 mg to 150 mg; ( ⁇ )- dimetindene or
  • a pharmaceutical composition comprising or consisting essentially of a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts
  • kits of the present invention comprises each of the drugs making up the composition of the invention, along with instructions for use.
  • each of the drug components of the combination may be combined into a single administrable dosage form such as a capsule.
  • Said kit may include one or more tablets, hard or soft capsules containing the Component (a) and Component (b), in the dosage amounts within the ranges described above.
  • compositions (a/b) of the kits of the present invention consisting of pharmaceutical composition in dosage unit form comprising, as active ingredient, a combination with a M 2 -antagonist and of a naAEA is novel and a further object of the present invention.
  • kits comprising a pharmaceutical composition in dosage unit form consisting essentially of
  • each of the above kits may comprise, as a further component of the combinations contained therein, as Component (c), an AChEI also formulated in a pharmaceutical composition in dosage unit form in admixture with a pharmaceutical carrier or vehicle, said AChEI being selected from the group consisting of l,2,3,4-tetrahydro-9-acridinamine (tacrine) and pharmaceutically acceptable salts and solvates thereof, ( ⁇ )-2,3-dihydro-5,6-dimethoxy-2-[[l- (phenylmethyl)-4-piperidinyl]methyl]-lH-inden-l-one (donepezil) and pharmaceutically acceptable salt and solvates thereof, (,S)-N-Ethyl-N-methyl-3-[l- (dimethylamino)ethyl]-phenyl carbamate (rivastigmine) and pharmaceutically acceptable salts and solvates thereof, 4aS,6R,8aS-3-methoxy
  • kits of the present invention as
  • donepezil hydrochloride is generally present at a dose of from 5 mg to 98 mg, advantageously from 15 mg to 69 mg, normally from 15 mg to 60 mg; rivastigmine, as hydrogen tartrate, is present, in a composition for oral administration, at a dose in rivastigmine, of from 1.5 mg to 30 mg, advantageously from 6 mg to 24 mg, normally from 9 mg to 18 mg; rivastigmine, as the free base, is present in patch releasing from 4.6mg/24h to 52mg/24h, advantageously from 9.6mg/24h to 39.9mg/24h, normally from 13.3mg/24h to 39.9mg/24h rivastigmine; and galantamine, as hydrobromide, is present in an amount of from 4 mg to 96 mg, advantageously from 12 mg to 96 mg, normally from 18 mg to 48 mg.
  • the present invention also provides a kit comprising or essentially consisting of
  • compositions in dosage unit form essentially consisting of a M2- antagonist, in admixture with a pharmaceutical carrier or vehicle;
  • compositions in dosage unit form essentially consisting of a naAEA, in admixture with a pharmaceutical carrier or vehicle;
  • a pharmaceutical composition in dosage unit form essentially consisting of an AChEI selected from the group consisting of donepezil hydrochloride in an amount of from 5 mg to 98 mg, advantageously from 15 mg to 69 mg, normally from 15 mg to 60 mg; rivastigmine, as hydrogen tartrate, in an amount, in rivastigmine, of from 1.5 mg to 30 mg, advantageously from 6 mg to 24 mg, normally from 9 mg to 18 mg; rivastigmine, as the free base, in patch releasing from 4.6mg/24h to 52mg/24h, advantageously from 9.6mg/24h to 39.9mg/24h, normally from 13.3mg/24h to 39.9mg/24h rivastigmine; and galantamine, as hydrobromide, in an amount (in galantamine, of from 4 mg to 96 mg, advantageously from 12 mg to 96 mg, normally from 18 mg to 48 mg,
  • the AChEI Component (c) may be combined with any M 2 -antagonist Component (a) and with any naAEA Component (b) illustrated in this section, in a triple combination useful as a cocktail for combating hypocholinergic disorders of the CNS as herein above defined.
  • a M 2 -antagonist selected from the group consisting of alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt, in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tripitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; ( ⁇ )-dimethindene or S(+)- dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount of from 100 mg to 500 mg, preferably from
  • a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated thereof, in particular its hydrochlor
  • netupitant in an amount of from 150 mg to 1800 mg
  • rolapitant in an amount of from 30 mg to 360 mg
  • casopitant in an amount of from 25 mg to 300 mg
  • a kit according to a preferred form of this second aspect of this third embodiment essentially consists of a combination of the above Components (a) and (b) with
  • composition in dosage unit form comprising or essentially consisting of an AChEI selected from the group consisting of donepezil hydrochloride, in an amount of from 5 mg to 60 mg, in admixture with a pharmaceutical carrier or vehicle.
  • a particularly preferred form of this second aspect of this third embodiment essentially consists of a combination of the above Component (a/b) fixed-dose combination with a Component (c) that is a pharmaceutical composition in dosage unit form comprising or consisting essentially of galantamine hydrobromide in an amount of from 24 mg to 98 mg, in admixture with a pharmaceutical carrier in an ER formulation.
  • compositions (a/b) of the kits of the present invention described above are each novel and a further object of the present invention.
  • the invention also provides a kit comprising
  • composition in dosage unit form comprising or consisting essentially of a M2-antagomist in admixture with a pharmaceutical carrier or vehicle;
  • kits have the great advantage of allowing an improvement in the treatment of a patient suffering from a hypocholinergic disorder.
  • the kit of the present invention allows the administration of a composition (b/c) comprising a naAEA and an AChEI that may be administered once or twice a day, thus rendering the treatment easier for the patient or for the caregiver.
  • a pharmaceutical composition in dosage unit form comprising or consisting essentially of a M2-antagomist selected from the group consisting of alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt, may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tripitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; ( ⁇ )-dimethindene or ,S'(+)-dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the
  • a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride,; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and pharmaceutically acceptable salts and solvates thereof, especially
  • an AChEI selected from the group consisting of donepezil and its pharmaceutically acceptable salts, rivastigmine and its pharmaceutically acceptable salts, and galantamine and its pharmaceutically acceptable saltsj in admixture with a pharmaceutical carrier or vehicle.
  • the fixed-dose combination (b/c) essentially consists of a pharmaceutical composition in dosage unit form comprising
  • a naAEA selected from the group consisting of alosetron hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg, tropisetron hydrochloride, in an amount (in tropisetron) of from 2.5 mg to 30 mg; domperidone and
  • the above Component (b/c) is a pharmaceutical composition in dosage unit form wherein said naAEA is granisetron and said AChEI is rivastigmine in patch releasing from 0.5mg/24h to 3mg/24h granisetron and from 4.6mg/24h to 52mg/24h rivastigmine, according to "The formulations" section below.
  • kits of this third embodiment may be compositions comprising or consisting essentially of, as Component (b/c), a naAEA (b) and an AChEI (c) in a pharmaceutical composition in dosage unit form as disclosed in US 2011/0201597, the contents of which are incorporated herein by reference in their entirety.
  • the above Component (b/c) is a pharmaceutical composition in dosage unit form wherein said naAEA and said AChEI are mixed together and with a pharmaceutical carrier in an oral IR- or ER-formulation, according to "The formulations" section below.
  • the above Component (b/c) is a pharmaceutical composition in dosage unit form wherein said naAEA is granisetron and said AChEI is rivastigmine in patch releasing from 0.5mg/24h to 3mg/24h granisetron and from 4.6mg/24h to 52mg/24h rivastigmine, according to "The formulations" section below
  • the (b/c) fixed-dose combination is administered to a patient in need of the treatment as a single unit form at the doses illustrated in "The Combinations" section.
  • This kit has the advantage of allowing an improvement in the treatment of a patient suffering from a hypocholinergic disorder due to synergistic action of the antiemetic/anti cholinergic combination.
  • the pharmaceutical compositions prepared by using the naAEA according to the present invention are present in unit forms also containing a M 2 -antagonist that acts by presynaptically releasing acetylcholine in the CNS to improve the symptoms of Alzheimer type dementia.
  • a muscarinic receptor antagonist selected from the group consisting of selective M 2 - antagonists
  • naAEA non-anticholinergic antiemetic agent
  • unit form will also be used to designate a “pharmaceutical composition in dosage unit form”.
  • the pharmaceutical composition to improve the treatment of human hypocholinergic disorders comprises or consists essentially of a mixture of a M 2 -antagonist [Component (a)], and of a naAEA [Component (b)] is present in a quantity sufficient or effective to maximally alleviate disease-associated neurobehavioral symptoms for the treatment of hypocholinergic disorders by acting to attenuate the dose-limiting side effects of the M2-antagonists, thus enabling a greater increase in the MTD of said M2-antagonists, with attending increase in the therapeutic efficacy of M2-antagonists. .
  • Such a composition allows high doses of M 2 -antagonist Component (a) to be safely used, that would have otherwise been dangerous in the absence of Component (b).
  • the pharmaceutical composition of the present invention improves the treatment of human hypocholinergic disorders of the CNS as described above, such as dementias of the Alzheimer type and schizophrenia.
  • Any M2-antagonist and any naAEA as described herein, and exemplified in the above "The Combinations" section may be formulated in a pharmaceutical composition in a single unit form, in admixture with at least one pharmaceutical carrier according to conventional methods in the art, and as exemplified in the "The Formulations” section below.
  • the M 2 -antagonist In unit form for immediate release or extended release, the M 2 -antagonist
  • Component (a) is present in an amount of from 0.5 mg to 1500 mg.
  • the M 2 - antagonist Component (a) is present, in an IR-form, in an amount of from 0.5 mg to 1000 mg and in an ER-form in an amount of from 1.5 mg to 1500 mg.
  • the M 2 - Antagonists may be a suitable Component (a), a M2-antagonist selected from the group consisting of alvameline, BIBN-99, otenzepad, (S)-(+)- otenzepad, AF-DX 384, dimethindene, (S)-(+)-dimethindene, tripitramine, himbacine, (+)-himbacine, the himbacine analog, i.e.
  • a a M2-antagonist selected from the group consisting of alvameline, BIBN-99, otenzepad, (S)-(+)- otenzepad, AF-DX 384, dimethindene, (S)-(+)-dimethindene, tripitramine, himbacine, (+)-himbacine, the himbacine analog, i.e.
  • a M 2 -antagonist selected from the group consisting of
  • - alvameline, as free base or a salt or solvate thereof, especially as its tartrate may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; - tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount of from 10 mg to 200 mg, preferably from 10 mg to 100 mg in a IR-form or from 25 mg to 200 mg in an ER-form;
  • - dimetindene preferably as the maleate thereof, as racemate or as its S(+) enantiomer, in an amount of from 1.2 mg to 30 mg, preferably from 1.2 mg to 15 mg in a IR-form or, as the free base or the maleate thereof, in an amount of from 3 mg to 30 mg, preferably from 3 mg to 10 mg, in an ER-form, including a TTS;
  • - otenzepad as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate (INN: monomesilate, US AN: monomesylate) thereof, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg in a IR unit form or as the free base or as one of the aforementioned salts, in an amount of from 200 mg to 500 mg, preferably from 300 mg 1500 mg, in an ER-form, including a TTS;
  • Any non-anticholinergic antiemetic agents especially those illustrated in the above "The naAEAs" section may be a suitable Component (b).
  • the Component (b) of the fixed-dose combination may be a non- anticholinergic antiemetic agent selected from the group consisting of (b l) 5HT3- antagonists, (b2) DA-antagonists, (b3) HI -antagonists, (b4) cannabinoids, (b5) NK1- antgagonists.
  • a non- anticholinergic antiemetic agent selected from the group consisting of (b l) 5HT3- antagonists, (b2) DA-antagonists, (b3) HI -antagonists, (b4) cannabinoids, (b5) NK1- antgagonists.
  • Component (b) of the fixed-dose combination is selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and pharmaceutically acceptable
  • the fixed-dose combination of the invention consists of a pharmaceutical composition in dosage unit form comprising or consisting essentially of (a) any of the M 2 -antagonists as illustrated in the above "The M2-antagonists" section, each in a pharmaceutical composition in admixture with a pharmaceutical carrier, said M 2 -antagonist being preferably selected from the group consisting of 5-(2- ethyl-2H-tetrazol-5-yl)- 1 -methyl- 1 ,2,3, 6-tetrahydropyri dine (alvameline) and pharmaceutically salts and solvates thereof, 5, l l-dihydro-8-chloro-l l-[[4-[3-[(2,2- dimethyl-l-oxopentyl)ethylamino]propyl]-l-piperidinyl]acetyl]-6H-pyrido[2,3- b][l,4]benzodiazepin-6-one (BIBN-99) and pharmaceutically acceptable salt
  • any of the naAEAs as illustrated in the above "The naAEAs" section said naAEA being preferably selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and
  • an advantageous fixed-dose combination consists a pharmaceutical composition comprising or consisting essentially of
  • a M 2 -antagonist selected from the group consisting of alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tripitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; ( ⁇ )-dimetindene or ,S'(+)-dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount of from 100 mg to 500
  • a particularly advantageous fixed-dose combination consists of a pharmaceutical unit form comprising or consisting essentially of
  • alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tripitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; ( ⁇ )-dimetindene or S(+)- dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg; and AQ- RX 7
  • a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated thereof, in particular its hydrochlor
  • a particularly advantageous fixed-dose combination consists of a pharmaceutical dosage unit form comprising or consisting essentially of
  • alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tripitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; ( ⁇ )-dimetindene or S(+)- dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, di hydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg; and AQ- RX 7
  • ondansetron as free base or hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg,
  • each of the above fixed-dose combinations may include, as a further component (c), an AChEI also formulated in a pharmaceutical composition, said AChEI being selected from the group consisting of 1,2,3,4- tetrahydro-9-acridinamine (tacrine) and pharmaceutically acceptable salts and solvates thereof, ( ⁇ )-2,3-dihydro-5,6-dimethoxy-2-[[l-(phenylmethyl)-4-piperidinyl]methyl]- lH-inden-l-one (donepezil) and pharmaceutically acceptable salt and solvates thereof, (,S)-N-Ethyl-N-methyl-3-[l-(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) and pharmaceutically acceptable salts and solvates thereof, 4aS,6R,8aS-3-methoxy-l l- methyl-4a,5,9, 10, l l, 12-hexahydroxy-6
  • any of the above fixed-dose combinations and any of the pharmaceutical compositions that are part of the above combinations and kits are formulated with pharmaceutical carriers, diluents, vehicles and devices according to known and conventional methods and/or technologies in the art and as illustrated in the "The Formulations" section below.
  • any of the above fixed-dose combinations and any of the above pharmaceutical compositions may further include, as Component (c), an AChEI.
  • the AChEI Component (c) when included in the combination with Component (a) and Component (b) as described herein, may be present in an amount of from about 100% to about 1000% of a recommended dose of Component (c) contained in a unit form used for the treatment of Alzheimer type dementia.
  • donepezil hydrochloride is present at a dose of from 5 mg to 98 mg, advantageously from 10 mg to 98 mg, preferably from 15 mg to 69 mg, normally from 15 mg to 60 mg; rivastigmine, as hydrogen tartrate, is present, in a composition for oral administration, at a dose, in rivastigmine, of from 1.5 mg to 30 mg, advantageously from 6 mg to 30 mg, preferably from 9 mg to 24 mg, normally from 9 mg to 18 mg; rivastigmine, as the free base, is present in patch releasing from 4.6mg/24h to 52mg/24h, advantageously from 9.6mg/24h to 39.9mg/24h, normally from 13.3mg/24h to 39.9mg/24h or from 4.6mg/24h to 13.3mg/24h rivastigmine; and galantamine, as hydrobromide, is present in an amount of from 5 mg to 98 mg, advantageously from 10 mg to 98 mg, preferably
  • the unit form of the present invention may be a vial for intramuscular or intravenous administration, a tablet, a capsule, a pre-measured volume of a liquid solution or suspension for oral administration or a TTS as a gel or patch, including spray patches, for transdermal application.
  • the nsPAChA and M2 antagonist, as free base are as a pharmaceutically acceptable salt or solvate thereof, may be mixed together or separated according to known technologies in admixture with a pharmaceutical carrier in a pharmaceutical composition.
  • Component (a), Component (b) and optional Component (c) are formulated with conventional pharmaceutical carriers in known formulations for oral use wherein said components are mixed together or separated, for example in two or three tablets introduced in a capsule or in a two-compartment capsule, wherein one of the Components (a) is in a first of the two compartments and Component (b), alone or mixed with Component (c) in the second of the two compartments, or in a multilayer (di-layer or tri-layer) tablet wherein either Component (a) in admixture with a pharmaceutical carrier is in one of the layers and Component (b), alone or mixed with Component (c) and a pharmaceutical carrier is in a second layer in a di-layer tablet or the Components (a), (b) and (c), in admixture with a pharmaceutical carrier, are each distributed, in admixture with a pharmaceutical carrier in the three layers of a tri-layer tablet.
  • the components are all in IR or in ER form, or one of the Components is in IR form and the other(s) is/are in ER form, according to known technologies.
  • the pharmaceutical carriers and vehicles are those commonly used for the preparation of compositions for oral, buccal, including sublingual, and parenteral, in particular transdermal, administration.
  • Appropriate unit forms comprise the oral forms, such as tablets, including orodispersible tablets and orosoluble tablets; soft or hard gelatin capsules; powders or granulates in sachets; and suitably measured oral solutions or suspensions, as well as transdermal therapeutic systems such as patches for transdermal administration.
  • Component (a), Component (b) and optional Component (c) may also be present in form of one of their complexes with a cyclodextrin, for example a-cyclodextrin, ⁇ - cyclodextrin, ⁇ -cyclodextrin, 2-hydroxypropyl- -cyclodextrin or methyl- -cyclodextrin.
  • a cyclodextrin for example a-cyclodextrin, ⁇ - cyclodextrin, ⁇ -cyclodextrin, 2-hydroxypropyl- -cyclodextrin or methyl- -cyclodextrin.
  • Component (a), Component (b) and optional Component (c) may also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
  • Component (a), Component (b) and optional Component (c), together or separately, are formulated by mixing the active ingredient with conventional pharmaceutical acceptable carriers enabling said active ingredients to be formulated in tablets, dragees, orally disintegrating tablets, capsules, liquid solutions or suspensions, syrups and the like.
  • Carriers for IR tablets may include, but are not limited to, starches, cellulose and derivatives thereof; lubricants such as talc, stearic acid or magnesium stearate; diluents such as talc, powdered cellulose, lactose, starches such as maize or corn starch, mannitol, sorbitol; disaggregating agents such as microcrystalline cellulose or crospovidone; lubricants such as polyethylene glycol or magnesium stearate; ligands such as methylcellulose, sodium carboxymethylcellulose, alginic acid, alginates; sweeteners, such as sucrose, dextrose, mannitol, saccharin; or flavoring agents such as natural or synthetic oils.
  • lubricants such as talc, stearic acid or magnesium stearate
  • diluents such as talc, powdered cellulose, lactose, starches such as maize or corn starch, mannitol,
  • Carriers for orally disintegrating tablets may include, but are not limited to, lubricants, aggregating, sweetening, flavoring or disaggregating agents as well as agents improving the buccal mucosa absorption of Component (a), Component (b) and optional Component (c) such as sorbitol, mannitol, lactose and cellulose.
  • Carriers for liquid, normally aqueous, suspensions or solutions may include, but are not limited to, antioxidants, such as sodium metabisulfite or sodium sulfite, thickening agents, such as microcrystalline cellulose, hydroxypropylcellulose, carboxymethylcellulose or polyvinylpyrrolidone, preservatives such as methyl paraben, ethyl paraben, sodium ethylenediaminotetracetate, sodium benzoate or an alkaline salt of sorbic acid, as well as flavoring and sweetening agents.
  • antioxidants such as sodium metabisulfite or sodium sulfite
  • thickening agents such as microcrystalline cellulose, hydroxypropylcellulose, carboxymethylcellulose or polyvinylpyrrolidone
  • preservatives such as methyl paraben, ethyl paraben, sodium ethylenediaminotetracetate, sodium benzoate or an alkaline salt of sorbic acid, as well as flavoring and sweetening agents.
  • the sweeteners contained in the orally disintegrating tablets and the liquid suspensions or solutions may be natural, optional reduced sugars such as sucrose, dextrose, xylitol, mannitol or sorbitol, or synthetic product such as sodium saccharine or aspartame.
  • the flavoring agents are pharmaceutically acceptable flavors and tastes of synthetic and natural oils, the latter extracted from plants, leaves, flowers, fruits and their combinations, which include, but are not limited to, cinnamon, peppermint, anise and citron leaves, bitter almond, or citrus fruits, in particular orange and/or lemon, linden and grapefruit oils.
  • chocolate, vanilla or eucalyptus flavor and essences of fruit, in particular apple, pear, peach, strawberry, cherry, apricot, orange, lemon and/or grapes may be advantageously used.
  • composition according to the present invention may be in form of a capsule containing two tablets as described herein above, one of them comprising Component (a), and the other comprising Component (b) and optional Component (c) in admixture with each other and with a pharmaceutical carrier.
  • the unit form may also be a capsule containing two tablets as described herein above, one of them comprising Component (b), and the other comprising Component (a) and optional Component (c) in admixture with each other and with a pharmaceutical carrier.
  • the unit form may also be a capsule containing two tablets as described herein above, one of them comprising Component (c), and the other comprising Component (a) and Component (b) in admixture each other and with a pharmaceutical carrier.
  • the unit form may also be a capsule containing three tablets as described herein above, one of them comprising Component (a), the second comprising Component (a) and the third comprising Component (c) in admixture with each other and with a pharmaceutical carrier.
  • the combination may be formulated in tablets in which one or both of the two components (a) and (b) is/are in controlled-release formulation, for example as a dispersion of said component in hydroxypropyl methyl cellulose or in a film-coated microgranule.
  • the M 2 -antagonist Component (a), in an ER-formulation is in the core and the naAEA Component (b), alone or in combination with the AChEI Component (c), in IR-formulation, are in the outer layer in multi-layer tablets in which, for example, both the core and the outer layers are coated with a film.
  • capsules made of two separated compartments, one containing Component (a), in IR- or ER-formulation and the other containing Component (b) and, optionally, Component (c), in ER- or, preferably, in IR formulation, may be used.
  • Carriers and vehicles for ER tablets may include, but are not limited to, retardant materials such as acrylic and methacrylic acid polymers and copolymers; cellulose derivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, or sodium carboxymethylcellulose; gums; waxes; glycerides or aliphatic alcohols or a mixture thereof.
  • Component (a), Component (b) and Component (c), as the base thereof or as a pharmaceutically acceptable salt thereof, may also be formulated, together or separately in any TTS such as a patch, a gel, a cream, a spray, an ointment, a lotion or a paste.
  • Component (a) or Component (b) or optional Component (c) is present in admixture with the common diluents and permeation enhancers for the TTS administration; or Component (a) and Component (c) are both present in admixture with the common diluents and permeation enhancers for the TTS administration; or the Component (a) and Component (c) are both present in admixture with the common diluents and permeation enhancers, or Component (a), Component (b) and Component (c) are altogether present in admixture with the common diluents and permeation enhancers.
  • the permeation enhancer may be any compound which allows the improved permeation of drugs through the skin (see for example the review in Pharmaceutical Technology, November 1997, pages 58-66, the disclosure of which is herein incorporated by reference in its entirety).
  • Such substances may include, but are not limited to, be lower (C 1-C4) alkanols; fatty alcohols such as lauryl alcohol (dodecanol), alone or in combination with a lower alkanol; fatty acids such as linolenic acid or oleic acid; fatty acid esters such as isopropyl palmitate, stearate, linoleate, oleate or myristate; glycerol; glycerol monoesters such as glycerol monostearate, monolinoleate or monooleate; glycerol diesters; glycerol triesters such as triacetin; sucrose monostearate, monolinoleate or monooleate; sorbitan esters
  • permeation enhancers are present in an amount from 0.01 to 20% by weight of the total weight of the composition, advantageously in an amount of from 0.05 to 10% by weight, preferably from 0.1 to 5% by weight.
  • Component (a), Component (b) and optional Component (c) may be administered concurrently or sequentially to a patient suffering from a hypocholinergic disorder of the CNS such as Alzheimer type dementia and schizophrenia.
  • Component (a), Component (b) and optional Component (c) can be administered in a specific dosage regimen as illustrated above - to treat Alzheimer type dementia and schizophrenia, Component (a), Component (b) and optional Component (c) being administered simultaneously or sequentially to one another, in each case by the same or different administration route.
  • Component (b) allows for the safe administration of high doses of Component (a) without dangerous adverse effects linked to the peripheral cholinergic action of said Component (a). Accordingly, the therapeutic efficacy of Component (a) to safely improve cognition of patients suffering from a hypocholinergic disorder of the CNS such as Alzheimer type dementia or schizophrenia is enhanced, due to the action of Component (b) annulling vomiting, i.e. the cause of the failure of all the precedent attempts of using a M 2 -antagonist for the treatment of Alzheimer type dementia and, in general, of hypocholinergic disorders of the CNS.
  • a hypocholinergic disorder of the CNS such as Alzheimer type dementia or schizophrenia
  • the present invention in one aspect, provides a combination comprising or consisting essentially of, as Components:
  • M 2 muscarinic cholinergic receptor antagonists (a) a M 2 muscarinic cholinergic receptor antagonists (M 2 -antagonist).
  • M 2 -antagonists used as Component (a), their properties and doses are described in the "The M 2 -antagonists" section above.
  • naAEAs used as Component (b), their properties and doses are described in the "naAEA” section above.
  • Component (a), Component (b) and optional Component (c), together or separately, are formulated in pharmaceutical compositions prepared as described in the "Formulation" section above.
  • the present invention in one aspect, provides a combination comprising or consisting essentially of, as Components:
  • M 2 muscarinic cholinergic receptor antagonists (a) a M 2 muscarinic cholinergic receptor antagonists (M 2 -antagonist).
  • the M 2 -antagonists used as Component (a), their properties and doses are described in the "The M 2 -antagonist s" section above.
  • naAEAs used as Component (b), their properties and doses are described in the "naAEA” section above.
  • Component (a) and Component (b), together or separately, are formulated in pharmaceutical compositions prepared as described in the "Formulation" section above.
  • Another aspect of the present invention provides a method for treating hypocholinergic disorders of the central nervous system, comprising, or consisting essentially of, the Components:
  • M2-antagonists a muscarinic cholinergic receptor agonists
  • the method is carried out by administering Component (a), Component (b) and optional Component (c) of said combination concurrently, or sequentially.
  • Component (a), Component (b) and optional Component (c) may be independently administered by oral or parenteral route, in particular by intramuscular or intravenous injection or by transdermal administration by a TTS such as a gel or a patch.
  • TTS such as a gel or a patch.
  • naAEA used as Component (b), their properties and doses are described in the "naAEAs section" above.
  • Component (a), Component (b) and optional Component (c), together or separately, are formulated in pharmaceutical compositions prepared as described in the "Formulation" section above.
  • Component (b) and Component (c), in admixture with a pharmaceutical carrier or vehicle may be associated in the same pharmaceutical composition, formulated as described in "The Formulations" section above, in a unit dose for oral or parenteral, including transdermal, route, according to known or conventional methods or technologies in the art.
  • the doses of the above dose-ranges are given in order to present the possibility of manufacturing pharmaceutical compositions and of administering said doses in said pharmaceutical composition.
  • the discovery of the beneficial action of the naAEA enables the full efficacy of the M2-antagonist and of the optional AChEI.
  • M Muscarinic receptors in coronary circulation: gene-targeted mice define the role of M2 and M3 receptors in response to acetylcholine. Arterioscler Thromb Vase Biol. 2004; Jul, 24(7): 1253- 1258.

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Abstract

A combination of a M2-receptor antagonist and a non-anticholinergic antiemetic agent, and optionally an anticholinesterase inhibitor, to treat hypocholinergic disorders such as Alzheimer type dementia, schizophrenia, schizophrenia associated dementia, and schizoaffective disorders.

Description

MUSCARINIC M2-ANTAGONIST COMBINATION
CROSS-REFERENCE TO RELATED PATENT APPLICATION This application claims the benefit of U.S. Provisional Application No. 62/377,873, filed August 22, 2016, in the United States Patent and Trademark Office, the disclosure of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The invention pertains to the field of treating hypocholinergic disorders of the central nervous system, in particular of Alzheimer's type dementias, AD-type dementia, schizophrenia, schizophrenia associated dementia, Parkinson's dementia, Lewy body diseases, Down Syndrome, and chronic neuropathic pain, and provides a new combination of a cholinergic M2-receptor antagonist agent and an antiemetic agent, which optionally further includes an acetylcholinesterase inhibitor.
More particularly, the present invention relates to a new combination of a centrally active, selective-muscarinic M2-receptor antagonist herein below also referred to as "M2-antagonist"or "M2-antagonist", with an antiemetic agent substantially devoid of anticholinergic activity herein below also referred to as "non-anticholinergic Antiemetic Agent" ("naAEA"), as well as the optional addition of an acetyl choline esterase inhibitor (AChEI) to said M2-antagonist/naAEA combination. This combination provides pro-cognitive activity by enabling safe administration of a M2- antagonist without inducing peripheral, dose-limiting adverse effects.
DEFINTIONS
- "AD": Alzheimer's disease.
- "CNS": Central Nervous System.
- "Muscarinic type receptors (mAChRs)": Five subtypes of muscarinic receptors, Ml through M5, have been identified.
- "ACh": refers to the neurotransmitter acetylcholine.
- "naAEA(s)": non-anticholinergic Anti -Emetic Agent(s).
- "Non-anticholinergic" refers to antiemetic medications not primarily regarded as anticholinergic agents; they are entirely devoid of anticholinergic activity or have an extremely low ability to prevent acetylcholine from acting at its cholinergic receptor sites.
- "Selective": refers to M2-antagonists, and applies to antagonists of the mAChR sharing an affinity for the M2 receptor subtype higher than that for the Mi and M3-M5 receptor subtypes, i.e. a muscarinic antagonist having a ratio of (Ki for Mi and, respectively, M3-M5/Ki for M2) greater than 1.
- "hypocholinergic disorder" means a pathologic condition of the CNS due to or derived from a decrease in cholinergic transmission typically associated with events or diseases including but not limited to: Alzheimer disease, Alzheimer-type dementia, mild cognitive impairment, Lewy body disease dementia, Parkinson's disease dementia, post-stroke dementia, vascular dementia, traumatic brain injury, Down syndrome, anorexia nervosa, Tourette disease, tardive dyskinesia, Pick's disease, Huntington's chorea, Friedrich's ataxia, chronic neuropathic pain, falls, post-operative delirium, schizophrenia, schizophrenia associated dementia, and schizoaffective disorders.
- "CSF": Cerebrospinal Fluid.
- "IR": Immediate Release of the active ingredient from a composition.
- "ER": Extended Release, including sustained release, controlled release and slow release of the active ingredient from a composition by any administration route, in particular, but not limited to oral and parenteral (including transcutaneous, transdermal, intramuscular, intravenous, and subcutaneous) routes.
- "AChE": Acetyl Choline Esterase.
- "AChEI(s)": Acetyl Choline Esterase Inhibitor(s).
- "Transdermal delivery": administration of drug via the skin which targets, without limitation, skin tissues just under the skin, other tissues or organs under the skin, systemic circulation, and/or the central nervous system..
- "Transdermal Therapeutic System (TTS)": administration of drug via transdermal delivery using transdermal drug formulations and transdermal patches incorporating such transdermal drug formulations.
- A "maximum tolerated dose," "maximal tolerated dose" or "MTD" refers to the highest dose of a drug or treatment that does not cause unacceptable side effects. 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. - "comprising" means that the compositions and methods include the recited elements, but do not exclude others, "comprising" is inclusive of the terms "consisting of and "consisting essentially of . - "consisting essentially of means that the methods and compositions may include additional steps, components or ingredients, but only if the additional steps, components or ingredients do not materially alter the basic and novel characteristics of the claimed methods and compositions. In certain embodiments, "consisting essentially of means that the subsequently named component(s) is necessarily included but that another unlisted ingredient(s) that does not materially affect the basic and novel properties can also be present. For example, when used to define compositions and methods, "consisting essentially of means excluding other elements of any essential significance to the combination for the intended use. Thus, for example, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants and pharmaceutically acceptable carriers.
- "pharmaceutically acceptable salt" means either a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.
- "hypocholinergic disorder" means a pathologic condition of the CNS due to or derived from a decrease in cholinergic transmission typically associated with events or diseases including but not limited to: Alzheimer disease, Alzheimer-type dementia, mild cognitive impairment, Lewy body disease dementia, Parkinson's disease dementia, post-stroke dementia, vascular dementia, traumatic brain injury, Down syndrome, anorexia nervosa, Tourette disease, tardive dyskinesia, Pick's disease, Huntington's chorea, Friedrich's ataxia, chronic neuropathic pain, falls, post-operative delirium, schizophrenia, schizophrenia associated dementia, and schizoaffective disorders.
- "combination therapy" means treating a patient with a combination of a selective- muscarinic M2-receptor antagonist that crosses the blood-brain barrier, with a non- anticholinergic antiemetic agent and/or a non-selective peripheral muscarinic receptor antagonist, and optionally further including an acetylcholinesterase inhibitor, as a therapeutic platform in a rotating, an alternating and/or a simultaneous treatment schedule or regimen. Combination therapy may include a temporal overlap of other therapeutic agents, depending on the clinical course of a given hypocholinergic disease in a subject. BACKGROUND OF THE INVENTION
Acetylcholinesterase inhibitors (AChEIs) currently constitute the major drug class used to treat AD type dementias. Medications of this type serve not only as part of the standard of care for patients suffering from a dementia of the AD type, but are also used off-label for various other, generally chronic and progressive, hypocholinergic CNS disorders. AChEIs have the enhancement of ACh-mediated neurotransmission as a general mechanism of action. All work to increase and prolong the availability of ACh in the brain by inhibiting its degradatory enzyme acetylcholinesterase. Four AChEIs have been approved by the U.S. F.D.A. for the treatment of dementias of the AD type: tacrine (now little used), donepezil [Aricept®], rivastigmine [Exelon®] and galantamine [Razadyne®]. Rivastigmine has also been approved for the treatment of Parkinson's disease dementia. AChEIs are available in various formulations including immediate release forms such as tablets, capsules and solutions as well as rapid dissolving and extended release forms for oral administration as well as those for parenteral (e.g. transdermal) administration.
Unfortunately, none of the AChEIs approved for use for AD type dementias provide more than modest symptomatic benefit to any of these disorders. A critical medical need thus exists to improve the efficacy of these cholinergic replacement therapies. Several alternative strategies exist to appropriately stimulate cholinergic transmission in the brain of those suffering from these hypocholinergic CNS disorders such as the AD type dementias.
Another approach to the treatment of AD type dementia is to inhibit presynaptic muscarinic receptors of the M2 subtype by administering an antagonist selective for these receptors. M2 muscarinic receptors are generously expressed on the presynaptic terminals of cholinergic neurons projecting to the hippocampus and cerebral cortex as well as in most other brain regions involved in learning and memory processes (Alcantara AA et al. 2001; and Rouse ST et al. 2000; the disclosures of which are incorporated herein in their entirety by reference). When stimulated by intrasynaptic ACh, these autoreceptors act to inhibit further ACh synthesis and release, thus attenuating cholinergic transmission (Tzavara ET et al. 2003; Lamping KG et al. 2004; and Zhang W et al. 2002; the disclosures of which are incorporated herein in their entirety by reference). Moreover, M2 receptor knockout mice showed an impaired performance in passive avoidance testing that suggests a crucial role for these muscarinic receptors in the regulation not only of acetylcholine efflux but also of cognitive function (Tzavara ET et al. 2003). Similarly, drugs that block M2 receptors increase ACh release and stimulate cholinergic transmission. For this reason, M2 muscarinic receptor antagonists have been proposed as a potential cholinomimetic treatment of AD type dementia (Stoll C et al. 2009; the disclosure of which is incorporated herein in its entirety by reference).
However, after two decades of pharmacological and clinical studies, determining the potential efficacy in humans of selective M2-antagonists remains an unsolved problem.
Numerous studies with a variety of M2 receptor-preferring antagonists have been conducted to evaluate the role of M2 muscarinic receptor blockade in the treatment of cognitive dysfunction. Most suggest that drugs acting to inhibit these receptors enhance learning and memory in the experimental animal. For example, treatment with the selective muscarinic M2 antagonist, 5,1 l-dihydro-8-chloro-l l-[[4-[3-[(2,2-dimethyl-l- oxopentyl)ethylamino]propyl]-l-piperidinyl]acetyl]-6H-pyrido[2,3- b][l,4]benzodiazepin-6-one (BIBN-99), reportedly reverses, in a dose-dependent manner, the impaired ACh release as well as the cognitive deficits observed in aged memory impaired rats. BIBN-99 also improves scopolamine-induced amnesia in young animals (Quirion R et al. 1995; the disclosure of which is incorporated herein in its entirety by reference). In traumatic brain-injured rats, BIBN 99 has been found to attenuate cognitive deficits (Pike BR et al. 1995; the disclosure of which is incorporated herein in its entirety by reference). The efficacy of BIBN-99 in these studies is presumed to relate to its antagonistic properties on negative muscarinic M2 autoreceptors. Taken together, the forgoing observations could have implications for the treatment of degenerative disorders associated with impaired cholinergic function such as the AD type dementias (Rowe WB et al. 2003; the disclosure of which is incorporated herein in its entirety by reference).
Piperazine, piperazinyl-piperidine and piperidinyl-piperidine derivatives form a series of muscarinic M2-antagonists studied for their pro-cognitive properties. For example, the muscarinic M2 receptor antagonist 4-cyclohexyl-alpha-[4[[4- methoxyphenyl]sulphinyl]-phenyl]-l-piperazineacetonitrile (SCH 57790) produces a dose-related increase in brain acetylcholine release and enhances cognitive performance in rodents and nonhuman primates, effects that were qualitatively similar to those produced by the AChEI donepezil. The forgoing results support the view that blockade of muscarinic M2 receptors is a viable approach to enhancing cognitive performance (Carey GJ et al. 2001; the disclosure of which is incorporated herein in its entirety by reference).
Similarly, the piperazinyl-piperidine derivative 4-[4-[l(S)-[4-[(l,3-benzodioxol-
5-yl)sulfonyl]phenyl]ethyl]-3(R)-methyl-l-piperazinyl]-4-methyl-l- (propylsulfonyl)piperidine (SCH 72788), has also been found to be a functional M2 receptor antagonist that increases ACh release and is active in a rodent model of cognition, suggesting that M2 receptor antagonists may be useful for treating the cognitive decline observed in AD and other dementias (Lachowicz JE et al. 2001; the disclosure of which is incorporated herein in its entirety by reference).
The piperidinyl-piperidine derivative SCH-217443, a potent and selective M2 antagonist, shows activity in a rat model of cognition (Greenlee W et al. 2001; the disclosure of which is incorporated herein in its entirety by reference).
Methoctramine, a polym ethyl enetetraamine, acts as a muscarinic antagonist that binds preferently to the pre-synaptic M2 receptor. In female rats, the bilateral intrastriatal infusion of methoctramine improves procedural memory performance presumably by enhancing the release of acetylcholine (Lazaris A et al. 2003; the disclosure of which is incorporated herein in its entirety by reference).
Other drugs, identified as having relatively selective M2 muscarinic receptor antagonist activity but receiving little or no investigative attention in preclinical cognitive models, include: otenzepad (AF-DX 116), its (+)-enantiomer (AF-DX 250) and its analog AF-DX 384, (±)-5, l 1-dihydro-l l-([(2-[(dipropylamino)methyl]-l- piperidinyl)ethyl)amino]carbonyl)-6H-pyrido(2,3-b)(l,4)benzodiazepine-6-one;
caproctamine; and benextramine.
Among these M2-antagonists, otenzepad only is reputed to have been administered to human beings. Studies in human volunteers, reviewed in Adis Drug R&D 1999, the disclosure of which is incorporated herein in its entirety by reference, showed that this drug:
- may be orally administered to a human being at a dose of 120 mg bid or 240 mg bid; - does not induce manifest muscarinic adverse effects after single oral doses of 120, 240 and 480 mg; and - gives mild and tolerable adverse events, including palpitations, dry mouth and headache in about 20% of the subjects, when administered at 270 to 810 mg/day, but no other information of a clinical nature concerning otenzepad appears in the subsequent literature, specifically, no information concerning the adequacy of its cognitive efficacy at the doses administered to patients with hypocholinergic type dementias is found in the literature.
Thus, notwithstanding the intense and protracted preclinical focus on studies of the relation between presynaptic M2 receptor blockade and cognitive function, there have been no (known published) favorable results of therapeutic trials of highly selective M2 antagonists in patients with AD type dementia. On the other hand, several pharmaceuticals with M2 receptor antagonist activity and other pharmacologic activities, have been evaluated, some as potential candidates for the treatment of dementia. These potential candidates are briefly illustrated herein below.
- Lu 25-109 - The arecoline bioisostere, 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6- tetrahydropyridine (INN alvameline), has been under development for the treatment of
AD type dementia. In a clinical study (Sramek JJ et al. 1998), the fixed-dose Maximum Tolerated Dose of LU-25-109 was established to be 150 mg t.i.d. In binding assays, alvameline acts as a partial Mi agonist and as a M3 and mainly M2 antagonist with low affinities for other receptor types but is extensively metabolized in rodents and humans (Christensen EB et al. 1999). To evaluate the therapeutic effect of LU 25- 109, a 6-month, randomized, double-blind, placebo-controlled trial comparing three doses of Lu25-109 with placebo was carried out in 496 patients with probable AD. There were no significant differences for either of the two primary or the secondary variables, but a trend was observed for patients on the highest drug dose to worsen in the completer's analysis. This lack of antidementia efficacy may be partially attributable to the fact that Lu 25-109, while inhibiting presynaptic M2 muscarinic receptors, also blocks postsynaptic Mi and M3 receptors. Additionally, the drug produced prominent cholinergic side effects, including anorexia, nausea, diarrhea and increased sweating, all of which increased with increasing drug dose, thus preventing the administration of doses sufficient to benefit cognition (Thai LJ et al. 2000 Jan 25;5 (2): 21 6; the disclosure of which is incorporated herein in its entirety by reference). Thus, this document does not give any report of the efficacy of alvameline in humans; on the contrary, it reports a lack of antidementia efficacy at the doses used, which were just below those maximally tolerated by humans.
- Dimethindene, also known as dimetindene (trade name Fenistil), is N,N-Dimethyl-3- [l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine, CAS 0005636-83-9. It can be prepared as described by Huebner et al, in US 2,970,149, which also describes the optically active form of 2-(2-dimethylamino-ethyl))-3-[l-(2-pyridyl)-ethyl]-indene with an [a]D 25° of +70, or in J Am Chem Soc 1960, 87, 2077; the disclosure of which is incorporated herein in its entirety by reference. Dimet(h)indene is sold OTC in a number of countries worldwide as orally or locally administered antipruritic. Dimethindene for oral administration is available for example in IR coated tablets containing 1 mg dimet(h)indene or in ER unit forms containing 4 mg dimet(h)indene and the daily recommended dose is from 3 to 6 mg. The ((S)-(+)-dimethindene, N,N- Dimethyl-3-[(l,S)-l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine, is a potent M2- selective muscarinic receptor antagonist (Pfaff et al. 1995; the disclosure of which is incorporated herein in its entirety by reference). The (R)-(-)-enantiomer is the eutomer (responsible for bioactivity) for histamine Hi receptor binding (Histamine ¾ -receptor antagonist).
- Tripitramine, 1 l-[2-[6-[8-[6-[bis[2-oxo-2-(6-oxo-5H-pyrido[2,3-b][l,4] benzodiazepin-1 l-yl)ethyl]amino]hexyl-methylamino]octyl- methylamino]hexylamino]acetyl]-5H-pyrido[2,3-b][l,4]benzodiazepin-6-one, is a selective M2 cholinergic antagonist. Binding selectivity results indicate that it binds to the muscarinic M2 receptor with a ¾ value of 0.27 +/- 0.02 nM (Maggio R et al. 1994; the disclosure of which is incorporated herein in its entirety by reference).
Tripitramine can be prepared as described by Melchiorre et al. 1993; the disclosure of which is incorporated herein in its entirety by reference).
- Himbacine (3aR,4R,4a^,8aR,9a^-4-{(/^-[(2R,65)-l,6-dimethylpiperidin-2-yl]vinyl}-
3-methyldecahydronaphtho[2,3-c]furan-l(3H)-one, an alkaloid isolated from the bark of Australian magnolia, is a potent muscarinic receptor antagonist that displays selectivity for the M2 and M4 receptors but failed in clinical development.
- (+)-Himbacine was obtained by total synthesis (S. Chackalamannil et al. 1999; the disclosure of which is incorporated herein in its entirety by reference.).
- The "himbacine analog" (3aR,4R,4a^,8aR,9a5)-4-{(£)-[(2R,65)-l,6- dimethylpiperidin-2-yl]ethynyl}-3-methyldecahydronaphtho[2,3-c]furan-l(3H)-one, differing from himbacine by the presence of a triple bond, instead of a double bond, in its side chain, was reported to be a M2 antagonist, but exhibited lower affinity and showed a 10-fold selectivity for the M2/M3 receptors (Gao et al. 2006; the disclosure of which is incorporated herein in their entirety by reference)- -AQ-RA741, - 1 l-([4-[4-(Diethylamino)butyl]-l-piperidinyl]acetyl)-5,l l-dihydro-6H- pyrido[2,3-b][l,4]benzodiazepin-6-one, is another otenzepad analog disclosed as a selective, in particular cardioselective, high affinity M2 muscarinic receptor antagonist. Its development by Boehringer Ingelheim Pharma KG was discontinued due to adverse effects including cardiac arrhythmias (ADIS Insight, "at a glance": discontinued in 1997 - http: at adisinsight.springer.com/drugs/800002261; the disclosure of which is incorporated herein in its entirety by reference).
US 5,952,349 (Asberom et al), the disclosure of which is incorporated herein in its entirety by reference, discloses 1,4-di-substituted piperidines wherein the position 4 bears an optionally substituted anilino-group and the position 1 bears a hydrogen atom or a functional group. These compounds, alone or in combination with acetylcholinesterase inhibitors, are considered useful in the treatment of cognitive disorders.
US 5,883,096, US 6,037,352, US 6,288,068 and US 6,498,168 (Lowe et al. - see also WO 96/26196), the disclosures of which are incorporated herein in their entirety by reference, disclose di-N- substituted piperazines and 1,4-di-substituted piperidines useful in the treatment of cognitive disorders, pharmaceutical compositions containing said compounds, methods of treatment using compounds, in particular for the treatment of Alzheimer-type dementia; and the use of said compounds in combination with acetylcholinesterase inhibitors. In particular, these di-N- substituted piperazines and 1,4-di-substituted piperidines are endowed with selective M2 and/or M4 muscarinic antagonizing activity.
US 5,935,958 (Kozlowski et al. - see also WO 98/00412), the disclosure of which is incorporated herein in its entirety by reference, discloses di-N- substituted piperazines and 1,4-di-substituted piperidines linked, via a nitrogen atom of said piperazine or the nitrogen atom of said piperidine, to a bicyclic structure. Said compounds are preferably M2 or M4 selective muscarinic antagonists. This document also discloses combinations of said compounds with an AChEI. WO0000488 (Kozlowski et al.), the disclosure of which is incorporated herein in its entirety by reference, discloses di-N-substituted piperazines and 1,4-di-substituted piperidines linked to a pyridine, pyrazine or thiophene group via a substituted methyl group. These compounds are muscarinic agonists useful in the treatment of cognitive disorders, pharmaceutical compositions containing the compounds, methods of treatment using the compounds, and to the use of said compounds in combination with acetylcholinesterase inhibitors.
US 6,294,554 (Clader et al.), the disclosure of which is incorporated herein in its entirety by reference, discloses diphenyl-sulfones and phenyl-sulfonyl pyridines linked to a bipiperidine moiety via an optionally substituted methyl group, said substitution also including an ethylenedioxy group. These compounds are endowed with a selective M2-antagonist activity. This document specifically describes the l'-(2- amino-3-methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]methyl]-l,4'- bipiperidine, also known as SCH-211803, and the l'-(2-amino-3-methylbenzoyl)-4- [[[(3-chlorophenyl)sulfonyl]phenyl]ethylenedioxymethyl]-l,4'-bipiperidine, also known as SCH-217443.
A selective M2 receptor antagonist with a bipiperidine moiety, showing superior M2 receptor selectivity profile over SCH 211803, is "Compound 30" of formula
Figure imgf000011_0001
(Compound 30),
herein below referred to as "Wang Compound 30", disclosed by Y. Wang et al in Bioorg Med Chem Lett. 2002, 12, Pages 1087-1099 ("Sulfide analogues as potent and selective M2 muscarinic receptor antagonist"), the disclosure of which is incorporated herein in its entirety by reference.
Other bipiperidine derivatives showing highly potent and selective M2 receptor antagonist activity include "Compound 19" of formula
Figure imgf000012_0001
(Compound 19),
herein below referred to as "Palani Compound 19", and its analog "Compound 31", of formula
Figure imgf000012_0002
(Compound 31)
herein below referred to as "Palani Compound 31", disclosed by A. Palani et al., Bioorg. Med. Chem Lett, 2004, 14(7) 1791-1794 ("Isopropyl amide derivatives of potent and selective muscarinic M2 receptor antagonists"), the disclosure of which is incorporated herein in their entirety by reference.
US 6,458,812 (McKittrick et al. - see also WO02/051808), the disclosure of which is incorporated herein in its entirety by reference, discloses amide derivatives of 1,4-di-substituted piperidines wherein the most represented substituent in position 4 is a cycloalkyl group. Also these compounds are selective M2 or M4 muscarinic antagonists that may be used, alone or in combination with an acetylcholinesterase inhibitor, for treating a cognitive or neurodegenerative disease.
US 6,906,081 (Hey et al. - see also WO02/072093), the disclosure of which is incorporated herein in its entirety by reference, discloses the use of a dual histamine H3 receptor antagonist/M2 muscarinic antagonist, or a combination of an histamine H3 receptor antagonist with a M2 muscarinic antagonist, for the treatment of cognition deficit disorders, in particular Alzheimer's type dementia. This document also discloses said dual 5HT3-antagonist/M2-antagonist medicament used in combination with an AChEI.
WO 03/031412 (Wang et al. - see also EP1434766 and US2003/0207917), the disclosure of which is incorporated herein in its entirety by reference, discloses piperidine compounds as muscarinic receptor antagonists, as well as methods for preparing such compounds. In another embodiment, this document discloses pharmaceutical compositions comprising such muscarinic receptor antagonists as well as methods for using them to treat cognitive disorders such as Alzheimer's disease.
US 6,890,936 (Boyle et al. - see also WO 03/091220), the disclosure of which is incorporated herein in its entirety by reference, discloses certain 6-aza- spiro[2,3]octanes as antagonists of the muscarinic receptors (M2 and/or M4) and methods of treatment, prevention or amelioration of one or more diseases associated with the muscarinic receptors also in combination with at least one acetylcholinesterase inhibitor.
US 7,361,668 (Guyaux et al.), the disclosure of which is incorporated herein in its entirety by reference, discloses alkyne-quinuclidines that are endowed with a potent M2 and/or M3 muscarinic-antagonist activity and show pIC50 values ranging from 7 to 10 for the M3 and/or the M2 receptors in the binding tests. However, these compounds have been mainly considered as M3-receptor antagonists (J. -P. Starck, 2006, the disclosure of which is incorporated herein in its entirety by reference).
It is also well documented that schizophrenic patients experience cognitive disturbances that are not well addressed by current medications (Foster DJ et al. 2012 Dec.; 14(79):413-20).
An improvement in the treatment of the cognitive disorders globally designated as hypocholinergic disorders of the CNS including dementias of Alzheimer's type, is possible by combining an AChEI with a nsPAChA (US 8,404,701, the disclosure of which is incorporated herein in its entirety by reference) or with a non-anticholinergic antiemetic agent (US 8,877,768, the disclosure of which is incorporated herein in its entirety by reference).
In summary, despite an interest in (see Brashear HR 1996), and the extensive studies conducted on a series of M2-antagonist compounds, none of these compounds showed efficacy in humans at safe and tolerable doses and, conversely, said compounds induced adverse effects that were dose-limiting.
SUMMARY OF THE INVENTION
The present inventors recognized the critical need to take advantage of the potent activity of a M2 muscarinic antagonist for the treatment of hypocholinergic disorders as defined above, in particular AD type dementia, schizophrenia, and schizophrenia associated dementia.
The present invention relates to a pharmaceutical combination comprising:
(a) a muscarinic receptor antagonist selected from the group consisting of centrally active, selective M2-muscarinic cholinergic receptor antagonists (M2-antagonist); and
(b) a non-anticholinergic antiemetic agent (naAEA); and, optionally,
(c) an acetyl choline esterase inhibitor (AChEI).
The M2-antagonist Component (a) in the combination of the present invention may be selected from the group consisting of:
- 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6-tetrahydropyridine (alvameline)
- 5,1 l-dihydro-8-chloro-l l-[[4-[3-[(2,2-dimethyl-l-oxopentyl)ethylamino]propyl]-l- piperidinyl]acetyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one (BIBN-99);
- racemic 1 l-[[2-(Diethylamino)methyl]-l-piperidinyl]-acetyl]-5,l l-dihydro-6H- pyrido[2,3-b][l,4] benzodiazepin-6-one (otenzepad);
- dextrorotatory 1 l-[[2-(diethylamino)methyl]-l-piperidinyl]-acetyl]-5, 1 l-dihydro-6H- pyrido[2,3-b]El,4] benzodiazepin-6-one [(+)-otenzepad];
- N-2-[2-[(dipropylamino)methyl]-l-piperidinyl]ethyl]-5-,6-dihydro-l l-H-pyrido[2,3- b] [ 1 ,4]benzodiazepine- 11 -carboxamide (AF-DX 384);
- 1 l-[[4-[4-(Diethylamino)butyl]-l -piped dinyl]acetyl]-5,l l-dihydro-6H-pyrido[2,3- 6][l,4]benzodiazepin-6-one (AQ-RA 741);
- N,N-Dimethyl-3-[l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine (dimethindene); - N,N-Dimethyl-3-[(15)-l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine [S-(+)- dimethindene];
- N,N'-bis[6-[([2-methoxyphenyl)methyl]amino]hexyl]-l,8-octanediamine
(methoctramine);
- 1,1,24— tris[[5,l l-dihydro-6-oxo-6H-pyrido[2,3b][l,4]-benzodiazepin-l l-yl)carbonyl] methyl]-8, 17-dimethyl- 1,8,17,24-tetraazatetracosane (tripitramine);
- (3aR,4R,4aS,8aR,9aS)-4-{(E)-2-[(2R,6S)-l,6-dimethylpiperidin-2-yl]ethenyl}-3- methyldecahydronaphtho[2,3-c]furan-l(3H)-one (himbacine;
- (3 S,3aR,4R,4aS,8aR,9aS)-3-Methyl-4-[2-((R)-l-methyl-6-(S)-methyl-piperidin-2-yl)- vinyl]-decahydro-naphtho[2,3-c]furan-l-one [(+)-himbacine]; - (3aR,4R,4aS,8aR,9aS)-4-{(E)-2-[(2R,6S)-l,6-dimethylpiperidin-2-yl]ethynyl}-3- methyldecahydronaphtho[2,3-c]furan-l(3H)-one (himbacine analog);
- 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-l-piperazineacetonitrile (SCH-57790);
- 4-[4-[l(S)-[4-[(l,3-benzodioxol-5-yl)sulfonyl]phenyl]ethyl]-3(R)-methyl-l- piperazinyl]-4-methyl-l-(propylsulfonyl)piperidine (SCH-72788);
- -(2-methylbenzoyl)-4-[[[(3,4-methylenedioxyphenyl)sulfonyl]phenyl]methyl]-l,4'- bipiperidine (SCH-76050);
- -(2-amino-3-methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]methyl]-l,4'- bipiperidine (SCH-211803);
- l'-(2-amino-3-methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]ethylenedioxy methyl]- 1 ,4'-bipiperidine (SCH-217443);
- -naphto-l-yl-4-[[4-[(methoxycarbonyl)methylthio]phenyl]methyl]-l,4'-bipiperidine (Wang Compound 30);
- -(indol-4-yl)carbonyl-4-[[(4-isopropyl)carbonyl]phenyl]methyl]-l,4'-biperidine (Palani Compound 19);
- -(indol-4-yl)carbonyl-4-[[(4-isopropyl)carbonyl]phenyl]ethylenedioxymethyl]-l,4'- biperidine (Palani Compound 30);
and pharmaceutically acceptable salts and solvates thereof.
In one embodiment, Component (a) is present in an amount from 0.5 mg to 1500 mg.
The naAEA Component (b) in the combination of the present invention may be any antiemetic agent currently used for suppress vomiting of any origin and is normally selected from the group consisting of (bl) 5-hydroxytryptamine -3 antagonists ("5-HT3- antagonists"); (b2) dopamine antagonists (DA-antagonists"); (b3) HI -histamine antagonists (HI -antagonists); (b4) cannabinoid agonists ("cannabinoids"); and (b5)
Neurokinine-1 antagonists (" K1 -antagonists").
Furthermore, the present inventors found that, in order to assure a safe treatment of hypocholinergic disorders, the non-anticholinergic antiemetic agent Component (b) must be administered in combination with the M2-antagonist Component (a) from the start of the treatment of a patient with this combination and that said combination is essential for the continuation of said therapeutic treatment. Thus, in order to assure said safe treatment, the invention provides a combination wherein said naAEA Component (b) and said M2-antagonist Component (a) are present in a fixed-dose combination as a pharmaceutical composition in dosage unit form comprising said naAEA and said M2-antagonist in admixture with a pharmaceutical carrier. Herein below, said the M2-antagonist/naAEA fixed-dose combination will also be referred to as "Component (a/b)".
According to the present invention, the novel pharmaceutical composition in dosage unit form comprising, as active ingredients, (a) a M2-antagonist; and (b) a naAEA, in admixture with a pharmaceutical carrier or vehicle, is a particularly advantageous embodiment of the present invention.
The present invention also provides the addition of an AChEI to the above M2- antagonist/naAEA combination, thus assuring a maximum supply of acetylcholine to the CNS by the administration of a combination of the three components. Herein below, the third AChEI component will also be designated as "Component (c)". When Components (b) and Component (c) are formulated in the same unit form, said fixed- dose combination will also be designated as "Component (b/c)".
The combination of the present invention allows the administration of a M2- antagonist at even high doses, never previously administered to a human being, without any sign of dose-limiting adverse effects thus, on one side, eliminating the dose-limit that heretofore did not permit the full expression of the M2-antagonists' potency and, on the other side, allowing the treatment with said M2-antagonists of patients suffering from hypocholinergic disorders such as Alzheimer type dementia.
The present invention also relates to a method of treating a hypocholinergic disorder comprising administering a pharmaceutical combination as described herein, to a mammalian, preferably human, subject in need thereof.
The method or the use according to the present invention involves administering to a patient in need thereof, an effective dose of a M2-antagonist, in combination with a non-anticholinergic antiemetic agent (naAEA)
According to an embodiment, the hypocholinergic disorder is selected from the group consisting of schizophrenia, schizophrenia associated dementia, and schizoaffective disorders.
In a particular embodiment, the hypocholinergic disorder is Alzheimer type dementia. DETAILED DESCRIPTION
Reduced levels of neurotransmitters including acetylcholine occur in dementias such as the Alzheimer disease (AD) type, and reduced cholinergic transmission is thought to attend the cognitive deficits observed in schizophrenia, and schizophrenia associated dementia. In particular, a deficit in acetylcholine (ACh)-mediated transmission is thought to contribute to the cognitive and neurobehavioral abnormalities associated with these disorders. Accordingly, drugs known to augment cholinergic transmission in the Central Nervous System (CNS) are the mainstay of current therapy. In addition, other diseases of the nervous system also involve decreased cholinergic transmission and are also known as hypocholinergic syndromes and disorders of the central nervous system, herein above referred to as "hypocholinergic disorders".
The present invention provides a combination of a muscarinic antagonist that is a M2-antagonist and a non-anticholinergic antiemetic agent.
The present invention provides a treatment based on selective M2 antagonism at doses that could not previously be achieved due to adverse effects. There have been no published accounts of clinical studies demonstrating the ability of selective M2 muscarinic antagonists to treat hypocholinergic disorders of the CNS such as dementia of the AD type and schizophrenia or schizophrenia associated dementia. A major deterrent to such clinical investigations, as described above, is that the treatment with muscarinic agonists and/or antagonists has been limited by dose-limiting side effects, especially those reflecting hyperstimulation of peripheral muscarinic receptors.
The present inventors discovered that the lack of efficacy of the tested M2- antagonists was not due to an intrinsic inactivity of said compounds in humans but to an insufficient M2-antagonist action in the CNS and that, as a consequence, a major cause of failure of such clinical investigations, as described above, was that the treatment with muscarinic agonists or antagonists has been limited by dose-limiting side effects, especially those reflecting hyperstimulation of peripheral muscarinic receptors.
It has been unexpectedly found that, by the combination of a selective muscarinic M2-antagonist that crosses the Blood Brain Barrier (BBB) with a non- anticholinergic antiemetic agent, it is possible not only to safely administer said M2- antagonist at the previously non-tolerated doses, but also to administer even high doses of said M2-antagonist, thus enabling greater efficacy for the treatment of the aforementioned hypocholinergic disorders. Specifically, previous studies with M2 antagonists do not mention a possible combination of M2 antagonists with non-anticholinergic antiemetic agents, nor that the administration of such a combination can enable the safe and tolerable administration of doses of M2-antagonists capable of potentiating central cholinergic transmission so as to achieve efficacy in those suffering from hypocholinergic disorders, such as AD type dementias and schizophrenia or schizophrenia associated dementia, as provided in the present invention.
In summary, none of the approaches in the art, as discussed herein, offered a clinical benefit to patients suffering from AD type dementias. Indeed, at present, only the AChEIs have been approved for the treatment of AD type dementia. On average, said AChEIs confer no more than 3 points of cognitive improvement on the standard 70 point ADAS-cog dementia scale, a degree of benefit that is generally of little functional significance (Birks J 2006).
More particularly, the present invention provides the combination of a centrally acting, selective muscarinic-M2-antagonist drug and a non-anticholinergic antiemetic agent for the safe treatment of hypocholinergic disorders such as Alzheimer, dementia of Alzheimer type, schizophrenia, schizophrenia associated dementia, and other hypocholinergic type cognitive or behavioral disorders.
The present invention thus enables the heretofore inapplicable, safe and tolerable use of a presynaptic M2 muscarinic receptor antagonist in the treatment of hypocholinergic disorders such as Alzheimer, dementia of Alzheimer type, schizophrenia, schizophrenia associated dementia, and other hypocholinergic type cognitive or behavioral disorders, such as those described above, by combining said M2- antagonist with a non-anticholinergic antiemetic agent. This combination allows M2- antagonists to be safely used at high doses, thus allowing therapeutically adequate blockade of M2-receptor with attending increase in acetylcholine presynaptic release.
The finding of the present invention eliminates the dose-limit that, in the past, caused the failure of all clinical trials to demonstrate efficacy, thus providing a method for treating Alzheimer type dementia as well as central hypocholinergic disorders of the CNS by enabling the full efficacy of M2-antagonists.
The present invention provides a composition useful for treating a patient with a hypocholinergic disorder as described herein, which comprises a non-anticholinergic antiemetic agent, in combination with a M2-antagonist. The present invention provides said pharmaceutical combination or composition comprising a M2-antagonist and a naAEA for use in combating a hypocholinergic disorder in a patient.
The present invention also provides the addition of an AChEI to the above combination, thus assuring a maximum supply of acetylcholine to the CNS by the administration of a triple combination.
The present invention provides a method for treating a patient with a hypocholinergic disorder of the CNS as described herein, which comprises treating such patient in need of treatment with a non-anticholinergic antiemetic agent, in combination with a M2-antagonist.
In another embodiment, the method of the present invention may further include administration of an AChEI.
Thus, the present invention provides a pharmaceutical combination comprising, as Components:
(a) a muscarinic receptor antagonist selected from the group consisting of M2- muscarinic cholinergic receptor antagonists (M2-antagonists);
(b) a naAEA; and, optionally
(c) an AChEI.
According to an embodiment, said pharmaceutical combination comprises, as Components:
(a) a M2-antagonist, in a pharmaceutical composition in admixture with a pharmaceutical carrier; and
(b) a naAEA, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
According to another embodiment, said pharmaceutical combination comprises, as
Components:
(a) a M2-antagonist, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle;
(b) a naAEA selected from the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, domperidone and pharmaceutically acceptable salts and solvates thereof, metoclopramide and pharmaceutically acceptable salts and solvates thereof, in an amount of from 50% to 300% the maximum amount contained in the commercial preparations of said naAEA at the time of this filing for the treatment of nausea/vomiting, in a pharmaceutical composition in admixture with a pharmaceutical carrier..
According to a particularly advantageous embodiment, said pharmaceutical combination comprises as Components:
(a/b) a pharmaceutical composition in dosage unit form comprising
(a) a M2-antagonist; and
(b) a naAEA,
in admixture with a pharmaceutical carrier or vehicle.
According to a further embodiment, said pharmaceutical combination comprises as Components:
(a/b) a pharmaceutical composition in dosage unit form comprising
(a) a M2-antagonist; and
(b) a naAEA,
in admixture with a pharmaceutical carrier; and
(c) an AChEI, in admixture with a pharmaceutical carrier or vehicle.
A preferred pharmaceutical combination comprises
(a) a M2-antagonist selected form the group consisting of alvameline and pharmaceutically acceptable salts thereof, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b) a naAEA selected from the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, domperidone and pharmaceutically acceptable salts and solvates thereof and metoclopramide and pharmaceutically acceptable salts and solvates thereof, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and, optionally,
(c) an AChEI consisting of rivastigmine in admixture with a pharmaceutical carrier or vehicle in a patch for transdermal administration.
In addition, the present invention provides a method of using the above combinations for the treatment of hypocholinergic disorders in CNS, as described herein.
When the AChEI Component (c) is present in the combination, said Component (c) may be also present in a fixed-dose combination Component (b/c) in admixture with the naAEA Component (b) and with a pharmaceutical carrier or vehicle, as illustrated in US 9.192,591, the contents of which are incorporated herein in their entirety. Thus, the present invention also provides a M2-antagonist/naAEA/AChEI combination as described herein wherein the naAEA Components (b) and the AChEI Component (c) are formulated in the same unit form.
The combinations of the invention may be used for the treatment of Alzheimer type dementia and more generally for hypocholinergic disorders of the central nervous system, including Parkinson's disease dementia, Lewy Body Dementia, Frontotemporal Lobar Dementia, Mild Cognitive Impairment (MCI), Vascular Dementia, Traumatic Brain Injury, falls, post-operative delirium, Down Syndrome, Anorexia nervosa, and Schizophrenia.
The M2-antagonists Component (a)
Any M2-antagonist which is able to cross the brain blood barrier of a human in order to block the presynaptic muscarinic M2-receptor thus allowing the increase of acetylcholine transmission in the CNS may be used as Component (a) according to the present invention.
The M2-antagonists used as Component (a) are muscarinic receptor antagonists that are selective - as herein above defined - for the M2-receptor subtype.
Preferred Component (a) is a M2-antagonist selected from the group consisting of
- 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6-tetrahydropyridine (alvameline) and pharmaceutically acceptable salts and solvates thereof, which can be prepared for example as described in USRE 36374E, the disclosure of which is incorporated herein in its entirety by reference, and used as free base or as its tartrate salt;
- 5,1 l-dihydro-8-chloro-l l-[[4-[3-[(2,2-dimethyl-l-oxopentyl)ethylamino]propyl]-l- piperidinyl]acetyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one (BIBN-99) and pharmaceutically acceptable salts and solvates thereof, which can be prepared for example as described in US. 5,641,772, the disclosure of which is incorporated herein in its entirety by reference, and used as free base or as its dihydrochloride salt;
- (±)1 l-[[2-[(diethylamino)methyl]-l-piperidinyl]acetyl]-5,l l-dihydro-6H-pyrido[2,3- b][l,4]benzodiazepin-6-one (otenzepad - AF-DX 116) and pharmaceutically acceptable salts and solvates thereof, which can be prepared, in particular as the monomethanesulfonate salt thereof, for example as described in US. 4,550, 107, the disclosure of which is incorporated herein in its entirety by reference, and used as free base or as its maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrobromide or monomethanesulfonate salt; - (+)1 l-[[2-[(diethylamino)methyl]-l-piperidinyl]acetyl]-5,l l-dihydro-6H-pyrido[2,3- b][l,4]benzodiazepin-6-one [(+)-otenzepad, AF-DX 250] and pharmaceutically acceptable salts and solvates thereof, which can be prepared for example as described in US. 4,550,107, the disclosure of which is incorporated herein in its entirety by reference, or as illustrated in J. Med. Chem. 32(8), 1718-24, 1989 (Engel et al. 1989), the disclosure of which is incorporated herein in its entirety by reference, and used as free base or as its dihydrobromide salt;
- N-(2-[(2R)-2-[(dipropylamino)methyl]piperidin-l-yl]ethyl)-6-oxo-5H-pyrido[2,3- £][l,4]benzodiazepine-l l-carboxamide( AF-DX 384) and pharmaceutically acceptable salts and solvates thereof, which can be prepared for example as described in US 4,873,236, the disclosure of which is incorporated herein in its entirety by reference, and used as free base or as its sesquimaleate, hydrochloride, dihydrochloride dihydrate, hydrobromide, sulfate or methanesulfonate salt;
- 1 l-[[4-[4-(Diethylamino)butyl]-l-piperidinyl]acetyl]-5,l l-dihydro-6H-pyrido[2,3- £][l,4]benzodiazepin-6-one (AQ-RA 741) and pharmaceutically acceptable salts and solvates thereof, which can be prepared for example as described in US 5, 175,158, the disclosure of which is incorporated herein in its entirety by reference;
- 6-[(2-methoxyphenyl)methyl-methylamino]-N-[8-[6-[(2-methoxyphenyl)methyl- methylamino]hexanoyl-methylamino]octyl]-N-methylhexanamide (caproctamine) and pharmaceutically acceptable salts and solvates thereof;
- N,N"-(dithiodi-2, l-ethanediyl)bis[N'-[(2-methoxyphenyl)methyl]-l,6-hexanediamine] (benextramine) and pharmaceutically acceptable salts and solvates thereof;
- N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-l,8-octanediamine (methoctramine) and pharmaceutically acceptable salts and solvates thereof, which can be prepared for example as described in Chemistry and Industry (London) 89(19), 652-653 (Minarini 1989); and in J. Med. Chem. 87 Volume 30 (1), 201-204 (Melchiorre 1987), and used as free base or as its hydrochloride or tetrahydrochloride hemihydrate salt;
- 4-cyclohexyl-a-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-l-piperazineacetonitrile (SCH-57790) and pharmaceutically acceptable salts and solvates thereof, which can be prepared for example as described in the aforementioned Lowe et al. WO 96/26196), the disclosure of which is incorporated herein in their entirety by reference;
- 4-(4-(l(S)-(4-((l,3-benzodioxol-5-yl)sulfonyl)phenyl)ethyl)-3(R)-methyl-l- piperazinyl)-4-methyl-l-(propylsulfonyl)piperidine (SCH-72788) and pharmaceutically acceptable salts and solvates thereof, also obtainable as described in WO 96/26196;
- l'-(2-methylbenzoyl)-4-[[[(3,4-methylenedioxyphenyl)sulfonyl]phenyl]methyl]-l,4'- bipiperidine (SCH-76050) and pharmaceutically acceptable salts and solvates thereof, also obtainable as described in WO 96/26196;
- l'-(2-amino-3-methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]methyl]-l,4'- bipiperidine (SCH-211803) and pharmaceutically acceptable salts and solvates thereof, which can be prepared for example as described in US 6,294,554, the disclosure of which is incorporated herein in its entirety by reference, and used as free base or as its hydrochloride;
- l'-(2-amino-3-methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]ethylenedioxy methyl]-l,4'-bipiperidine (SCH-217443) and pharmaceutically acceptable salts and solvates thereof which can be prepared for example as described in US 6,294,554, the disclosure of which is incorporated herein in its entirety by reference, and used as free base or as its hydrochloride;
- -naphto-l-yl-4-[[4-[(methoxycarbonyl)methylthio]phenyl]methyl]-l,4'-bipiperidine (Wang Compound 30); and pharmaceutically acceptable salts and solvates thereof,
- -(indol-4-yl)carbonyl-4-[[(4-isopropyl)carbonyl]phenyl]methyl]-l,4'-biperidine and pharmaceutically acceptable salts and solvates thereof, (Palani Compound 19);
- -(indol-4-yl)carbonyl-4-[[(4-isopropyl)carbonyl]phenyl]ethylenedioxymethyl]-l,4'- biperidine and pharmaceutically acceptable salts and solvates thereof, (Palani Compound 30);
- N,N-dimethyl-3-[l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine (dimethindene) and pharmaceutically acceptable salts and solvates thereof, in particular its maleate;
- N,N-dimethyl-3-[(15)-l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine [(S)-(+)- dimethindene] and pharmaceutically acceptable salts and solvates thereof;
- 10, 19-dimethyl-l,28-bis(6-oxo-5,6-dihydro-l lH-pyrido[2,3-b][l,4]benzodiazepin-l l- yl)-3-[2-oxo-2-(6-oxo-5,6-dihydro-HH-pyrido[2,3-b][l,4]benzodiazepin-l l-yl)ethyl]- 3, 10,19,26-tetraazaoctacosane-l,28-dione (tripitramine) and pharmaceutically acceptable salts and solvates thereof, which can be prepared for example as described in J. Med. Chem. 1993 : 36, 3734-3737 (Melchiorre 1993), the disclosure of which is incorporated herein in its entirety by reference, and used as free base or as its sesquifumarate or tetraoxalate salts; - (3aR,4R,4a^,8aR,9a^-4-{(/^ (2R,6^-l,6-dimethylpiperidin-2-yl]vinyl}-3- methyldecahydronaphtho[2,3-c]furan-l(3H)-one (himbacine), that can be prepared, as (+)-Himbacine, as described in J Org Chem. 1999, Mar 19;64(6): 1932-1940 (Chackalamannil 1999), and pharmaceutically acceptable salts and solvates thereof; - (3aR,4R,4a^,8aR,9a^-4-{(^ (2R,65)-l,6-dimethylpiperidin-2-yl]ethynyl}-3- methyldecahydronaphtho[2,3-c]furan-l(3H)-one (himbacine analog) and pharmaceutically acceptable salts and solvates thereof.
The M2-antagonists are formulated in a pharmaceutical composition in IR- form or in ER-form, including a TTS, in admixture with a pharmaceutical carrier or vehicle. The compositions in dosage unit form contain said M2-antagonist at a dose which is dependent on the intrinsic potency of said M2-antagonist and is from 0.5 mg to 1500 mg, normally from 0.5 mg to 1000 mg, when included in a pharmaceutical composition in dosage unit form, as set forth above, wherein said M2-antagonist is present alone or in combination with a naAEA in a fixed-dose combination in said unit form, generally in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
For their use in combination with a naAEA for the treatment of Alzheimer type dementias, schizophrenia, schizophrenia associated dementia, schioaffective disorders and other hypocholinergic disorders described herein, said M2-antagonists are administered to patients in need of said treatment at a daily dose of from 1.5 mg to 3000 mg, or from 1.5 mg to 1500 mg by any administration route.
The pharmaceutical composition comprising the M2-antagonist may be used, in combination with Component (b) and, optionally, with an AChEI Component (c), for the treatment of a patient suffering from any of the hypocholinergic disorders described herein with a dose of M2-antagonist heretofore never tested for the adverse effects exhaustively illustrated herein above and in the literature.
The compositions are preferably formulated in dosage unit forms for oral, including buccal (as orodispersible or orosoluble preparations), topical, transmucosal or parenteral, in particular, transdermal, administration, wherein the active ingredient is mixed with a pharmaceutical carrier or vehicle.
Typically, in said compositions,
- alvameline, as free base or a salt or solvate thereof, especially as its tartrate, may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg;
- tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, may be present in an amount of from 10 mg to 200 mg, preferably from 25 mg to 100 mg;
- dimethindene, preferably as the maleate thereof, is present as racemate or as its S(+) enantiomer, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg, from 1.5 mg to 8 mg, from 1.5 to 6 mg or from 1.5 to 4 mg in a IR-form or, as the free base or the maleate thereof, in an amount of from 3 mg to 32mg, preferably from 4 mg to 32 mg , from 4.4 to 32 mg, from 6 mg to 32 mg, from 6 mg to 16 mg or from 3 mg to 10 mg, in an ER-form, including a TTS;
- otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate (INN: monomesilate, US AN: monomesylate) thereof, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg in a IR unit form or as the free base or as one of the aforementioned salts, in an amount of from 200mg to 500 mg, preferably from 300 mg 500 mg, in an ER-form, including a TTS;
- AQ-RX 741, as free base or as a salt or solvate thereof, especially as its monomethanesulfonate salt, may be present in an amount of from 10 mg to 500 mg, preferably from 10 mg to 250 mg in a IR-form or, as the free base or the methanesulfonate salt thereof, in an amount of from 20 mg to 500 mg, preferably from 50 mg to 500 mg, in an ER-form, including a TTS.
These compositions are destined for their use in the treatment of hypocholinergic disorders such as AD type dementia by administering said compositions once, twice or three times per day.
According to an advantageous embodiment, the pharmaceutical compositions prepared by using the M2-antagonist Component (a), which acts as cholinergic agent in the CNS to improve the symptoms of Alzheimer type dementia, in a quantity sufficient to maximally alleviate disease-associated neurobehavioral symptoms, are present in unit forms also containing other active ingredients, in particular the naAEA Component (b) to form a fixed-dose combination assuring a minimum of treatment-associated adverse effect according to the present invention. Said fixed dose combination may be concurrently or sequentially administered in combination with a pharmaceutical composition in dosage unit form comprising an AChEI in admixture with a pharmaceutical carrier.
The naAEAs Component (b)
Antiemetic medications commonly used to treat emesis, and not primarily regarded as anticholinergic agents, that are entirely devoid of anticholinergic activity or have an extremely low ability to prevent acetylcholine from acting at its cholinergic receptor sites in the brain may be used as Component (b) of the pharmaceutical combination of the present invention.
Preferably, said Component (b) is a non-anticholinergic antiemetic agent selected from the group consisting of (bl) 5HT3 -antagonists, (b2) DA-antagonists, (b3) HI -antagonists, (b4) cannabinoids, (b5) K1 -antagonists.
Typical non-anticholinergic antiemetic agents are
- 5-HT3 receptor antagonists (5HT3 -antagonists), such as 9-methyl-3-[(2-methyl-lH- imidazol-l-yl)methyl]-l,2,3,9-tetrahydrocarbazol-4-one (ondansetron) and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride dihydrate, described in EP 191562; 3S-ondansetron; 3R-onsdansetron; (3R)-10-oxo-8- azatricyclo[5.3.1.03,8]undec-5-yl lH-indole-3-carboxylate (dolasetron) and pharmaceutically acceptable salts and solvates thereof, in particular its monomethanesulfonate (mesylate or mesilate) monohydrate, described in EP 266730; 1 -methyl -N-(9-methyl-9-azabicyclo[3.3. l]non-3-yl)-indazole-3-carboxamide
(granisetron) and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, described in EP 200444; [(l S,5S)-8-methyl-8-azabicyclo[3.2.1]oct- 3-yl] lH-indole-3-carboxylate (tropisetron) and pharmaceutically acceptable salts and solvates thereof, in particular its monohydrochloride, described in U.S. Pat. No. 4,789,673; l-phenylmethyl-2-piperazinyl-lH-benzimidazole (lerisetron) and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, described in EP 512939; (R)-5-[(l-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-lH- benzimidazole (ramosetron) and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, described in U.S. Pat. No. 5,344,927; (3aR)-2- [(3S)-l-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-lH-benz[de]isoquinolin-l- one (palonosetron) and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, described in U.S. Pat. No. 5,202,333; 2,3,4,5-tetrahydro- 5-methyl-2-[(5-methyl-lH-imidazol-4-yl)methyl]-lH-pyrido[4,3-b]indol-l-one (alosetron) and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, described in U.S. Pat. No. 5,360,800; and (±)-6-chloro-,3,4-dihydro-4- methyl-3-oxo-N-(quinuclidinyl)-2H-l,4-benzoxazine-8-carboxamide (azasetron) and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, described in U.S. Pat. No. 4,892,872; which are known to be serotonin receptors blockers in the central nervous system and gastrointestinal tract and have been proposed for use to treat post-operative and cytotoxic drug nausea and vomiting;
- dopamine antagonists ("DA-antagonists"), such as 5-chloro-l-(l-[3-(2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)propyl]piperidin-4-yl)-lH-benzo[d]imidazol- 2(3H)-one (domperidone) and pharmaceutically acceptable salts and solvates thereof, particularly its maleate; l-[l-[4-(4-fluorophenyl)-4-oxo-butyl]-3,6-dihydro-2H- pyridin-4-yl]-3H-benzoimidazol-2-one (droperidol); 4-[4-(4-chlorophenyl)-4-hydroxy- 1 -piperidyl]- 1 -(4-fluorophenyl)-butan- 1 -one (haloperidol); 3 -(2-chloro- 10H- phenothiazin- 10-yl)-N,N-dimethyl-propan- 1 -amine (chlorpromazine) and pharmaceutically acceptable salts and solvates thereof, particularly its hydrochloride; 2-chloro-10-[3-(4-methyl-l-piperazinyl)propyl]-10H-phenothiazine
(prochlorperazine), and pharmaceutically acceptable salts and solvates thereof, particularly its dimaleate, dimesylate or 1,2-ethanedi sulfonate (1 : 1) (edisilate); dimethyl [ 1 -( 1 OH-phenothiazin- 10-yl)propan-2-yl ] amine (promethazine) and pharmaceutically acceptable salts and solvates thereof, particularly its hydrochloride; 4-aminosalicylamide and benzamide derivatives like 4-amino-5-chloro-N-[2- (diethylamino)ethyl]-2-methoxybenzamide (metoclopramide) and pharmaceutically acceptable salts and solvates thereof such as its monohydrochloride monohydrate; 4- amino-5-bromo-N-[2-(diethylamino)ethyl]-2-methoxybenzamide (bromopride) and pharmaceutically acceptable salts and solvates thereof, particularly its monohydrochloride and its dihydrochloride monohydrate; 4-amino-N-(l- benzylpiperidin-4-yl)-5-chloro-2-methoxybenzamide (clebopride) and pharmaceutically acceptable salts and solvates thereof, particularly its malate or its hydrochloride monohydrate; N-[(l-allylpyrrolidin-2-yl)methyl]-6-methoxy-lH- benzo[d][l,2,3]triazole-5-carboxamide (alizapride) and pharmaceutically acceptable salts and solvates thereof, particularly its hydrochloride; (L)-2-methoxy-N-((l- propylpyrrolidin-2-yl)methyl)-5-sulfamoylbenzamide (levosulpiride); N-{ [4-(2- dimethylaminoethoxy)phenyl]methyl}-3,4,5-trimethoxy-benzamide (trimethobenzamide) and pharmaceutically acceptable salts and solvates thereof, particularly its hydrochloride;
which act in the brain and especially at the chemoreceptor trigger zone and are known to be used to treat nausea and vomiting associated with neoplastic disease, radiation sickness, opioids, cytotoxic drugs and general anesthetics;
- HI histamine receptor antagonists ("HI -antagonists"), such as l-[(4-chlorophenyl)- phenyl-methyl]-4-[(3-methylphenyl)methyl]piperazine (meclizine or meclozine) and pharmaceutically acceptable salts and solvates thereof, particularly its dihydrochloride monohydrate; dimethyl [ 1 -( 1 OH-phenothiazin- 10-yl)propan-2-yl]amine (promethazine) and pharmaceutically acceptable salts and solvates thereof, particularly its hydrochloride; 3 -(2-chloro-l OH-phenothiazin- 10-yl)-N,N-dimethyl-propan-l -amine (chlorpromazine) or a salt thereof, particularly its hydrochloride; 2-chloro-10-[3-(4- methyl-l-piperazinyl)propyl]-10H-phenothiazine (prochlorperazine) and pharmaceutically acceptable salts and solvates thereof, particularly its dimaleate, dimesylate or 1,2-ethanedisulfonate (1 : 1) (edisilate); and 2-(2-{4-[(4- chlorophenyl)(phenyl)methyl]piperazin- 1 -yl } ethoxy)ethanol (hydroxyzine) and pharmaceutically acceptable salts and solvates thereof such as its hydrochloride or l,l '-methylene-bis(2-hydroxy-3-naphthalenecarboxylic acid salt (pamoate), which are known to be effective in many conditions, including motion sickness and severe morning sickness in pregnancy;
- cannabinoid receptor agonists ("cannabinoids"), such as cannabis; (6aR-trans)- 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-l-ol
(dronabinol); (6aR, 10aR)-rel-3 -(1,1 -dimethylheptyl)-6,6a,7, 8, 10, 1 Oa-hexahydro- 1 - hydroxy,6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one (nabilone); and (-)-cis-3-[2- hydroxy-4-(l, l-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP 55,940);
which are known to be used in patients with cachexia and cytotoxic nausea and vomiting; and
- antagonists of the neurokinin 1 receptor ( K1 -antagonists) such as 5-[[(2R,3S)-2- [(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4- mo holinyl]methyl]-l,2-dihydro-3H-l,2,4-triazol-3-one (aprepitant); (2S,4S)-4-(4- Acetyl- 1 -piperazinyl)-N- [( 1 R)- 1 - [3 , 5 -bi s(trifluoromethyl)phenyl] ethyl] -2-(4-fluoro-2- methylphenyl)-N-methyl-l-piperidinecarboxamide (casopitant); 2-[3,5- bis(trifluoromethyl)phenyl]-N,2-dim
piperazinyl)-3-pyridinyl]propanamide (netupitant) described in US 6,297,375, US 6,719,996 and US 6,593,47; the disclosures of which are incorporated herein in their entirety; and (5,S',8)S)-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 entireties;
which are known to be neurokinine-1 receptors blockers in both the central and peripheral nervous system and have been proposed for use to treat cytotoxic drug nausea and vomiting.
Advantageous naAEAs are the compounds available in drugs for the current antiemetic therapy, in particular,
- alosetron hydrochloride, available at the oral dose/unit form (in alosetron) of 0.5-1 mg;
- azasetron hydrochloride or mesilate monohydrate, available at the oral or i.v. dose/unit form of 10 mg;
- dolasetron mesylate monohydrate, available at the oral dose (in dolasetron) of 50-100 mg;
- granisetron hydrochloride, available at the oral dose (in granisetron) of 1-2 mg;
- ondansetron hydrochloride dihydrate, available at the oral dose (in ondansetron) of 4-8 mg;
- palonosetron hydrochloride, available at a the oral dose (in palonosetron) of 0.5 mg and i.v. dose (in palonosetron) of 0.25 mg;
- tropisetron hydrochloride, available at the oral dose (in tropisetron) of 5 mg;
- domperidone, available at the dose of 10 mg;
- haloperidol, available at the oral dose of 1-10 mg;
- chlorpromazine hydrochloride available at the oral dose (in chlorpromazine) of 25-100 mg;
- prochlorperazine dimaleate, available at the oral dose of 5 mg;
- metoclopramide hydrochloride, available dihydrate, at the oral dose (in metoclopramide) of 10 mg;
- bromopride dihydrochloride monohydrate, available at the oral dose (in bromopride) of 10 mg; - clebopride malate (1 : 1), available at a oral dose (in clebopride) of 1 mg;
- levosulpiride, at the oral dose of 25-100 mg;
- alizapride hydrochloride, available at the oral dose (in alizapride) of 50 mg;
- trimethobenzamide hydrochloride, available at the oral dose (in trimethobenzamide) of 100 mg
- meclizine (also called meclozine), available at the oral dose of 12.5-50 mg;
- promethazine hydrochloride, available at the oral dose (in promethazine) of 25 mg;
- dronabinol, available at the oral dose of 0.5-1 mg;
- aprepitant, available at the oral dose of 40-125 mg;
- netupitant, available at the oral dose of 300 mg; and
- casopitant, at the oral dose of 50 mg;
- rolapitant, available at the oral dose of 60 mg;
- the palonosetron-0.5 mg/netupitant-300 mg oral fixed-dose combination.
In the pharmaceutical combination to improve the treatment of human dementias of the Alzheimer type, schizophrenia, schizophrenia associated dementia, schizoaffective disorders and other hypocholinergic disorders described herein, according to the present invention, the non-anticholinergic antiemetic agent Component (b) is formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier to be administered with the M2-antagonist Component (a) The pharmaceutical combination may further include, as Component (c), an AChEI.
Said amount of Component (a) sufficient to maximally alleviate disease- associated cognitive and other neurobehavioral symptoms is illustrated in the above "The M2-antagonists" section.
The Component (b) is advantageously selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; bromopride and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride or the dihydrochloride monohydrate; alizapride and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; clebopride and pharmaceutically acceptable salts and solvates thereof, especially its malate and the hydrochloride monohydrate; meclizine (meclozine) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; promethazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, especially its dimaleate, its dimesylate and its the 1,2-ethanedisulfonate (1 : 1) (edisilate); hydroxyzine and pharmaceutically acceptable salts and solvates thereof such as the dihydrochloride or the 1,1 '-methylene bis(2-hydroxy-3-naphthalenecarboxylic acid (pamoate) dronabinol; nabilone; aprepitant; netupitant; rolapitant; netupitant/palonosetron hydrochloride fixed- dose combination; and casopitant.
In the combination of the present invention, the non-anticholinergic antiemetic agent, Component (b) is present, generally in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle, in an amount of from 50% to 600%, normally 50% to 300%, of the amount of the said non-anticholinergic antiemetic agent contained as a sole active ingredient in the aforementioned, currently used brand or generic drugs. Each of said typical non-anticholinergic antiemetic agents is present in the pharmaceutical composition, as Component (b), in an amount ranging from 50% of the minimum amount to 600%, and in some cases beyond 600%, normally 300%, of the maximum amount of said typical non-anticholinergic antiemetic agent contained in the corresponding, currently used generic or brand drug for its antiemetic indication in IR form.
Advantageous Component (b) is selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 3 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 300 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 3 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 48 mg, up to 64 mg; palonosetron, and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount of from 2.5 mg to 15 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 30 mg; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, in particular the dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in particular the monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and pharmaceutically acceptable salts and solvates, in particular the monohydrochloride and the dihydrochloride monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrogen malate and the hydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mg to 1.5 mg; levosulpiride, in an amount of from 12.5 mg to 300 mg; alizapride and pharmaceutically acceptable salts thereof, in particular the hydrochloride, in an amount (in alizapride) of from 25 mg to 150 mg; trimethobenzamide and pharmaceutically acceptable salts thereof such as the monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine (also called meclozine) and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; rolapitant, in an amount of from 90 mg to 540 mg; and casopitant, in an amount of from 25 mg to 300 mg; in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
Preferred Component (b) is selected from the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in ondansetron) of from 2 mg to 32 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in granisetron) of from 0.5 mg to 3 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in an amount (in metoclopramide) of from 5 mg to 30 mg; dronabinol, in an amount of from 1.25 mg to 30 mg; nabilone, in an amount of from 0.25 mg to 3 mg; aprepitant, in an amount of from 20 mg to 375 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 90 mg to 360 mg; and casopitant, in an amount of from 25 mg to 150 mg.
According to an embodiment, the non-anticholinergic antiemetic agent is present, in an IR unit form, in an amount ranging from 50% to 200% of the maximum amount of said antiemetic agent contained in the currently administered IR dosage unit forms for the treatment of emesis or, in an ER unit form, in an amount ranging from 75%) to 300%) of the currently administered IR dosage unit forms for the treatment of emesis.
For example, according to this embodiment, among the advantageous non- anticholinergic antiemetic agents used as Component (b), ondansetron or a pharmaceutically acceptable salt or solvate thereof, in particular its hydrochloride dihydrate, is present in an amount (in ondansetron) of from 2 mg to 16 mg per dosage unit in an IR unit form or in an amount of from 3 mg to 24 mg, preferably from 8 mg to 24 mg in an ER unit form; alosetron or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, is present in an amount (in alosetron) of from 0.25 mg to 2 mg per dosage unit in an IR unit form or in an amount of from 0.375 mg to 3 mg, preferably from 1 mg to 3 mg, in an ER unit form; azasetron or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, is present in an amount of from 5 mg to 20 mg per dosage unit in an IR unit form or in an amount of from 7.5 mg to 30 mg, preferably from 10 mg to 30 mg, in an ER unit form; ramosetron or a pharmaceutically acceptable salts thereof, in particular its hydrochloride, is present in an amount (in ramosetron) of from 0.025 mg to 0.1 mg per dosage unit in an IR unit form or in an amount of from 0.0375 mg to 0.3 mg, preferably from 0.05 mg to 0.3 mg, in an ER unit form; tropisetron or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, is present in an amount (in tropisetron) of from 2.5 mg to 10 mg per dosage unit in an IR unit form or in an amount of from 3.75 mg to 15 mg, preferably from 5 mg to 15 mg, in an ER unit form; granisetron or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, is present in an amount (in granisetron) of from 0.5 mg to 2 mg per dosage unit in an IR unit form or in an amount of from 0.75 mg to 3 mg, preferably from 1 mg to 3 mg, in an ER unit form; dolasetron, or a pharmaceutically acceptable salt thereof, in particular its mesilate, is present in an amount (in dolasetron) of from 25 mg to 200 mg per dosage unit in an IR unit form or in an amount of from 37.5 mg to 300 mg, preferably from 100 mg to 300 mg, in an ER unit form; palonosetron, or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, is present (a) in an amount (in palonosetron) of from 0.25 mg to 1 mg in an IR dosage unit form or from 0.375 mg to 1.5 mg in an ER dosage unit form, or (b) in an amount (in palonosetron) of from 0.25 mg to 12 mg, in a fixed-dose combination with netupitant, in an amount of from 200 mg to 600 mg, said fixed-dose combination being in an IR dosage unit form; domperidone or a pharmaceutically acceptable salt thereof, in particular its maleate, is present in an amount (in domperidone) of from 5 mg to 20 mg per dosage unit in an IR unit form or in an amount of from 7.5 mg to 60 mg, preferably from 10 mg to 60 mg, in an ER unit form; metoclopramide or a pharmaceutically acceptable salt or solvate thereof, in particular its monohydrochloride monohydrate, is present in an amount (in metoclopramide) of from 5 mg to 20 mg per dosage unit in an IR unit form or in an amount of from 7.5 mg to 30 mg, preferably from 10.0 mg to 30.0 mg, in an ER unit form; alizapride or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, is present in an amount (in alizapride) of from 25 mg to 100 mg per dosage unit in an IR unit form or in an amount of from 37.5 mg to 300 mg, preferably from 100 mg to 300 mg, in an ER unit form; meclizine or a pharmaceutically acceptable salt thereof, in particular its hydrochloride is present in an amount (in meclizine) of from 25 mg to 100 mg per dosage unit in an IR unit form or in an amount of from 37.5 mg to 150 mg, preferably from 50 mg to 150 mg, in an ER unit form; chlorpromazine or a pharmaceutically acceptable salt thereof, in particular its hydrochloride is present in an amount (in chlorpromazine) of from 12.5 mg to 200 mg per dosage unit in an IR unit form or in an amount of from 75 mg to 300 mg, preferably from 100 mg to 300 mg, in an ER unit form; prochlorperazine or a pharmaceutically acceptable salt thereof, in particular its maleate is present in an amount (in prochlorperazine) of from 2.5 mg to 10 mg per dosage unit in an IR unit form or in an amount of from 3.75 mg to 15 mg, preferably from 5 mg to 15 mg, in an ER unit form; ; dronabinol is present in an amount of from 1.25 mg to 20 mg per dosage unit in an IR unit form or in an amount of from 1.8 mg to 60 mg, preferably from 2.5 mg to 60 mg, in an ER unit form; nabilone is present in an amount of from 0.25 mg to 2 mg per dosage unit in an IR unit form or in an amount of from 0.75 mg to 3 mg per dosage unit in an ER unit form; aprepitant is present in an amount of from 20 mg to 250 mg per dosage unit in an IR unit form or in an amount of from 30 mg to 750 mg, preferably from 125 mg to 500 mg, in an ER unit form; netupitant is present in an amount of from 150 mg to 600 mg, in an IR unit form or in an amount of from 225 to 900 mg, preferably from 300 mg to 900 mg, in an ER unit form; rolapitant, in an amount of form 30 mg to 120 mg, in an IR unit form or in an amount of from 45 mg to 180 mg, preferably from 60 mg to 180 mg, in an ER unit form; and casopitant is present in an amount of from 25 mg to 150 mg per dosage unit in an IR unit form or in an amount of from 37.5 mg to 150, preferably from 50 mg to 150 mg, in an ER unit form, in admixture with a pharmaceutical carrier or vehicle in a pharmaceutical composition in dosage unit form.
Preferred Component (b) is a pharmaceutical composition in dosage unit form comprising a non-anticholinergic antiemetic agent selected from the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in ondansetron) of from 8 mg to 24 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in granisetron) of from 0.5 mg to 3 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 10 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in an amount (in metoclopramide) of from 105- mg to 30 mg; dronabinol, in an amount of from 10 mg to 30 mg; nabilone, in an amount of from 1 mg to 3 mg; aprepitant, in an amount of from 125 mg to 375 mg; netupitant, in an amount of from 300 mg to 900 mg; rolapitant, in an amount of form 60 mg to 180 mg; and casopitant, in an amount of from 50 mg to 150 mg, in admixture with a pharmaceutical carrier or vehicle.
Thus, the invention provides compositions and methods for treating hypocholinergic disorders, which comprises administering to a patient in need of said treatment the above-illustrated combination. In such a treatment, Component (a) and Component (b) of the combination may be administered simultaneously or sequentially to said patient, Component (a) being indifferently administered before or after Component (b). Component (a) and Component (b) may also be administered by the same or a different administration route.
The invention may also include a third component, Component (c) that is an AChEI, also formulated in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
The Combinations
The present invention provides the combination of any M2-antagonist and any naAEA as exemplified in the respective sections herein, each formulated in pharmaceutical composition in admixture with a pharmaceutical carrier.
In particular, the combination of the present invention may be a combination comprising or consisting essentially of
(a) any of the M2-antagonists such as those described herein, each in a pharmaceutical composition in dosage unit form, in admixture with a pharmaceutical carrier, said M2-antagonist being preferably selected from the group consisting of 5-(2-ethyl- 2H-tetrazol-5-yl)-l-methyl-l,2, 3,6-tetrahydropyridine (alvameline) and pharmaceutically acceptable salts and solvates thereof), 5,l l-dihydro-8-chloro-l l- [[4-[3-[(2,2-dimethyl-l-oxopentyl)ethylamino]propyl]-l-piperidinyl]acetyl]-6H- pyrido[2,3-b][l,4]benzodiazepin-6-one (BIBN-99) and pharmaceutically acceptable salts and solvates thereof; racemic l l-[[2-(Diethylamino)methyl]-l-piperidinyl]- acetyl]-5, l l-dihydro-6H-pyrido[2,3-b][l,4] benzodiazepin-6-one (otenzepad) and pharmaceutically acceptable salts and solvates thereof; dextrorotatory 11-[[2- (diethylamino)methyl]-l-piperidinyl]-acetyl]-5, l l-dihydro-6H-pyrido[2,3-b]El,4] benzodiazepin-6-one [(+)-otenzepad] and pharmaceutically acceptable salts and solvates thereof; N-2-[2-[(dipropylamino)methyl]-l-piperidinyl]ethyl]-5-,6- dihydro- 11 -H-pyrido[2,3 -b] [ 1 ,4]benzodiazepine- 11 -carboxamide (AF-DX 384) and pharmaceutically acceptable salts and solvates thereof; l l-[[4-[4- (Diethylamino)butyl]-l-piperidinyl]acetyl]-5, l l-dihydro-6H-pyrido[2,3- £][l,4]benzodiazepin-6-one (AQ-RA 741) and pharmaceutically acceptable salts and solvates thereof; N,N-Dimethyl-3-[l-(2-pyridinyl)ethyl]-lH-indene-2- ethanamine (dimethindene) and pharmaceutically acceptable salts and solvates thereof; N,N-Dimethyl-3-[(15)-l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine [S- (+)-dimethindene] and pharmaceutically acceptable salts and solvates thereof; Ν,Ν'- bis[6-[([2-methoxyphenyl)methyl]amino]hexyl]-l,8-octanedi amine
(methoctramine) and pharmaceutically acceptable salts and solvates thereof; 1,1,24- tris[[5,l l-dihydro-6-oxo-6H-pyrido[2,3b][l,4]-benzodiazepin-l l-yl)carbonyl] methyl]-8,17-dimethyl-l,8, 17,24-tetraazatetracosane (tripitramine) and pharmaceutically acceptable salts and solvates thereof; (3aR,4R,4aS,8aR,9aS)-4- {(E)-2-[(2R,6S)-l,6-dimethylpiperidin-2-yl]ethenyl}-3- methyldecahydronaphtho[2,3-c]furan-l(3H)-one (himbacine) and pharmaceutically acceptable salts and solvates thereof; (3 S,3aR,4R,4aS,8aR,9aS)-3-Methyl-4-[2- ((R)-l-methyl-6-(S)-methyl-piperidin-2-yl)-vinyl]-decahydro-naphtho[2,3-c]furan- 1-one [(+)-himbacine] and pharmaceutically acceptable salts and solvates thereof; (3aR,4R,4aS,8aR,9aS)-4-{(E)-2-[(2R,6S)-l,6-dimethylpiperidin-2-yl]ethynyl}-3- methyldecahydronaphtho[2,3-c]furan-l(3H)-one (himbacine analog) and pharmaceutically acceptable salts and solvates thereof; 4-cyclohexyl-alpha-[4[[4- methoxyphenyl]sulphinyl]-phenyl]-l-piperazineacetonitrile (SCH-57790) and pharmaceutically acceptable salts and solvates thereof; 4-[4-[l(S)-[4-[(l,3- benzodioxol-5-yl)sulfonyl]phenyl]ethyl]-3(R)-methyl-l-piperazinyl]-4-methyl-l- (propylsulfonyl)piperidine (SCH-72788) and pharmaceutically acceptable salts and solvates thereof; l'-(2-methylbenzoyl)-4-[[[(3,4- methylenedioxyphenyl)sulfonyl]phenyl]methyl]-l,4'-bipiperidine (SCH-76050) and pharmaceutically acceptable salts and solvates thereof; l'-(2-amino-3- methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]methyl]-l,4'-bipiperidine (SCH-211803) and pharmaceutically acceptable salts and solvates thereof; l'-(2- amino-3-methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]ethylenedioxy methyl]-l,4'-bipiperidine (SCH-217443) and pharmaceutically acceptable salts and solvates thereof; l '-naphto-l-yl-4-[[4-
[(methoxycarbonyl)methylthio]phenyl]methyl]-l,4'-bipiperidine (Wang Compound 30) salts and solvates thereof; l '-(indol-4-yl)carbonyl-4-[[(4- isopropyl)carbonyl]phenyl]methyl]-l,4'-biperidine (Palani Compound 19) and pharmaceutically acceptable salts and solvates thereof; and l '-(indol-4-yl)carbonyl- 4-[[(4-isopropyl)carbonyl]phenyl]ethylenedioxymethyl]-l,4'-biperidine (Palani Compound 30); and
any of the naAEA such as those described herein, each in a pharmaceutical composition in admixture with a pharmaceutical carrier, said naAEA being (bl) a 5HT3 -antagonist; (b2) a DA-antagonist; (b3) a Hl-antagonint; (b4) a cannabinoid or (b5) a K1 -antagonist, preferably selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; bromopride and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride or the dihydrochloride monohydrate; alizapride and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; clebopride and pharmaceutically acceptable salts and solvates thereof, especially its malate and the hydrochloride monohydrate; meclizine (meclozine) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; promethazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, especially its dimaleate, its dimesylate and its the 1,2-ethanedi sulfonate (1 : 1) (edisilate); hydroxyzine and pharmaceutically acceptable salts and solvates thereof such as the dihydrochloride or the 1, 1 '-methylene bis(2-hydroxy-3- naphthalenecarboxylic acid (pamoate) dronabinol; nabilone; aprepitant; netupitant; rolapitant; the netupitant/palonosetron hydrochloride fixed-dose combination; and casopitant.
In the above combination, each of the Components (a) and (b) is in pharmaceutical composition in dosage unit form wherein each of said components is in admixture with a pharmaceutical carrier or vehicle.
According to this first embodiment, an advantageous combination may be a combination comprising or consisting essentially of
(a) a M2-antagonist selected from the group consisting of alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt, may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tripitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; (±)-dimethindene or ,S'(+)-dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount, in otenzepad, of from 100 mg to 500 mg, preferably from 150 mg to 350 mg; and AQ-RX 741, as free base or as a salt or solvate thereof, especially as its monomethanesulfonate salt, in an amount, in AQ-RX 741, of from 10 mg to 500 mg, preferably from 10 mg to 250 mg; in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b) a naAEA, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
According to this first embodiment, another advantageous combination may be a combination comprising or consisting essentially of
(a) a M2-antagonist selected from the group consisting of alvameline, as free base or a salt or solvate thereof, especially as its tartrate, in an amount, in alvameline, of from 200 mg to 600 mg; tripitramine sesquifumarate in an amount, in tripitramine, of from 15 mg to 150 mg; (±)-dimethindene or ,S'(+)-dimethindene maleate, in an amount of from 1.5 mg to 25 mg; otenzepad maleate (1 : 1), in an amount of from 200 mg to 400 mg; and AQ-RX 741 monomethanesulfonate, in an amount of from 15 mg to 300 mg, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b) a naAEA in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
The pharmaceutical combinations of this first embodiment of the present invention are useful for the treatment of hypocholinergic disorders, and even high doses of a M2-antagonist Component (a), may be present to improve symptoms of AD type dementia or schizophrenia without adverse effects to a greater extent.
Thus, the present invention provides a method for treating hypocholinergic disorders, which comprises administering to a patient in need of said treatment the combinations described herein in one embodiment. In such a treatment, Component (a), and Component (b) of the combination may be administered simultaneously or sequentially to said patient, Component (a) being indifferently administered before or after Component (b). Component (a) and Component (b) may also be administered by the same or a different administration route.
According to a second embodiment, the present invention provides a pharmaceutical combination comprising or consisting essentially of, as Components: (a) a M2-antagonist, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b) a naAEA selected from the group consisting of (bl) 5HT3 -antagonists, (b2) DA- antagonists, (b3) HI -antagonists, (b4) cannabinoids, (b5) K1 -antagonists, and the netupitant-palonosetron fixed-dose combination, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
Another advantageous combination is one comprising or consisting essentially of
(a) a M2-antagonist, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b) a naAEA consisting of a 5HT3 -antagonist selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, azasetron and pharmaceutically acceptable salts and solvates thereof; ondansetron and pharmaceutically acceptable salts and solvates thereof; granisetron and pharmaceutically acceptable salts and solvates thereof; dolasetron and pharmaceutically acceptable salts and solvates thereof, ramosetron and pharmaceutically acceptable salts and solvates thereof; tropisetron and pharmaceutically acceptable salts and solvates thereof; and palonosetron and pharmaceutically acceptable salts and solvates thereof, alone or in combination with the K1 -antagonist netupitant, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
According to this second embodiment, another advantageous combination is a combination comprising or consisting essentially of:
(a) a M2-antagonist, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b) a naAEA consisting of a 5HT3 -antagonist selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts thereof, iu particular the hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts thereof, in particular its hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg, tropisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount of from 2.5 mg to 30 mg, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
According to this second embodiment, a further advantageous combination is a combination comprising or consisting essentially of:
(a) a M2-antagonist, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b) a naAEA consisting of a DA-antagonist consisting of domperidone and pharmaceutically acceptable salts and solvates thereof such as the maleate; metoclopramide and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride monohydrate, bromopride and pharmaceutically acceptable salts and solvates thereof such as the monohydrochloride or the dihydrochloride monohydrate, alizapride and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride, and clebopride and pharmaceutically acceptable salts and solvates thereof such as the malate and the hydrochloride monohydrate; in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
An advantageous combination according to this second embodiment is a combination comprising or consisting essentially of the following Components:
(a) a M2-antagonist, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b) a naAEA consisting of a DA-antagonist consisting of domperidone or a pharmaceutically acceptable salt thereof, in particular its maleate, in an amount (in domperidone) of from 5 mg to 20 mg per dosage unit in an IR unit form or in an amount of from 7.5 mg to 60 mg, preferably from 10 mg to 60 mg, in an ER unit form; metoclopramide or a pharmaceutically acceptable salt or solvate thereof, in particular its monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 20 mg per dosage unit in an IR unit form or in an amount of from 7.5 mg to 30 mg, preferably from 10 mg to 30 mg, in an ER unit form; alizapride or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, in an amount (in alizapride) of from 25 mg to 100 mg per dosage unit in an IR unit form or in an amount of from 37.5 mg to 300 mg, preferably from 100 mg to 300 mg, in an ER unit form; in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
A further advantageous combination according to this second embodiment is a combination comprising or consisting essentially of the following Components:
(a) a M2-antagonist, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b) a naAEA consisting of a histamine HI receptor antagonists selected from the group consisting of meclizine (meclozine) and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride monohydrate; promethazine and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride; chlorpromazine and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride, prochlorperazine and pharmaceutically acceptable salts and solvates thereof such as the dimaleate, the dimesylate or the 1,2-ethanedisulfonate (1 : 1) (edisilate); hydroxyzine and pharmaceutically acceptable salts and solvates thereof such as the dihydrochloride or the 1, 1 '-methylene bis(2-hydroxy-3- naphthalenecarboxylic acid (pamoate) salt; in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
According to this second embodiment, a further advantageous combination is a combination comprising or consisting essentially of the following Components:
(a) a M2-antagonist, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b) a naAEA consisting of a histamine HI receptor antagonists selected from the group consisting of meclizine or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, in an amount (in meclizine) of from 6.25 mg to 100 mg per dosage unit in an IR unit form or in an amount of from 37.5 mg to 150 mg, preferably from 50 mg to 150 mg, in an ER unit form; chlorpromazine or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 200 mg per dosage unit in an IR unit form or in an amount of from 75 mg to 300 mg, preferably from 150 mg to 300 mg, in an ER unit form; prochlorperazine or a pharmaceutically acceptable salt thereof, in particular its maleate, in an amount (in prochlorperazine) of from 6.25 mg to 100 mg per dosage unit in an IR unit form or in an amount of from 37.5 mg to 150 mg, preferably from 50 mg to 150 mg, in an ER unit form; in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
According to a third embodiment, the invention provides a specific M2- antagonist/naAEA combination comprising
(a) a M2-antagonist, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b) a naAEA consisting of a fixed-dose combination comprising palonosetron, in an amount of from 0.25 mg to 3 mg of palonosetron or a pharmaceutically acceptable salt thereof such as its hydrochloride and from 150 mg to 600 mg of netupitant, in admixture with a pharmaceutical carrier formulated in an oral IR formulation.
According to a fourth embodiment, an advantageous combination may be a combination comprising or consisting essentially of (a) a pharmaceutical composition comprising alvameline or a pharmaceutically acceptable salt or solvate thereof, an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg,
in admixture with a pharmaceutical carrier or vehicle; and
(b) a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, azasetron and pharmaceutically acceptable salts and solvates thereof; ondansetron and pharmaceutically acceptable salts and solvates thereof; granisetron and pharmaceutically acceptable salts and solvates thereof; dolasetron and pharmaceutically acceptable salts and solvates thereof, ramosetron and pharmaceutically acceptable salts and solvates thereof; tropisetron and pharmaceutically acceptable salts and solvates thereof; and palonosetron and pharmaceutically acceptable salts and solvates thereof, domperidone and pharmaceutically acceptable salts and solvates thereof such as the maleate; chlorpromazine and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride; prochlorperazine and its salts and solvates, particularly the dimaleate and the dimesylate; promethazine and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride; and 4-aminosalicylamide derivatives such as metoclopramide and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride monohydrate, bromopride and pharmaceutically acceptable salts and solvates thereof such as the monohydrochloride or the dihydrochloride monohydrate, alizapride and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride, and clebopride and pharmaceutically acceptable salts and solvates thereof such as the malate and the hydrochloride monohydrate, dronabinol, nabilone, aprepitant, netupitant, rolapitant, and casopitant,
in admixture with a pharmaceutical carrier or vehicle.
An advantageous combination according to this fourth embodiment may be a combination comprising or consisting essentially of, as Components:
(a) a pharmaceutical composition comprising alvameline tartrate, in an amount, in alvameline, of from 200 mg to 600 mg, in admixture with a pharmaceutical carrier; and a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated thereof, in particular its hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount of from 2.5 mg to 30 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, in particular the dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in particular the monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and pharmaceutically acceptable salts and solvates, in particular the monohydrochloride and the dihydrochloride monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrogen malate and the hydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically acceptable salts thereof, in particular the hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide and pharmaceutically acceptable salts thereof such as the monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine (also called meclozine) and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg; in admixture with a pharmaceutical carrier or vehicle.
Preferably, according to this fourth embodiment, the pharmaceutical composition Component (a) comprises alvameline, as free base or as its tartrate, in an amount from 160 mg to 960 mg, in particular, from 160 mg to 480 mg in an IR- formulated oral composition or in an amount of from 240 mg to 960 mg in an ER- formulated composition or device, including a TTS, in admixture with a pharmaceutical carrier or vehicle.
According to a fifth embodiment, an advantageous M2- antagonist/naAEA/nsPAChA combination according to the present invention may be a combination comprising or consisting essentially of
(a) a pharmaceutical composition comprising dimethindene or S-(+)- dimethindene, or a pharmaceutically acceptable salt or solvate thereof, in an amount, in dimethindene or ,S'-(+)-dimethindene, of from 1.1 mg to 32 mg, normally from 1.5 mg to 32 mg, in admixture with a pharmaceutical carrier or vehicle; and
(b) a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, azasetron and pharmaceutically acceptable salts and solvates thereof; ondansetron and pharmaceutically acceptable salts and solvates thereof; granisetron and pharmaceutically acceptable salts and solvates thereof; dolasetron and pharmaceutically acceptable salts and solvates thereof, ramosetron and pharmaceutically acceptable salts and solvates thereof; tropisetron and pharmaceutically acceptable salts and solvates thereof; and palonosetron and pharmaceutically acceptable salts and solvates thereof, domperidone and pharmaceutically acceptable salts and solvates thereof such as the maleate; chlorpromazine and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride; prochlorperazine and its salts and solvates, particularly the dimaleate and the dimesylate; promethazine and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride; and 4-aminosalicylamide derivatives such as metoclopramide and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride monohydrate, bromopride and pharmaceutically acceptable salts and solvates thereof such as the monohydrochloride or the dihydrochloride monohydrate, alizapride and pharmaceutically acceptable salts and solvates thereof such as the hydrochloride, and clebopride and pharmaceutically acceptable salts and solvates thereof such as the malate and the hydrochloride monohydrate, dronabinol, nabilone, aprepitant, netupitant, rolapitant; and casopitant,
in admixture with a pharmaceutical carrier or vehicle.
An advantageous combination according to this fifth embodiment may be a combination comprising or consisting essentially of, as Components:
(a) a pharmaceutical composition comprising dimethindene or S-(+)- dimethindene, or a pharmaceutically acceptable salt or solvate thereof, in an amount, in dimethindene or ,S'-(+)-dimethindene, of from 1.1 mg to 32 mg, normally from 1.5 mg to 32 mg, in admixture with a pharmaceutical carrier or vehicle; and
(b) a pharmaceutical composition comprising a naAEA selected from the group consisting of a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated thereof, in particular its hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount of from 2.5 mg to 30 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, in particular the dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in particular the monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and pharmaceutically acceptable salts and solvates, in particular the monohydrochloride and the dihydrochloride monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrogen malate and the hydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically acceptable salts thereof, in particular the hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide and pharmaceutically acceptable salts thereof such as the monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine (also called meclozine) and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg,
in admixture with a pharmaceutical carrier or vehicle.
Preferably, according to this fifth embodiment, the pharmaceutical composition Component (a) comprises a pharmaceutical composition comprising dimethindene or S- (+)-dimethindene, as free base or as maleate, in an amount, in dimethindene or S-(+)- dimethindene, of from 1.1 mg to 16 mg, normally from 1.5 mg to mg, in admixture with a pharmaceutical carrier in an IR-unit form or in an amount of from 4.1 mg to 32 mg, normally from 6 mg to 32 mg, preferably from 6 mg to 24 mg, in admixture with a pharmaceutical carrier or vehicle in a ER-unit form, including TTS forms.
In another useful combinations according to this fifth embodiment, the pharmaceutical composition Component (a) comprises a pharmaceutical composition comprising dimethindene or ,S'-(+)-dimethindene, as free base or as maleate, in an amount, in dimethindene or ,S'-(+)-dimethindene, selected from the groups ranges consisting of: from 3 mg to 32 mg; from 4 mg to 32 mg; from 4.4 to 32 mg; from 6 mg to 32 mg; from 6 mg to 16 mg; and from 3 mg to 10 mg, in admixture with a pharmaceutical carrier in an ER-form, including a TTS.
According to a sixth embodiment, an advantageous M2- antagonist/naAEA/combi nation may be a combination comprising or consisting essentially of
(a) a pharmaceutical composition comprising otenzepad or a pharmaceutically acceptable salt or solvate thereof, in an amount of 100 mg to 500 mg, normally from 150 mg to 350 mg, in admixture with a pharmaceutical carrier or vehicle; and
(b) a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; bromopride and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride or the dihydrochloride monohydrate; alizapride and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; clebopride and pharmaceutically acceptable salts and solvates thereof, especially its malate and the hydrochloride monohydrate; meclizine (meclozine) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; promethazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, especially its dimaleate, its dimesylate and its the 1,2-ethanedi sulfonate (1 : 1) (edisilate); hydroxyzine and pharmaceutically acceptable salts and solvates thereof such as the dihydrochloride or the 1, 1 '-methylene bis(2-hydroxy-3- naphthalenecarboxylic acid (pamoate) dronabinol; nabilone; aprepitant; netupitant; rolapitant; netupitant/palonosetron hydrochloride fixed-dose combination; and casopitant,
in admixture with a pharmaceutical carrier or vehicle.
According to a further aspect of this sixth embodiment, an advantageous M2- antagonist/naAEA/nsPAChA/combination may be a combination comprising or consisting essentially of
(a) a pharmaceutical composition comprising otenzepad or a pharmaceutically acceptable salt or solvate thereof, in an amount of 100 mg to 500 mg, normally from 150 mg to 350 mg, in admixture with a pharmaceutical carrier or vehicle; and
(b) a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated thereof, in particular its hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount of from 2.5 mg to 30 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, in particular the dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in particular the monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and pharmaceutically acceptable salts and solvates, in particular the monohydrochloride and the di hydrochloride monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrogen malate and the hydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically acceptable salts thereof, in particular the hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide and pharmaceutically acceptable salts thereof such as the monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine (also called meclozine) and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg, in admixture with a pharmaceutical carrier or vehicle.
Preferably, according to this sixth embodiment, the pharmaceutical composition Component (a) comprises a pharmaceutical composition comprising otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate thereof, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg in a IR unit form or as the free base or as one of the aforementioned salts, in an amount of from 200 mg to 500 mg, preferably from 300 mg 500 mg, in an ER-form, including a TTS.
According to this sixth embodiment, the present invention also provides a pharmaceutical combination comprises or consist essentially of, as Components:
(a) a M2-antagonist selected from the group consisting of otenzepad and pharmaceutically acceptable salts thereof in an amount, in otenzepad, of from 100 mg to 500 mg, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b) a naAEA essentially consisting of palonosetron hydrochloride, in an amount, in palonosetron, of 0.5 mg; and netupitant, in an amount of 300 mg, in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
According to a seventh embodiment, an advantageous M2-antagonist/naAEA combination according to the present invention is a combination comprising or consisting essentially of, as Components,
(a) a pharmaceutical composition comprising AQ-RX 741 or a pharmaceutically acceptable salt or solvate thereof, in an amount of from 10 mg to 500 mg, normally from 10 mg to 250 mg, in admixture with a pharmaceutical carrier or vehicle; and
(b) a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; bromopride and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride or the dihydrochloride monohydrate; alizapride and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; clebopride and pharmaceutically acceptable salts and solvates thereof, especially its malate and the hydrochloride monohydrate; meclizine (meclozine) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; promethazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, especially its dimaleate, its dimesylate and its the 1,2-ethanedi sulfonate (1 : 1) (edisilate); hydroxyzine and pharmaceutically acceptable salts and solvates thereof such as the dihydrochloride or the 1, 1 '-methylene bis(2-hydroxy-3- naphthalenecarboxylic acid (pamoate) dronabinol; nabilone; aprepitant; netupitant; rolapitant; netupitant/palonosetron hydrochloride fixed-dose combination; and casopitant,
in admixture with a pharmaceutical carrier or vehicle.
According to a further aspect of this seventh embodiment, an advantageous M2-antagonist/naAEA/nsPAChA combination may be a combination comprising or consisting essentially of
(a) a pharmaceutical composition comprising AQ-RX 741 or a pharmaceutically acceptable salt or solvate thereof, in an amount of from 10 mg to 500 mg, normally from 10 mg to 250 mg, in admixture with a pharmaceutical carrier or vehicle; and
(b) a pharmaceutical composition comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated thereof, in particular its hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount of from 2.5 mg to 30 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, in particular the dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in particular the monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and pharmaceutically acceptable salts and solvates, in particular the monohydrochloride and the di hydrochloride monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrogen malate and the hydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically acceptable salts thereof, in particular the hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide and pharmaceutically acceptable salts thereof such as the monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine (also called meclozine) and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg, in admixture with a pharmaceutical carrier or vehicle.
Advantageously, according to this seventh embodiment, the pharmaceutical composition Component (a) comprises AQ-RX 741 as free base or as monomethanesulfonate, in an amount of from 10 mg to 500 mg, normally from 10 mg to 250 mg, in admixture with a pharmaceutical carrier formulated IR or ER administration. Preferably, Component (a) comprises AQ-RX 741 as free base or as monomethanesulfonate, in an amount of from 10 mg to 500 mg, preferably from 10 mg to 250 mg in a IR-form or, as the free base or the methanesulfonate salt thereof, in an amount of from 20 mg to 500 mg, preferably from 50 mg to 500 mg, in an ER-form, including a TTS.
Any of the above combinations may contain, as a further component, Component (c), an AChEI. Said AChEI may include, but is not limited to, 1,2,3,4- tetrahydro-9-acridinamine (tacrine) and pharmaceutically acceptable salts and solvates thereof, (±)-2,3-dihydro-5,6-dimethoxy-2-[[l-(phenylmethyl)-4-piperidinyl]methyl]- lH-inden-l-one (donepezil) and pharmaceutically acceptable salt and solvates thereof, (,S)-N-Ethyl-N-methyl-3-[l-(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) and pharmaceutically acceptable salts and solvates thereof, or 4aS,6R,8aS-3-methoxy-l l- methyl-4a,5,9, 10,l l, 12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol
(galantamine) and pharmaceutically acceptable salts and solvates thereof.
Donepezil hydrochloride, available in 5-mg, 10-mg and 23-mg tablets; rivastigmine, preferably as free base or as hydrogen tartrate, available in 1.5-mg, 3-mg and 6-mg, capsules, as a 2-mg/dose oral solution, and in form of a transdermal patch releasing rivastigmine at 4.6 mg/24 hours, 9.5 mg/24 hour or 13.3 mg/24h; and galantamine, preferably as hydrobromide, available as a 4-mg/ml oral solution, in 4- mg, 8-mg and 12-mg IR-tablets and in 8-mg, 16-mg and 24-mg ER-capsules; are particularly preferred AChEIs.
Among the preferred AChEIs, in the combinations of the present invention donepezil hydrochloride is present at a dose of from 5 mg to 98 mg, advantageously from 10 mg to 98 mg, preferably from 15 mg to 69 mg, normally from 15 mg to 60 mg; rivastigmine, as hydrogen tartrate, is present, in a composition for oral administration, at a dose, in rivastigmine, of from 1.5 mg to 30 mg, advantageously from 6 mg to 30 mg, preferably from 9 mg to 24 mg, normally from 9 mg to 18 mg; rivastigmine, as the free base, is present in patch releasing from 4.6mg/24h to 52mg/24h, advantageously from 9.6mg/24h to 39.9mg/24h, normally from 13.3mg/24h to 39.9mg/24h or from 4.6mg/24h to 13.3mg/24h nvastigmine; and galantamine, as hydrobromide, is present in an amount of from 4 mg to 96 mg, advantageously from 12 mg to 96 mg, normally from 18 mg to 48 mg.
In said combinations, said AChEI Component (c) may be formulated, in admixture with a pharmaceutical carrier or vehicle, in a pharmaceutical composition or device in dosage unit form or also used as a brand preparation.
For example, rivastigmine may be also used by orally administering EXELON® immediate-release 6mg-capsules or by applying one or more EXELON® patches releasing 4.6mg/24 hours, 9.5mg/24 hours, or 13.3 mg/24 hours on the subject's skin, to daily release rivastigmine at a dose/24h of from 4.6 mg to 53.2 mg or from 19.95 to 53.2 mg, normally from 14.1 mg to 46 m, in combination with the above-illustrated M2- antagonist /naAEA combination.
Donepezil hydrochloride may be also used by orally administering one or more ARICEPT® immediate-release 5mg- or lOmg-tablets or the 23-mg tablets. In particular, donepezil hydrochloride may be orally administered, in combination with the above- illustrated M2-antagonist /naAEA combination, at a daily dose of from 5 mg to 100 mg or from 15 mg to 70 mg.
Similarly, galantamine (as hydrobromide) may be also administered as a brand preparation, for example by orally administering RAZADYNE® immediate-release 8mg- or 12mg-tablets or RAZADYNE® ER 8mg-, 16mg- or 24mg-capsules. In particular, galantamine hydrobromide may be orally administered, in combination with the above-illustrated M2-antagonist/naAEA combination, at a daily dose (in galantamine) of from 36 mg to 96 mg, normally at a daily dose or from 36 mg to 72 mg, preferably in an ER-form.
The AChEI Component (c) when included in the combination with Component (a) and Component (b) as described herein, may be present in an amount of from about 100% to about 1000% of a recommended dose of Component (c) contained in a unit form used for the treatment of Alzheimer type dementia.
The Combinations in Kits
The present invention also provides a kit or package containing a combination as described herein, accompanied by instructions for use. In particular, a kit of the present invention is a kit comprising a combination of medicaments for the treatment of hypocholinergic disorders of the CNS.
According to the present invention the kit allows for the maximal functional capacity and safety during the treatment of a patient with a combination wherein the components may be administered concurrently or sequentially.
Component (a) and Component (b) may be present in the kit all in IR or in ER form or one of the Components is in IR form and at least one of the others are in ER form, each in admixture with a pharmaceutical carrier in a composition formulated as illustrated in "The Formulations" section, according to known technologies.
The kit according to the present invention may also comprise an AChEI Component (c), also in an IR or ER form, in admixture with a pharmaceutical carrier in a composition formulated as illustrated in "The Formulations" section below, according to known technologies.
When the AChEI Component (c) is present in the kit, it may be in a separate unit form wherein said AChEI is mixed with a pharmaceutical carrier in a pharmaceutical composition formulated in an IR or ER unit forrnr
More particularly, the kit of the present invention comprises
(a) a pharmaceutical composition in IR or ER dosage unit form comprising or consisting essentially of a therapeutically effective amount of a M2-antagonist in admixture with a pharmaceutical carrier or vehicle; and
(b) a pharmaceutical composition in IR or ER dosage unit form comprising or consisting essentially of a therapeutically effective amount of a naAEA in admixture with a pharmaceutical carrie or vehicle,
for concurrent, sequential or separate administration.
The pharmaceutical compositions may be packaged in any manner suitable for administration to a patient suffering from a hypocholinergic disorder of the CNS dementia and the packaging is manufactured according to known technologies and completed with instructions for use clearly showing to the patient or to the caregiver how to take each of the units forms to be administered.
Said kit comprises a Component (a) selected among the M2-antagonists illustrated in the above section "The M2-antagonists", a Component (b) selected among the naAEAs illustrated in the above section "The naAEAs" and, optionally, a Component (c) selected among the AChEIs illustrated above.
According to a first embodiment, the kit of the present invention comprises a M2-antagonist selected from the group consisting of 5-(2-ethyl-2H-tetrazol-5-yl)- l-methyl-1,2, 3,6-tetrahydropyridine (alvameline) and pharmaceutically salts and solvates thereof, 5,1 l-dihydro-8-chloro-l l-[[4-[3-[(2,2-dimethyl-l- oxopentyl)ethylamino]propyl]-l-piperidinyl]acetyl]-6H-pyrido[2,3- b][l,4]benzodiazepin-6-one (BIBN-99) and pharmaceutically acceptable salts and solvates thereof; racemic l l-[[2-(Diethylamino)methyl]-l-piperidinyl]-acetyl]- 5,l l-dihydro-6H-pyrido[2,3-b][l,4] benzodiazepin-6-one (otenzepad) and pharmaceutically acceptable salts and solvates thereof; dextrorotatory 11-[[2- (diethylamino)methyl]-l-piperidinyl]-acetyl]-5, l l-dihydro-6H-pyrido[2,3-b]El,4] benzodiazepin-6-one [(+)-otenzepad] and pharmaceutically acceptable salts and solvates thereof; N-2-[2-[(dipropylamino)methyl]-l-piperidinyl]ethyl]-5-,6- dihydro- 11 -H-pyrido[2,3 -b] [ 1 ,4]benzodiazepine- 11 -carboxamide (AF-DX 384) and pharmaceutically acceptable salts and solvates thereof; l l-[[4-[4- (Diethylamino)butyl]-l-piperidinyl]acetyl]-5, l l-dihydro-6H-pyrido[2,3- £][l,4]benzodiazepin-6-one (AQ-RA 741) and pharmaceutically acceptable salts and solvates thereof; N,N-Dimethyl-3-[l-(2-pyridinyl)ethyl]-lH-indene-2- ethanamine (dimethindene) and pharmaceutically acceptable salts and solvates thereof; N,N-Dimethyl-3-[(15)-l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine [S- (+)-dimethindene] and pharmaceutically acceptable salts and solvates thereof; Ν,Ν'- bis[6-[([2-methoxyphenyl)methyl]amino]hexyl]-l,8-octanedi amine
(methoctramine) and pharmaceutically acceptable salts and solvates thereof; 1,1,24- -tris[[5,l l-dihydro-6-oxo-6H-pyrido[2,3b][l,4]-benzodiazepin-l l-yl)carbonyl] methyl]-8,17-dimethyl-l,8, 17,24-tetraazatetracosane (tripitramine) and pharmaceutically acceptable salts and solvates thereof; (3aR,4R,4aS,8aR,9aS)-4- {(E)-2-[(2R,6S)-l,6-dimethylpiperidin-2-yl]ethenyl}-3- methyldecahydronaphtho[2,3-c]furan-l(3H)-one (himbacine) and pharmaceutically acceptable salts and solvates thereof; (3S,3aR,4R,4aS,8aR,9aS)-3-Methyl-4-[2- ((R)-l-methyl-6-(S)-methyl-piperidin-2-yl)-vinyl]-decahydro-naphtho[2,3-c]furan- 1-one [(+)-himbacine] and pharmaceutically acceptable salts and solvates thereof; (3aR,4R,4aS,8aR,9aS)-4-{(E)-2-[(2R,6S)-l,6-dimethylpiperidin-2-yl]ethynyl}-3- methyldecahydronaphtho[2,3-c]furan-l(3H)-one (himbacine analog) and pharmaceutically acceptable salts and solvates thereof; 4-cyclohexyl-alpha-[4[[4- methoxyphenyl]sulphinyl]-phenyl]-l-piperazineacetonitrile (SCH-57790) and pharmaceutically acceptable salts and solvates thereof; 4-[4-[l(S)-[4-[(l,3- benzodioxol-5-yl)sulfonyl]phenyl]ethyl]-3(R)-methyl-l-piperazinyl]-4-methyl-l- (propylsulfonyl)piperidine (SCH-72788) and pharmaceutically acceptable salts and solvates thereof; l'-(2-methylbenzoyl)-4-[[[(3,4- methylenedioxyphenyl)sulfonyl]phenyl]methyl]-l,4'-bipiperidine (SCH-76050) and pharmaceutically acceptable salts and solvates thereof; l'-(2-amino-3- methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]methyl]-l,4'-bipiperidine (SCH-211803) and pharmaceutically acceptable salts and solvates thereof; l'-(2- amino-3-methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]ethylenedioxy methyl]-l,4'-bipiperidine (SCH-217443) and pharmaceutically acceptable salts and solvates thereof; l '-naphto-l-yl-4-[[4-
[(methoxycarbonyl)methylthio]phenyl]methyl]-l,4'-bipiperidine (Wang Compound 30) salts and solvates thereof; l '-(indol-4-yl)carbonyl-4-[[(4- isopropyl)carbonyl]phenyl]methyl]-l,4'-biperidine (Palani Compound 19) and pharmaceutically acceptable salts and solvates thereof; and l '-(indol-4-yl)carbonyl- 4-[[(4-isopropyl)carbonyl]phenyl]ethylenedioxymethyl]-l,4'-biperidine (Palani Compound 30); and
(b) a naAEA selected from the group consisting of (bl) 5HT3 -antagonists, (b2) DA- antagonists, (b3) HI -antagonists, (b4) cannabinoids, and (b5) K1 -antagonists; said combination being in a fixed-dose combination formulated in admixture with a pharmaceutical carrier.
According to this first embodiment, the fixed-dose (a/b) combination, illustrated in the "The Fixed Combinations" section, is administered to a patient in need of the treatment as a single unite form at the doses illustrated in said section.
According to a second embodiment, the invention provides a kit comprising
(a) a pharmaceutical composition in dosage unit form comprising or consisting essentially of a M2-antagonist in admixture with a pharmaceutical carrier or vehicle; and
(b) a pharmaceutical composition comprising or consisting essentially of a naAEA, in admixture with a pharmaceutical carrier or vehicle.
For example, a kit according to this second embodiment may comprise:
(a) a pharmaceutical composition in dosage unit form comprising or consisting essentially of a M2-antagonist selected from the group consisting of alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt, in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tnpitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tnpitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; (±)-dimethindene or ,S'(+)-dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg; and AQ-RX 741, as free base or as a salt or solvate thereof, especially as its monomethanesulfonate salt, in an amount of from 10 mg to 500 mg, preferably from 10 mg to 250 mg;
admixture with a pharmaceutical carrier or vehicle; and
) a pharmaceutical composition comprising or consisting essentially of a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; bromopride and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride or the dihydrochloride monohydrate; alizapride and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; clebopride and pharmaceutically acceptable salts and solvates thereof, especially its malate and the hydrochloride monohydrate; meclizine (meclozine) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; promethazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, especially its dimaleate, its dimesylate and its the 1,2-ethanedi sulfonate (1 : 1) (edisilate); hydroxyzine and pharmaceutically acceptable salts and solvates thereof such as the dihydrochloride or the 1,1 '-methylene bis(2-hydroxy-3-naphthalenecarboxylic acid (pamoate) dronabinol; nabilone; aprepitant; netupitant; rolapitant; and casopitant,
admixture with a pharmaceutical carrier or vehicle.
Another kit of this second embodiment may comprise:
) a pharmaceutical composition in dosage unit form comprising or consisting essentially of a M2-antagonist selected from the group consisting of alvameline tartrate, in an amount, in alvameline, of from 200 mg to 600 mg; tripitramine sesquifumarate in an amount, in tripitramine, of from 15 mg to 150 mg; (±)- dimetindene or ,S'(+)-dimethindene maleate, in an amount of from 1.5 mg to 25 mg; otenzepad maleate (1 : 1), in an amount of from 200 mg to 400 mg; and AQ-RX 741 monomethanesulfonate, in an amount of from 15 mg to 300 mg;
admixture with a pharmaceutical carrier or vehicle; and
a pharmaceutical composition comprising or consisting essentially of a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated thereof, in particular its hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount of from 2.5 mg to 30 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, in particular the dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in particular the monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and pharmaceutically acceptable salts and solvates, in particular the monohydrochloride and the dihydrochloride monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrogen malate and the hydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically acceptable salts thereof, in particular the hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide and pharmaceutically acceptable salts thereof such as the monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine (also called meclozine) and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg,
in admixture with a pharmaceutical carrier or vehicle.
For example, in instances in which each of the drugs themselves of this embodiment are administered as individual or separate dosage forms (e.g., capsules or tablets), the kit of the present invention comprises each of the drugs making up the composition of the invention, along with instructions for use. Alternatively, each of the drug components of the combination may be combined into a single administrable dosage form such as a capsule.
Said kit may include one or more tablets, hard or soft capsules containing the Component (a) and Component (b), in the dosage amounts within the ranges described above.
Compositions (a/b) of the kits of the present invention, consisting of pharmaceutical composition in dosage unit form comprising, as active ingredient, a combination with a M2-antagonist and of a naAEA is novel and a further object of the present invention.
Thus, the present invention further provides a kit comprising a pharmaceutical composition in dosage unit form consisting essentially of
(a) a M2-antagonist; and
(b) a naAEA,
in admixture with a pharmaceutical carrier.
The characteristics, the doses and the use of this pharmaceutical composition are exhaustively illustrated herein above.
According to a third embodiment, each of the above kits may comprise, as a further component of the combinations contained therein, as Component (c), an AChEI also formulated in a pharmaceutical composition in dosage unit form in admixture with a pharmaceutical carrier or vehicle, said AChEI being selected from the group consisting of l,2,3,4-tetrahydro-9-acridinamine (tacrine) and pharmaceutically acceptable salts and solvates thereof, (±)-2,3-dihydro-5,6-dimethoxy-2-[[l- (phenylmethyl)-4-piperidinyl]methyl]-lH-inden-l-one (donepezil) and pharmaceutically acceptable salt and solvates thereof, (,S)-N-Ethyl-N-methyl-3-[l- (dimethylamino)ethyl]-phenyl carbamate (rivastigmine) and pharmaceutically acceptable salts and solvates thereof, 4aS,6R,8aS-3-methoxy-l l-methyl- 4a,5,9,10, l l,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol (galantamine) and pharmaceutically acceptable salts and solvates thereof.
Among the above preferred AChEIs, in the kits of the present invention, as
Component (c), donepezil hydrochloride is generally present at a dose of from 5 mg to 98 mg, advantageously from 15 mg to 69 mg, normally from 15 mg to 60 mg; rivastigmine, as hydrogen tartrate, is present, in a composition for oral administration, at a dose in rivastigmine, of from 1.5 mg to 30 mg, advantageously from 6 mg to 24 mg, normally from 9 mg to 18 mg; rivastigmine, as the free base, is present in patch releasing from 4.6mg/24h to 52mg/24h, advantageously from 9.6mg/24h to 39.9mg/24h, normally from 13.3mg/24h to 39.9mg/24h rivastigmine; and galantamine, as hydrobromide, is present in an amount of from 4 mg to 96 mg, advantageously from 12 mg to 96 mg, normally from 18 mg to 48 mg.
Thus, according to one aspect of this third embodiment, the present invention also provides a kit comprising or essentially consisting of
(a) a pharmaceutical composition in dosage unit form essentially consisting of a M2- antagonist, in admixture with a pharmaceutical carrier or vehicle; and
(b) a pharmaceutical composition in dosage unit form essentially consisting of a naAEA, in admixture with a pharmaceutical carrier or vehicle; and
(c) a pharmaceutical composition in dosage unit form essentially consisting of an AChEI selected from the group consisting of donepezil hydrochloride in an amount of from 5 mg to 98 mg, advantageously from 15 mg to 69 mg, normally from 15 mg to 60 mg; rivastigmine, as hydrogen tartrate, in an amount, in rivastigmine, of from 1.5 mg to 30 mg, advantageously from 6 mg to 24 mg, normally from 9 mg to 18 mg; rivastigmine, as the free base, in patch releasing from 4.6mg/24h to 52mg/24h, advantageously from 9.6mg/24h to 39.9mg/24h, normally from 13.3mg/24h to 39.9mg/24h rivastigmine; and galantamine, as hydrobromide, in an amount (in galantamine, of from 4 mg to 96 mg, advantageously from 12 mg to 96 mg, normally from 18 mg to 48 mg,
in admixture with a pharmaceutical carrier or vehicle.
According to this aspect of this third embodiment, in the above combination in the kit, the AChEI Component (c) may be combined with any M2-antagonist Component (a) and with any naAEA Component (b) illustrated in this section, in a triple combination useful as a cocktail for combating hypocholinergic disorders of the CNS as herein above defined.
A second aspect of this third embodiment provides a kit comprising:
(a/b) a fixed-dose combination that is a pharmaceutical composition comprising or consisting essentially of
(a) a M2-antagonist selected from the group consisting of alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt, in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tripitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; (±)-dimethindene or S(+)- dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg; and AQ-RX 741, as free base or as a salt or solvate thereof, especially as its monomethanesulfonate salt, in an amount of from 10 mg to 500 mg, preferably from 10 mg to 250 mg; and
(b) a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated thereof, in particular its hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount of from 2.5 mg to 30 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, in particular the dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in particular the monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and pharmaceutically acceptable salts and solvates, in particular the monohydrochloride and the dihydrochloride monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrogen malate and the hydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically acceptable salts thereof, in particular the hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide and pharmaceutically acceptable salts thereof such as the monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine (also called meclozine) and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from
20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg,
in admixture with a pharmaceutical carrier or vehicle; and
(c) an AChEI selected from the group consisting of donepezil hydrochloride, in an amount of from 5 mg to 98 mg, advantageously from 15 mg to 69 mg, normally from 15 mg to 60 mg; rivastigmine, as hydrogen tartrate, is present, in an amount, in rivastigmine, of from 1.5 mg to 30 mg, advantageously from 6 mg to 24 mg, normally from 9 mg to 18 mg; rivastigmine, as the free base, in patch releasing from 4.6mg/24h to 52mg/24h, advantageously from 9.6mg/24h to 39.9mg/24h, normally from 13.3mg/24h to 39.9mg/24h or from 4.6mg/24h to 13.3mg/24h rivastigmine; and galantamine, as hydrobromide, in an amount (in galantamine of from 4 mg to 96 mg, advantageously from 12 mg to 96 mg, normally from 18 mg to 48 mg.
in admixture with a pharmaceutical carrier or vehicle.
A kit according to a preferred form of this second aspect of this third embodiment essentially consists of a combination of the above Components (a) and (b) with
(c) a pharmaceutical composition in dosage unit form comprising or essentially consisting of an AChEI selected from the group consisting of donepezil hydrochloride, in an amount of from 5 mg to 60 mg, in admixture with a pharmaceutical carrier or vehicle.
A particularly preferred form of this second aspect of this third embodiment essentially consists of a combination of the above Component (a/b) fixed-dose combination with a Component (c) that is a pharmaceutical composition in dosage unit form comprising or consisting essentially of galantamine hydrobromide in an amount of from 24 mg to 98 mg, in admixture with a pharmaceutical carrier in an ER formulation.
Compositions (a/b) of the kits of the present invention described above, are each novel and a further object of the present invention.
The characteristics, the doses and the use of this pharmaceutical composition are exhaustively illustrated herein above.
According to a fourth embodiment, the invention also provides a kit comprising
(a) a pharmaceutical composition in dosage unit form comprising or consisting essentially of a M2-antagomist in admixture with a pharmaceutical carrier or vehicle; and
(b/c) a fixed-dose combination that is a pharmaceutical composition comprising or consisting essentially of
(b) a naAEA; and
(c) an AChEI,
in admixture with a pharmaceutical carrier or vehicle.
This kit has the great advantage of allowing an improvement in the treatment of a patient suffering from a hypocholinergic disorder. In fact, in the case of the prescription of a M2-antagonist that must be taken three or four times/day the kit of the present invention allows the administration of a composition (b/c) comprising a naAEA and an AChEI that may be administered once or twice a day, thus rendering the treatment easier for the patient or for the caregiver.
A first aspect of this fourth embodiment provides a kit comprising
(a) a pharmaceutical composition in dosage unit form comprising or consisting essentially of a M2-antagomist selected from the group consisting of alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt, may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tripitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; (±)-dimethindene or ,S'(+)-dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount, in otenzepad, of from 100 mg to 500 mg, preferably from 150 mg to 350 mg; and AQ-RX 741, as free base or as a salt or solvate thereof, especially as its monomethanesulfonate salt, in an amount, in AQ-RX 741, of from 10 mg to 500 mg, preferably from 10 mg to 250 mg; in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle; and
(b/c) a fixed-dose combination that is a pharmaceutical composition comprising or consisting essentially of
(b) a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride,; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; bromopride and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride or the dihydrochloride monohydrate; alizapride and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; clebopride and pharmaceutically acceptable salts and solvates thereof, especially its malate and the hydrochloride monohydrate; meclizine (meclozine) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; promethazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, especially its dimaleate, its dimesylate and its the 1,2-ethanedisulfonate (1 : 1) (edisilate); hydroxyzine and pharmaceutically acceptable salts and solvates thereof such as the dihydrochloride or the 1,1 '- methylene bis(2-hydroxy-3-naphthalenecarboxylic acid (pamoate) dronabinol; nabilone; aprepitant, netupitant, rolapitant, and casopitant; and
(c) an AChEI selected from the group consisting of donepezil and its pharmaceutically acceptable salts, rivastigmine and its pharmaceutically acceptable salts, and galantamine and its pharmaceutically acceptable saltsj in admixture with a pharmaceutical carrier or vehicle..
Advantageously, according to this first aspect of this third embodiment, the fixed-dose combination (b/c) essentially consists of a pharmaceutical composition in dosage unit form comprising
(b) a naAEA selected from the group consisting of alosetron hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg, tropisetron hydrochloride, in an amount (in tropisetron) of from 2.5 mg to 30 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride monohydrochloride or di hydrochloride monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride hydrogen malate or hydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine (also called meclozine) and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg; in a pharmaceutical composition in admixture with a pharmaceutical carrier; and
(c) an AChEI selected from the group consisting of donepezil hydrochloride, in an amount of from 5 mg to 40 mg; rivastigmine hydrogen tartrate, in an amount of from 1.5 mg to 36 mg; and galantamine hydrobromide, in an amount of from 4 mg to 48 mg,
in admixture with a pharmaceutical carrier.
According to this first aspect of this this third embodiment, the above Component (b/c), is a pharmaceutical composition in dosage unit form wherein said naAEA is granisetron and said AChEI is rivastigmine in patch releasing from 0.5mg/24h to 3mg/24h granisetron and from 4.6mg/24h to 52mg/24h rivastigmine, according to "The formulations" section below.
Preferred pharmaceutical compositions that may be used in a kit of this third embodiment may be compositions comprising or consisting essentially of, as Component (b/c), a naAEA (b) and an AChEI (c) in a pharmaceutical composition in dosage unit form as disclosed in US 2011/0201597, the contents of which are incorporated herein by reference in their entirety.
According to a particular aspect of this third embodiment, the above Component (b/c) is a pharmaceutical composition in dosage unit form wherein said naAEA and said AChEI are mixed together and with a pharmaceutical carrier in an oral IR- or ER-formulation, according to "The formulations" section below.
According to another particular aspect of this this third embodiment, the above Component (b/c) is a pharmaceutical composition in dosage unit form wherein said naAEA is granisetron and said AChEI is rivastigmine in patch releasing from 0.5mg/24h to 3mg/24h granisetron and from 4.6mg/24h to 52mg/24h rivastigmine, according to "The formulations" section below
According to this third embodiment, the (b/c) fixed-dose combination is administered to a patient in need of the treatment as a single unit form at the doses illustrated in "The Combinations" section.
This kit has the advantage of allowing an improvement in the treatment of a patient suffering from a hypocholinergic disorder due to synergistic action of the antiemetic/anti cholinergic combination.
The Fixed-Dose Combination
As indicated above, the pharmaceutical compositions prepared by using the naAEA according to the present invention are present in unit forms also containing a M2-antagonist that acts by presynaptically releasing acetylcholine in the CNS to improve the symptoms of Alzheimer type dementia.
Thus, it is another object of the present invention to provide a pharmaceutical unit form that comprises
(a) a muscarinic receptor antagonist selected from the group consisting of selective M2- antagonists; and
(b) a non-anticholinergic antiemetic agent (naAEA);
in admixture with at least one pharmaceutical carrier or vehicle.
Herein below, the expression "unit form" will also be used to designate a "pharmaceutical composition in dosage unit form".
The pharmaceutical composition to improve the treatment of human hypocholinergic disorders according to the present invention comprises or consists essentially of a mixture of a M2-antagonist [Component (a)], and of a naAEA [Component (b)] is present in a quantity sufficient or effective to maximally alleviate disease-associated neurobehavioral symptoms for the treatment of hypocholinergic disorders by acting to attenuate the dose-limiting side effects of the M2-antagonists, thus enabling a greater increase in the MTD of said M2-antagonists, with attending increase in the therapeutic efficacy of M2-antagonists. . Such a composition allows high doses of M2-antagonist Component (a) to be safely used, that would have otherwise been dangerous in the absence of Component (b).
The pharmaceutical composition of the present invention improves the treatment of human hypocholinergic disorders of the CNS as described above, such as dementias of the Alzheimer type and schizophrenia.
Any M2-antagonist and any naAEA as described herein, and exemplified in the above "The Combinations" section may be formulated in a pharmaceutical composition in a single unit form, in admixture with at least one pharmaceutical carrier according to conventional methods in the art, and as exemplified in the "The Formulations" section below.
In unit form for immediate release or extended release, the M2-antagonist
Component (a) is present in an amount of from 0.5 mg to 1500 mg. Normally, the M2- antagonist Component (a) is present, in an IR-form, in an amount of from 0.5 mg to 1000 mg and in an ER-form in an amount of from 1.5 mg to 1500 mg.
Any one of the antagonists of the M2 receptor subtype illustrated in the above "The M2- Antagonists" section may be a suitable Component (a), a M2-antagonist selected from the group consisting of alvameline, BIBN-99, otenzepad, (S)-(+)- otenzepad, AF-DX 384, dimethindene, (S)-(+)-dimethindene, tripitramine, himbacine, (+)-himbacine, the himbacine analog, i.e. the (3aR,4R,4a,S',8aR,9a)S)-4-{(JE)-[(2R,65)- l,6-dimethylpiperidin-2-yl]ethynyl}-3-methyldecahydronaphtho[2,3-c]furan-l(3H)-one, AQ-RA741, SCH-57790, SCH-72788, SCH-76050, SCH-211803, SCH-217443, Wang Compound 30, Palani Compound 19 and Palani Compound 31 and their pharmaceutically acceptable salts and solvates, as illustrated in the above "The M2- antagononists"section, being preferable.
According to an embodiment, a M2-antagonist selected from the group consisting of
- alvameline, as free base or a salt or solvate thereof, especially as its tartrate, may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; - tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount of from 10 mg to 200 mg, preferably from 10 mg to 100 mg in a IR-form or from 25 mg to 200 mg in an ER-form;
- dimetindene, preferably as the maleate thereof, as racemate or as its S(+) enantiomer, in an amount of from 1.2 mg to 30 mg, preferably from 1.2 mg to 15 mg in a IR-form or, as the free base or the maleate thereof, in an amount of from 3 mg to 30 mg, preferably from 3 mg to 10 mg, in an ER-form, including a TTS;
- otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate (INN: monomesilate, US AN: monomesylate) thereof, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg in a IR unit form or as the free base or as one of the aforementioned salts, in an amount of from 200 mg to 500 mg, preferably from 300 mg 1500 mg, in an ER-form, including a TTS;
- AQ-RX 741, as free base or as a salt or solvate thereof, especially as its monomethanesulfonate salt, in an amount of from 10 mg to 500 mg, preferably from
10 mg to 250 mg in a IR-form or, as the free base or the methanesulfonate salt thereof, in an amount of from 20 mg to 500 mg, preferably from 50 mg to 500 mg, in an ER- form, including a TTS;
is a particularly preferred Component (a) of the fixed-dose combination.
Any non-anticholinergic antiemetic agents, especially those illustrated in the above "The naAEAs" section may be a suitable Component (b).
The Component (b) of the fixed-dose combination may be a non- anticholinergic antiemetic agent selected from the group consisting of (b l) 5HT3- antagonists, (b2) DA-antagonists, (b3) HI -antagonists, (b4) cannabinoids, (b5) NK1- antgagonists.
In a preferred embodiment, Component (b) of the fixed-dose combination is selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; metoclopramide and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; bromopride and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride or the dihydrochloride monohydrate; alizapride and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; clebopride and pharmaceutically acceptable salts and solvates thereof, especially its malate and the hydrochloride monohydrate; meclizine (meclozine) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; promethazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, especially its dimaleate, its dimesylate and its the 1,2-ethanedi sulfonate (1 : 1) (edisilate); hydroxyzine and pharmaceutically acceptable salts and solvates thereof such as the dihydrochloride or the 1,1 '-methylene bis(2- hydroxy-3-naphthalenecarboxylic acid (pamoate) dronabinol; nabilone; aprepitant; netupitant; rolapitant; netupitant/palonosetron hydrochloride fixed-dose combination; and casopitant.
In particular, the fixed-dose combination of the invention consists of a pharmaceutical composition in dosage unit form comprising or consisting essentially of (a) any of the M2-antagonists as illustrated in the above "The M2-antagonists" section, each in a pharmaceutical composition in admixture with a pharmaceutical carrier, said M2-antagonist being preferably selected from the group consisting of 5-(2- ethyl-2H-tetrazol-5-yl)- 1 -methyl- 1 ,2,3, 6-tetrahydropyri dine (alvameline) and pharmaceutically salts and solvates thereof, 5, l l-dihydro-8-chloro-l l-[[4-[3-[(2,2- dimethyl-l-oxopentyl)ethylamino]propyl]-l-piperidinyl]acetyl]-6H-pyrido[2,3- b][l,4]benzodiazepin-6-one (BIBN-99) and pharmaceutically acceptable salts and solvates thereof; racemic l l-[[2-(Diethylamino)methyl]-l-piperidinyl]-acetyl]- 5,l l-dihydro-6H-pyrido[2,3-b][l,4] benzodiazepin-6-one (otenzepad) and pharmaceutically acceptable salts and solvates thereof; dextrorotatory l l-[[2- (diethylamino)methyl]-l-piperidinyl]-acetyl]-5, l l-dihydro-6H-pyrido[2,3-b]El,4] benzodiazepin-6-one [(+)-otenzepad] and pharmaceutically acceptable salts and solvates thereof; N-2-[2-[(dipropylamino)methyl]-l-piperidinyl]ethyl]-5-,6- dihydro- 11 -H-pyrido[2,3 -b] [ 1 ,4]benzodiazepine- 11 -carboxamide (AF-DX 384) and pharmaceutically acceptable salts and solvates thereof; l l-[[4-[4- (Diethylamino)butyl]-l-piperidinyl]acetyl]-5, l l-dihydro-6H-pyrido[2,3- £][l,4]benzodiazepin-6-one (AQ-RA 741) and pharmaceutically acceptable salts and solvates thereof; N,N-Dimethyl-3-[l-(2-pyridinyl)ethyl]-lH-indene-2- ethanamine (dimethindene) and pharmaceutically acceptable salts and solvates thereof; N,N-Dimethyl-3-[(15)-l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine [S- (+)-dimethindene] and pharmaceutically acceptable salts and solvates thereof; Ν,Ν'- bis[6-[([2-methoxyphenyl)methyl]amino]hexyl]-l,8-octanedi amine
(methoctramine) and pharmaceutically acceptable salts and solvates thereof; 1,1,24- -tris[[5,l l-dihydro-6-oxo-6H-pyrido[2,3b][l,4]-benzodiazepin-l l-yl)carbonyl] methyl]-8,17-dimethyl-l,8, 17,24-tetraazatetracosane (tripitramine) and pharmaceutically acceptable salts and solvates thereof; (3aR,4R,4aS,8aR,9aS)-4- {(E)-2-[(2R,6S)-l,6-dimethylpiperidin-2-yl]ethenyl}-3- methyldecahydronaphtho[2,3-c]furan-l(3H)-one (himbacine) and pharmaceutically acceptable salts and solvates thereof; (3 S,3aR,4R,4aS,8aR,9aS)-3-Methyl-4-[2- ((R)-l-methyl-6-(S)-methyl-piperidin-2-yl)-vinyl]-decahydro-naphtho[2,3-c]furan- 1-one [(+)-himbacine] and pharmaceutically acceptable salts and solvates thereof; (3aR,4R,4aS,8aR,9aS)-4-{(E)-2-[(2R,6S)-l,6-dimethylpiperidin-2-yl]ethynyl}-3- methyldecahydronaphtho[2,3-c]furan-l(3H)-one (himbacine analog) and pharmaceutically acceptable salts and solvates thereof; 4-cyclohexyl-alpha-[4[[4- methoxyphenyl]sulphinyl]-phenyl]-l-piperazineacetonitrile (SCH-57790) and pharmaceutically acceptable salts and solvates thereof; 4-[4-[l(S)-[4-[(l,3- benzodioxol-5-yl)sulfonyl]phenyl]ethyl]-3(R)-methyl-l-piperazinyl]-4-methyl-l- (propylsulfonyl)piperidine (SCH-72788) and pharmaceutically acceptable salts and solvates thereof; l'-(2-methylbenzoyl)-4-[[[(3,4- methylenedioxyphenyl)sulfonyl]phenyl]methyl]-l,4'-bipiperidine (SCH-76050) and pharmaceutically acceptable salts and solvates thereof; l'-(2-amino-3- methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]methyl]-l,4'-bipiperidine (SCH-211803) and pharmaceutically acceptable salts and solvates thereof; l'-(2- amino-3-methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]ethylenedioxy methyl]-l,4'-bipiperidine (SCH-217443) and pharmaceutically acceptable salts and solvates thereof; l '-naphto-l-yl-4-[[4-
[(methoxycarbonyl)methylthio]phenyl]methyl]-l,4'-bipiperidine (Wang Compound 30) salts and solvates thereof; l '-(indol-4-yl)carbonyl-4-[[(4- isopropyl)carbonyl]phenyl]methyl]-l,4'-biperidine (Palani Compound 19) and pharmaceutically acceptable salts and solvates thereof; and l '-(indol-4-yl)carbonyl- 4-[[(4-isopropyl)carbonyl]phenyl]ethylenedioxymethyl]-l,4'-biperidine (Palani Compound 30); and
(b) any of the naAEAs as illustrated in the above "The naAEAs" section, said naAEA being preferably selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; azasetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; ondansetron and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride dihydrate; granisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; dolasetron and pharmaceutically acceptable salts and solvates thereof, especially its monomethanesulfonate monohydrate, ramosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; tropisetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; palonosetron and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; domperidone and pharmaceutically acceptable salts and solvates thereof, especially its maleate; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; metoclopramide and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; bromopride and pharmaceutically acceptable salts and solvates thereof, especially its monohydrochloride or the dihydrochloride monohydrate; alizapride and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; clebopride and pharmaceutically acceptable salts and solvates thereof, especially its malate and the hydrochloride monohydrate; meclizine (meclozine) and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride monohydrate; promethazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, especially its hydrochloride; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, especially its dimaleate, its dimesylate and its the 1,2-ethanedi sulfonate (1 : 1) (edisilate); hydroxyzine and pharmaceutically acceptable salts and solvates thereof such as the dihydrochloride or the 1, 1 '-methylene bis(2-hydroxy-3- naphthalenecarboxylic acid (pamoate) dronabinol; nabilone; aprepitant; netupitant; rolapitant; netupitant/palonosetron hydrochloride fixed-dose combination; and casopitant
admixture with at least one pharmaceutical carrier or vehicle.
According to an embodiment, an advantageous fixed-dose combination consists a pharmaceutical composition comprising or consisting essentially of
) a M2-antagonist selected from the group consisting of alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt, may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tripitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; (±)-dimetindene or ,S'(+)-dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg; and AQ-RX 741, as free base or as a salt or solvate thereof, especially as its monomethanesulfonate salt, in an amount of from 10 mg to 500 mg, preferably from 10 mg to 250 mg; and a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated thereof, in particular its hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount of from 2.5 mg to 30 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, in particular the dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in particular the monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and pharmaceutically acceptable salts and solvates, in particular the monohydrochloride and the dihydrochloride monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrogen malate and the hydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically acceptable salts thereof, in particular the hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide and pharmaceutically acceptable salts thereof such as the monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine (also called meclozine) and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg, said composition being formulated in an IR dosage unit form in admixture with a pharmaceutical carrier or vehicle.
According to another embodiment, a particularly advantageous fixed-dose combination consists of a pharmaceutical unit form comprising or consisting essentially of
(a) alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt, may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tripitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; (±)-dimetindene or S(+)- dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg; and AQ- RX 741, as free base or as a salt or solvate thereof, especially as its monomethanesulfonate salt, in an amount of from 10 mg to 500 mg, preferably from 10 mg to 250 mg; and
(b) a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated thereof, in particular its hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount of from 2.5 mg to 30 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, in particular the dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in particular the monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and pharmaceutically acceptable salts and solvates, in particular the monohydrochloride and the dihydrochloride monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrogen malate and the hydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically acceptable salts thereof, in particular the hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide and pharmaceutically acceptable salts thereof such as the monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine (also called meclozine) and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg
in admixture with a pharmaceutical carrier.
According to another embodiment, a particularly advantageous fixed-dose combination consists of a pharmaceutical dosage unit form comprising or consisting essentially of
(a) alvameline, as free base or a salt or solvate thereof, especially as its tartrate salt, may be present in an amount, in alvameline, of from 160 mg to 960 mg, preferably from 240 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, especially as its sesquifumarate or tetraoxalate salt, in an amount, in tripitramine, of from 10 mg to 200 mg, preferably from 25 mg to 100 mg; (±)-dimetindene or S(+)- dimethindene, in an amount of from 1.1 mg to 32 mg, preferably from 1.2 mg to 15 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, di hydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount of from 100 mg to 500 mg, preferably from 150 mg to 350 mg; and AQ- RX 741, as free base or as a salt or solvate thereof, especially as its monomethanesulfonate salt, in an amount of from 10 mg to 500 mg, preferably from 10 mg to 250 mg; and
(b) ondansetron, as free base or hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg,
in admixture with a pharmaceutical carrier for oral administration.
According to the present invention each of the above fixed-dose combinations may include, as a further component (c), an AChEI also formulated in a pharmaceutical composition, said AChEI being selected from the group consisting of 1,2,3,4- tetrahydro-9-acridinamine (tacrine) and pharmaceutically acceptable salts and solvates thereof, (±)-2,3-dihydro-5,6-dimethoxy-2-[[l-(phenylmethyl)-4-piperidinyl]methyl]- lH-inden-l-one (donepezil) and pharmaceutically acceptable salt and solvates thereof, (,S)-N-Ethyl-N-methyl-3-[l-(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) and pharmaceutically acceptable salts and solvates thereof, 4aS,6R,8aS-3-methoxy-l l- methyl-4a,5,9, 10, l l, 12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol
(galantamine) and pharmaceutically acceptable salts and solvates thereof.
The above fixed-dose combinations and any of the pharmaceutical compositions that are part of the above combinations and kits are formulated with pharmaceutical carriers, diluents, vehicles and devices according to known and conventional methods and/or technologies in the art and as illustrated in the "The Formulations" section below. In addition, any of the above fixed-dose combinations and any of the above pharmaceutical compositions may further include, as Component (c), an AChEI.
The AChEI Component (c) when included in the combination with Component (a) and Component (b) as described herein, may be present in an amount of from about 100% to about 1000% of a recommended dose of Component (c) contained in a unit form used for the treatment of Alzheimer type dementia. Among the preferred AChEIs, in the fixed-dose combinations of the present invention donepezil hydrochloride is present at a dose of from 5 mg to 98 mg, advantageously from 10 mg to 98 mg, preferably from 15 mg to 69 mg, normally from 15 mg to 60 mg; rivastigmine, as hydrogen tartrate, is present, in a composition for oral administration, at a dose, in rivastigmine, of from 1.5 mg to 30 mg, advantageously from 6 mg to 30 mg, preferably from 9 mg to 24 mg, normally from 9 mg to 18 mg; rivastigmine, as the free base, is present in patch releasing from 4.6mg/24h to 52mg/24h, advantageously from 9.6mg/24h to 39.9mg/24h, normally from 13.3mg/24h to 39.9mg/24h or from 4.6mg/24h to 13.3mg/24h rivastigmine; and galantamine, as hydrobromide, is present in an amount of from 4 mg to 96 mg, advantageously from 12 mg to 96 mg, normally from 18 mg to 48 mg.
The Formulations
The unit form of the present invention may be a vial for intramuscular or intravenous administration, a tablet, a capsule, a pre-measured volume of a liquid solution or suspension for oral administration or a TTS as a gel or patch, including spray patches, for transdermal application. In said unit form the nsPAChA and M2 antagonist, as free base are as a pharmaceutically acceptable salt or solvate thereof, may be mixed together or separated according to known technologies in admixture with a pharmaceutical carrier in a pharmaceutical composition.
Component (a), Component (b) and optional Component (c) are formulated with conventional pharmaceutical carriers in known formulations for oral use wherein said components are mixed together or separated, for example in two or three tablets introduced in a capsule or in a two-compartment capsule, wherein one of the Components (a) is in a first of the two compartments and Component (b), alone or mixed with Component (c) in the second of the two compartments, or in a multilayer (di-layer or tri-layer) tablet wherein either Component (a) in admixture with a pharmaceutical carrier is in one of the layers and Component (b), alone or mixed with Component (c) and a pharmaceutical carrier is in a second layer in a di-layer tablet or the Components (a), (b) and (c), in admixture with a pharmaceutical carrier, are each distributed, in admixture with a pharmaceutical carrier in the three layers of a tri-layer tablet. The components are all in IR or in ER form, or one of the Components is in IR form and the other(s) is/are in ER form, according to known technologies. The pharmaceutical carriers and vehicles are those commonly used for the preparation of compositions for oral, buccal, including sublingual, and parenteral, in particular transdermal, administration. Appropriate unit forms comprise the oral forms, such as tablets, including orodispersible tablets and orosoluble tablets; soft or hard gelatin capsules; powders or granulates in sachets; and suitably measured oral solutions or suspensions, as well as transdermal therapeutic systems such as patches for transdermal administration.
Component (a), Component (b) and optional Component (c) may also be present in form of one of their complexes with a cyclodextrin, for example a-cyclodextrin, β- cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl- -cyclodextrin or methyl- -cyclodextrin.
Component (a), Component (b) and optional Component (c) may also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
For oral administration, Component (a), Component (b) and optional Component (c), together or separately, are formulated by mixing the active ingredient with conventional pharmaceutical acceptable carriers enabling said active ingredients to be formulated in tablets, dragees, orally disintegrating tablets, capsules, liquid solutions or suspensions, syrups and the like.
Carriers for IR tablets may include, but are not limited to, starches, cellulose and derivatives thereof; lubricants such as talc, stearic acid or magnesium stearate; diluents such as talc, powdered cellulose, lactose, starches such as maize or corn starch, mannitol, sorbitol; disaggregating agents such as microcrystalline cellulose or crospovidone; lubricants such as polyethylene glycol or magnesium stearate; ligands such as methylcellulose, sodium carboxymethylcellulose, alginic acid, alginates; sweeteners, such as sucrose, dextrose, mannitol, saccharin; or flavoring agents such as natural or synthetic oils.
Carriers for orally disintegrating tablets may include, but are not limited to, lubricants, aggregating, sweetening, flavoring or disaggregating agents as well as agents improving the buccal mucosa absorption of Component (a), Component (b) and optional Component (c) such as sorbitol, mannitol, lactose and cellulose.
Carriers for liquid, normally aqueous, suspensions or solutions may include, but are not limited to, antioxidants, such as sodium metabisulfite or sodium sulfite, thickening agents, such as microcrystalline cellulose, hydroxypropylcellulose, carboxymethylcellulose or polyvinylpyrrolidone, preservatives such as methyl paraben, ethyl paraben, sodium ethylenediaminotetracetate, sodium benzoate or an alkaline salt of sorbic acid, as well as flavoring and sweetening agents.
The sweeteners contained in the orally disintegrating tablets and the liquid suspensions or solutions may be natural, optional reduced sugars such as sucrose, dextrose, xylitol, mannitol or sorbitol, or synthetic product such as sodium saccharine or aspartame.
The flavoring agents are pharmaceutically acceptable flavors and tastes of synthetic and natural oils, the latter extracted from plants, leaves, flowers, fruits and their combinations, which include, but are not limited to, cinnamon, peppermint, anise and citron leaves, bitter almond, or citrus fruits, in particular orange and/or lemon, linden and grapefruit oils. Also chocolate, vanilla or eucalyptus flavor and essences of fruit, in particular apple, pear, peach, strawberry, cherry, apricot, orange, lemon and/or grapes may be advantageously used.
The composition according to the present invention may be in form of a capsule containing two tablets as described herein above, one of them comprising Component (a), and the other comprising Component (b) and optional Component (c) in admixture with each other and with a pharmaceutical carrier. The unit form may also be a capsule containing two tablets as described herein above, one of them comprising Component (b), and the other comprising Component (a) and optional Component (c) in admixture with each other and with a pharmaceutical carrier. The unit form may also be a capsule containing two tablets as described herein above, one of them comprising Component (c), and the other comprising Component (a) and Component (b) in admixture each other and with a pharmaceutical carrier.
The unit form may also be a capsule containing three tablets as described herein above, one of them comprising Component (a), the second comprising Component (a) and the third comprising Component (c) in admixture with each other and with a pharmaceutical carrier.
The combination may be formulated in tablets in which one or both of the two components (a) and (b) is/are in controlled-release formulation, for example as a dispersion of said component in hydroxypropyl methyl cellulose or in a film-coated microgranule. Advantageously, the M2-antagonist Component (a), in an ER-formulation is in the core and the naAEA Component (b), alone or in combination with the AChEI Component (c), in IR-formulation, are in the outer layer in multi-layer tablets in which, for example, both the core and the outer layers are coated with a film. Analogously, capsules made of two separated compartments, one containing Component (a), in IR- or ER-formulation and the other containing Component (b) and, optionally, Component (c), in ER- or, preferably, in IR formulation, may be used.
Carriers and vehicles for ER tablets may include, but are not limited to, retardant materials such as acrylic and methacrylic acid polymers and copolymers; cellulose derivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, or sodium carboxymethylcellulose; gums; waxes; glycerides or aliphatic alcohols or a mixture thereof.
Component (a), Component (b) and Component (c), as the base thereof or as a pharmaceutically acceptable salt thereof, may also be formulated, together or separately in any TTS such as a patch, a gel, a cream, a spray, an ointment, a lotion or a paste. Advantageously, in said TTS, Component (a) or Component (b) or optional Component (c) is present in admixture with the common diluents and permeation enhancers for the TTS administration; or Component (a) and Component (c) are both present in admixture with the common diluents and permeation enhancers for the TTS administration; or the Component (a) and Component (c) are both present in admixture with the common diluents and permeation enhancers, or Component (a), Component (b) and Component (c) are altogether present in admixture with the common diluents and permeation enhancers.
The permeation enhancer may be any compound which allows the improved permeation of drugs through the skin (see for example the review in Pharmaceutical Technology, November 1997, pages 58-66, the disclosure of which is herein incorporated by reference in its entirety). Such substances may include, but are not limited to, be lower (C 1-C4) alkanols; fatty alcohols such as lauryl alcohol (dodecanol), alone or in combination with a lower alkanol; fatty acids such as linolenic acid or oleic acid; fatty acid esters such as isopropyl palmitate, stearate, linoleate, oleate or myristate; glycerol; glycerol monoesters such as glycerol monostearate, monolinoleate or monooleate; glycerol diesters; glycerol triesters such as triacetin; sucrose monostearate, monolinoleate or monooleate; sorbitan esters; fatty alcohol ethers having from 10 to 20 carbon atoms; glycols, such as diethylene glycol or propylene glycol; or glycols lower alkyl ethers, such as diethylene glycol mono(C2-C4)alkyl ether, in particular diethylene glycol monoethyl ether.
These permeation enhancers are present in an amount from 0.01 to 20% by weight of the total weight of the composition, advantageously in an amount of from 0.05 to 10% by weight, preferably from 0.1 to 5% by weight.
Use
As set forth herein, Component (a), Component (b) and optional Component (c) may be administered concurrently or sequentially to a patient suffering from a hypocholinergic disorder of the CNS such as Alzheimer type dementia and schizophrenia. In particular, Component (a), Component (b) and optional Component (c) can be administered in a specific dosage regimen as illustrated above - to treat Alzheimer type dementia and schizophrenia, Component (a), Component (b) and optional Component (c) being administered simultaneously or sequentially to one another, in each case by the same or different administration route.
By the combination of Component (a) and Component (b) such as in the same unit form, Component (b) allows for the safe administration of high doses of Component (a) without dangerous adverse effects linked to the peripheral cholinergic action of said Component (a). Accordingly, the therapeutic efficacy of Component (a) to safely improve cognition of patients suffering from a hypocholinergic disorder of the CNS such as Alzheimer type dementia or schizophrenia is enhanced, due to the action of Component (b) annulling vomiting, i.e. the cause of the failure of all the precedent attempts of using a M2-antagonist for the treatment of Alzheimer type dementia and, in general, of hypocholinergic disorders of the CNS.
The presence of a naAEA in a combination wherein, besides the M2-antagonist Component (a) and the naAEA Component (b), an AChEI Component (c) is also present, is of great importance
Thus, the present invention, in one aspect, provides a combination comprising or consisting essentially of, as Components:
(a) a M2 muscarinic cholinergic receptor antagonists (M2-antagonist); and
(b) a non-anticholinergic antiemetic agent; and, optionally,
(c) an acetylcholinesterase inhibitor (AChEI)
for use in the treatment of a hypocholinergic disorder of the CNS. The M2-antagonists used as Component (a), their properties and doses are described in the "The M2-antagonists" section above.
The naAEAs used as Component (b), their properties and doses are described in the "naAEA" section above.
The AChEI optionally used as Component (c), their properties and doses are described at the end of "The Combinations" section.
For use, Component (a), Component (b) and optional Component (c), together or separately, are formulated in pharmaceutical compositions prepared as described in the "Formulation" section above.
Thus, the present invention, in one aspect, provides a combination comprising or consisting essentially of, as Components:
(a) a M2 muscarinic cholinergic receptor antagonists (M2-antagonist); and
(b) a non-anticholinergic antiemetic agent
for use in the treatment of a hypocholinergic disorder of the CNS.
The M2-antagonists used as Component (a), their properties and doses are described in the "The M2-antagonist s" section above.
The naAEAs used as Component (b), their properties and doses are described in the "naAEA" section above.
For use, Component (a) and Component (b), together or separately, are formulated in pharmaceutical compositions prepared as described in the "Formulation" section above.
Another aspect of the present invention provides a method for treating hypocholinergic disorders of the central nervous system, comprising, or consisting essentially of, the Components:
(a) a muscarinic cholinergic receptor agonists (M2-antagonists); and
(b) a non-anticholinergic antiemetic agent; and, optionally,
(c) an acetylcholinesterase inhibitor (AChEI).
The method is carried out by administering Component (a), Component (b) and optional Component (c) of said combination concurrently, or sequentially. Component (a), Component (b) and optional Component (c) may be independently administered by oral or parenteral route, in particular by intramuscular or intravenous injection or by transdermal administration by a TTS such as a gel or a patch. The M2-antagonists used as Component (a), their properties and doses are described in the "M2-antagonist s" section above.
The naAEA used as Component (b), their properties and doses are described in the "naAEAs section" above.
The AChEI optionally used as Component (c), their properties and doses are described at the end of "The Combinations" section.
For administering the combination to said patient, Component (a), Component (b) and optional Component (c), together or separately, are formulated in pharmaceutical compositions prepared as described in the "Formulation" section above.
In the case of simultaneous administration of the components, Component (a),
Component (b) and Component (c), in admixture with a pharmaceutical carrier or vehicle, may be associated in the same pharmaceutical composition, formulated as described in "The Formulations" section above, in a unit dose for oral or parenteral, including transdermal, route, according to known or conventional methods or technologies in the art.
The doses of the above dose-ranges are given in order to present the possibility of manufacturing pharmaceutical compositions and of administering said doses in said pharmaceutical composition. However, the discovery of the beneficial action of the naAEA enables the full efficacy of the M2-antagonist and of the optional AChEI.
REFERENCES
- Adis R&D Profile - "Otenzepad AFDX 116" Drug R&D 1999; Apr 1(4):319-320.
- Alcantara AA, Mrzljak L, Jakab RL, Levey AI, Hersch SM, Goldman-Rakic PS.
"Muscarinic ml and m2 receptor proteins in local circuit and projection neurons of the primate striatum: anatomical evidence for cholinergic modulation of glutamatergic prefronto-striatal pathway". J Comp Neurol. 2001; Jun 11;434(4):445-60.
- Anagnostaras SG 1, Murphy GG, Hamilton SE, Mitchell SL, Rahnama NP, Nathanson NM, Silva AJ. "Selective cognitive dysfunction in ACh Ml muscarinic receptor mutant mice". Nat Neurosci 2003; Jan;6(l):51-58.
- Birks J. "Cholinesterase inhibitors for Alzheimer's disease". Cochrane Database Syst Rev. 2006; Jan; 25(1):CD005593.
- Brashear HR 1997. Review of book "Muscarinic Agonists and the Treatment of Alzheimer Disease" (Edited by Abraham Fisher and R.G. Landes, 1996) in
Neurology;49. - Carey GJ, Billard W, Binch H, 3rd, Cohen-Williams M, Crosby G, Grzelak M, Guzik H, Kozlowski JA, Lowe DB, Pond AJ, Tedesco RP, Watkins RW, Coffin VL. "SCH 57790, a selective muscarinic M2 receptor antagonist, releases acetylcholine and produces cognitive enhancement in laboratory animals". Eur J Pharmacol
2001; 16: 189-200.
- Chackalamannil S,. Davies RJ, Wang Y, Asberom T, Doller D, Wong J, Leone D. "Total Synthesis of (+)-Himbacine and (+)-Himbeline". J Org Chem
1999;64(6): 1932-1940.
- Christensen EB, Andersen JB, Pedersen H, Jensen KG, Dalgaard L. "Metabolites of [(14)C]-5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3, 6-tetrahydropyridine in mice, rats, dogs, and humans" Drug Metab Dispos 1999; Nov;7(l l): 1341-1349.
- Engel WW, Eberlein WG, Mihm G, Hammer R, Trummlitz G. "Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics". J Med Chem 1989;32(8): 1718-1724. - Foster DJ, Jones CK, Conn PJ; "Emerging approaches for treatment of schizophrenia: modulation of cholinergic signaling". Discov Med. 2012; Dec; 14(79):413-420.
- Gao L, Waelrroeck M, Hofman S, Van Haver D, Milanesio M, Viterbo D, De Clercq P. "Synthesis and affinity studies of himbacine derived muscarinic receptor antagonists". Bioorg Med Chem Lett. 2002; 12(15): 1909-1912.
- Greenlee W, Clader J, Asberom T, McCombie S, Ford J, Guzik H, Kozlowski J, Li S, Liu C, Lowe D, Vice S, Zhao H, Zhou G, Billard W, Binch H, Crosby R, Duffy R, Lachowicz J, Coffin V, Watkins R, Ruperto V, Strader C, Taylor L, Cox K,
"Muscarinic agonists and antagonists in the treatment of Alzheimer's disease". II Farmaco 2001; Apr;56(4):247-250.
- http://adisinsight.springer.com/search AQRA 741
- Huebner CF, Donoghue E, Wenk PE. Nelson SJA. "A New Class of Highly Active Antihistaminics". J Am Chem Soc 1960;82(8):2077-2078.
- Lachowicz JE, Duffy RA, Ruperto V, Kozlowski J, Zhou G, Clader J, Billard W, Binch H, 3rd, Crosby G, Cohen-Williams M, Strader CD, Coffin V: "Facilitation of acetylcholine release and improvement in cognition by a selective M2 muscarinic antagonist, SCH 72788". Life Sci 2001;68:2585-2592.
- Lamping KG, Wess J, Cui Y, Nuno DW, Faraci FM. "Muscarinic (M) receptors in coronary circulation: gene-targeted mice define the role of M2 and M3 receptors in response to acetylcholine". Arterioscler Thromb Vase Biol. 2004; Jul, 24(7): 1253- 1258.
- Lazaris A, Cassel S, Stemmelin J, Cassel JC, Kelche C, "Intrastriatal infusions of methoctramine improve memory in cognitively impaired aged rats". Neurobiol Aging 2003; Mar-Apr;24(2):379-383.
- Maggio R, Barbier P, Bolognesi ML, Minarini A, Tedeschi D, Melchiorre C, "Binding profile of the selective muscarinic receptor antagonist tripitramine", Eur J Pharmacol 1994; Aug 16; 268(3):459-462.
- Melchiorre C, Cassinelli A, Quaglia W. "Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac
M-2 muscarinic receptors". J Med Chem. 1987; Jan;30(l):201-204.
- Melchiorre C, Bolognesi ML, Chiarini A, Minarini A, Spampinato S. "Synthesis and biological activity of some methoctramine-related tetraamines bearing a 11 -acetyl - 5,l l-dihydro-6H-pyrido[2,3-b][l,4]-benzodiazepin-6-one moiety as antimuscarinics: a second generation of highly selective M2 muscarinic receptor antagonists". J Med Chem 1993;36, 3734-3737.
- Minarini A, Quaglia W, Tumiatti V, Melchiorre C. "An improved synthesis of Ν,Ν'- bis[6-o-methoxyphenyl methyl hexylamino]-l,8-octanediamine (methoctramine)". Chem Ind (London) 2 October 1989, page 652.
- Palani A, Dugar S, Clader JW, Greenlee WJ, Ruperto V, Duffy RA, Lachowicz JE. "Isopropyl amide derivatives of potent and selective muscarinic M2 receptor antagonists". Bioorg.MedChem Lett 2004; 14(7): 1791-1794.
- Pfaff O, Hildebrandt C, Waelbroeck M, Hou X, Moser U, Mutschler E, Lambrecht G. "The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist". Eur J Pharmacol 1995. Nov 24;286(3):229-240.
- Pike BR, Hamm RJ. "Post-injury administration of BIBN 99, a selective muscarinic M2 receptor antagonist, improves cognitive performance following traumatic brain injury in rats" Brain Res 1995; 686:37-43.
- Quirion R, Wilson A, Rowe W, Aubert I, Richard J, Doods H, Parent A, White N, Meaney MJ. "Facilitation of acetylcholine release and cognitive performance by an
M(2)-muscarinic receptor antagonist in aged memory-impaired". J Neurosci 1995 Feb; 15(2): 1455-1462. - Rouse ST, Edmunds SM, Yi H, Gilmor ML, Levey AI. "Localization of M(2) muscarinic acetylcholine receptor protein in cholinergic and non-cholinergic terminals in rat hippocampus". Neurosci Lett 2000 Apr 28; 284(3): 182-186.
- Rowe WB, O'Donnell JP, Pearson D, Rose GM, Meaney MJ, Quirion R. "Long-term effects of BIBN-99, a selective muscarinic M2 receptor antagonist, on improving spatial memory performance in aged cognitively impaired rats". Behav Brain Res 2003; 145: 171-178.
- Sramek JJ, Forrest M, Mengel H, Jhee SS, Hourani J, Cutler NR. "A bridging study of LU 25-109 in patients with probable Alzheimer's disease", Life Sci. 1998;62(3): 195- 202.
- Starck J-P, Talaga P., Quere L, Collart P, Christophe B, Lo Brutto P, Jadot S, Chimmanamada D, Zanda M, Wagner A, Mioskowski C,. Massingham R Guyaux M. "Potent anti-muscarinic activity in a novel series of quinuclidine derivatives"; Bioorg Med Chem Lett. 2006, 15 Jan; 16(2):373-377.
- Stoll C, Eltze M, Lambrecht G, Zentner J, Feuerstein TJ, Jackisch R. "Functional characterization of muscarinic autoreceptors in rat and human neocortex". J
Neurochem. 2009 Aug; l 10(3):837-847.
- Thai LJ, Forrest M, Loft H, Mengel H. "Lu 25-109, a muscarinic agonist, fails to improve cognition in Alzheimer's disease. Lu25-109 Study Group". Neurology 2000 Jan 25;54(2):421-426.
- Tzavara ET, Bymaster FP, Felder CC, Wade M, Gomeza J, Wess J, McKinzie DL, Nomikos GG. "Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice". Mol Psychiatry, 2003; Jul, 8(7):673-679.
- Wang Y, Chackalamannil S, Hu Z, McKittrick BA, Greenlee W, Ruperto V, Duffy RA, Lachowicz JE.. "Sulfide analogues as potent and selective M2 muscarinic receptor antagonists". Bioorg Med Chem Lett 2002; 12, 1087-1099.
- Zhang W, Basile AS, Gomeza J, Volpicelli LA, Levey AI, Wess J. "Characterization of Central Inhibitory Muscarinic Autoreceptors by the Use of Muscarinic
Acetylcholine Receptor Knock-Out Mice". J Neurosci 2002 Mar 1;22(5): 1709-1717.

Claims

1. A pharmaceutical combination comprising:
(a) muscarinic receptor antagonist selected from the group consisting of centrally active, selective M2-muscarinic cholinergic receptor antagonists (M2-antagonist); and
(b) a non-anti cholinergic antiemetic agent (naAEA)..
2. The pharmaceutical combination of claim 1, wherein said M2-antagonist Component (a) is selected from the group consisting of
- 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2, 3,6-tetrahydropyridine (alvameline)
- 5,1 l-dihydro-8-chloro-l l-[[4-[3-[(2,2-dimethyl-l-oxopentyl)ethylamino]propyl]-l- piperidinyl]acetyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one (BIBN-99);
- racemic 1 l-[[2-(Diethylamino)methyl]-l-piperidinyl]-acetyl]-5,l l-dihydro-6H- pyrido[2,3-b][l,4] benzodiazepin-6-one (otenzepad);
- dextrorotatory 1 l-[[2-(diethylamino)methyl]-l-piperidinyl]-acetyl]-5, 1 l-dihydro-6H- pyrido[2,3-b]El,4] benzodiazepin-6-one [(+)-otenzepad];
- N-2-[2-[(dipropylamino)methyl]-l-piperidinyl]ethyl]-5-,6-dihydro-l l-H-pyrido[2,3- b] [ 1 ,4]benzodiazepine- 11 -carboxamide (AF-DX 384),
- 1 l-[[4-[4-(Diethylamino)butyl]-l-piperidinyl]acetyl]-5,l l-dihydro-6H-pyrido[2,3- 6][l,4]benzodiazepin-6-one (AQ-RA 741),
- N,N-Dimethyl-3-[l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine (dimethindene) - N,N-Dimethyl-3-[(15)-l-(2-pyridinyl)ethyl]-lH-indene-2-ethanamine [S-(+ dimethindene];
- N,N'-bis[6-[([2-methoxyphenyl)methyl]amino]hexyl]-l,8-octanediamine
(methoctramine),
- 1,1,24— tris[[5,l l-dihydro-6-oxo-6H-pyrido[2,3b][l,4]-benzodiazepin-l l-yl)carbonyl] methyl]-8, 17-dimethyl- 1,8,17,24-tetraazatetracosane (tripitramine);
- (3aR,4R,4aS,8aR,9aS)-4-{(E)-2-[(2R,6S)-l,6-dimethylpiperidin-2-yl]ethenyl}-3- methyldecahydronaphtho[2,3-c]furan-l(3H)-one (himbacine
- (3S,3aR,4R,4aS,8aR,9aS)-3-Methyl-4-[2-((R)-l-methyl-6-(S)-methyl-piperidin-2-yl)- vinyl]-decahydro-naphtho[2,3-c]furan-l-one [(+)-himbacine];
- (3aR,4R,4aS,8aR,9aS)-4-{(E)-2-[(2R,6S)-l,6-dimethylpiperidin-2-yl]ethynyl}-3- methyldecahydronaphtho[2,3-c]furan-l(3H)-one (himbacine analog); - 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-l-piperazineacetonitrile (SCH-57790);
- 4-[4-[l(S)-[4-[(l,3-benzodioxol-5-yl)sulfonyl]phenyl]ethyl]-3(R)-methyl-l- piperazinyl]-4-methyl-l-(propylsulfonyl)piperidine (SCH-72788);
- -(2-methylbenzoyl)-4-[[[(3,4-methylenedioxyphenyl)sulfonyl]phenyl]methyl]-l,4'- bipiperidine (SCH-76050);
- -(2-amino-3-methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]methyl]-l,4'- bipiperidine (SCH-211803);
- l'-(2-amino-3-methylbenzoyl)-4-[[[(3-chlorophenyl)sulfonyl]phenyl]ethylenedioxy methyl]- 1 ,4'-bipiperidine (SCH-217443);
- -naphto-l-yl-4-[[4-[(methoxycarbonyl)methylthio]phenyl]methyl]-l,4'-bipiperidine (Wang Compound 30);
- -(indol-4-yl)carbonyl-4-[[(4-isopropyl)carbonyl]phenyl]methyl]-l,4'-biperidine (Palani Compound 19);
- -(indol-4-yl)carbonyl-4-[[(4-isopropyl)carbonyl]phenyl]ethylenedioxymethyl]-l,4'- biperidine (Palani Compound 30);
and pharmaceutically acceptable salts and solvates thereof.
3. The pharmaceutical combination of claim 1 wherein said naAEA Component (b) is selected from the group consisting of (bl) 5-HT3 receptor antagonists (5HT3 -antagonists), (b2) dopamine antagonists (DA-antagonists), (b3) HI histamine receptor antagonists (HI -antagonists), (b4) cannabinoid agonists (cannabinoids), and (b5) neurokinine-1 receptor antagonists ( K1 -antagonists).
4. The pharmaceutical combination of claim 1 wherein said naAEA is selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in particular the mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated thereof, in particular its hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts and solvates thereof, in particular its hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount of from 2.5 mg to 30 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, in particular the dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in particular the monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and pharmaceutically acceptable salts and solvates, in particular the monohydrochloride and the dihydrochloride monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrogen malate and the hydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically acceptable salts thereof, in particular the hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide and pharmaceutically acceptable salts thereof such as the monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine (also called meclozine) and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine and pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg.
5. The pharmaceutical combination of claim 1, wherein said Component (a) is selected from the group consisting of alvameline, as free base or a salt or solvate thereof, in an amount, in alvameline, of from 160 mg to 960 mg; tripitramine, as free base or a salt or solvate thereof, in an amount, in tripitramine, of from 10 mg to 200 mg; (±)-dimetindene or ,S'(+)-dimethindene and pharmaceutically acceptable salts and solvates thereof, in an amount of from 1.1 mg to 32 mg; otenzepad, as free base or as the maleate (1 : 1), fumarate (1 : 1), dihydrochloride, dihydrochloride dihydrate, dihydrobromide or the monomethanesulfonate, in an amount of from 100 mg to 500 mg and AQ-RX 741, as free base or as a salt or solvate thereof, in an amount of from 10 mg to 500 mg; in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
6. The pharmaceutical combination of claim 1, wherein said Component (b) is selected from the group consisting of alosetron hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron hydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron hydrochloride, in an amount (in tropisetron) of from 2.5 mg to 30 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide monohydrochloride monohydrate, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride monohydrochloride or dihydrochloride monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride and pharmaceutically acceptable salts and solvates thereof, in particular the hydrogen malate or hydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; the palonosetron hydrochloride 0.5 mg/netupitamt 300 mg fixed- dose combination; and casopitant, in an amount of from 25 mg to 300 mg; in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle.
7. The pharmaceutical combination of claim 1 wherein said M2-antagonist Component (a) is in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle, in an amount of from 0.5 mg to 1500 mg.
8 The pharmaceutical combination of claim 1 wherein said naAEA Component (b) is in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle, in an IR unit form, in an amount ranging from 50% to 200% of the maximum amount of said antiemetic agent contained in the currently administered IR dosage unit forms for the treatment of emesis or, in an ER unit form, in an amount ranging from 75% to 300% of the currently administered IR dosage unit forms for the treatment of emesis.
9. The pharmaceutical combination of claim 1, wherein said Component (a) is in a pharmaceutical composition in admixture with a pharmaceutical carrier or vehicle, in an amount of from about 0.5 mg to 1500 mg.
10. The pharmaceutical combination of claim 1, further comprising a Component (c) an acetylcholinesterase inhibitor.
11. A method of treating a hypocholinergic disorder comprising administering the pharmaceutical combination of claim 1, to a mammalian subject in need thereof.
12. The method of claim 11, wherein said mammalian is a human and the hypocholinergic disorder is selected from the group consisting of schizophrenia, schizophrenia associated dementia, and schizoaffective disorders.
13. The method of claim 11, wherein said mammalian is a human and the hypocholinergic disorder is Alzheimer type dementia.
14. The combination according to any one of claims 1-.10, for use in the treatment of hypocholinergic disorders of the Central Nervous System.
15. The combination of claim 14, wherein said hypocholinergic disorder of the central nervous system is selected from the group consisting of Alzheimer disease, Alzheimer-type dementia, mild cognitive impairment, Lewy body disease dementia, Parkinson's disease dementia, post-stroke dementia, vascular dementia, traumatic brain injury, Down syndrome, anorexia nervosa, Tourette disease, tardive dyskinesia, Pick's disease, Huntington's chorea, Friedrich's ataxia, chronic neuropathic pain, falls, postoperative delirium and schizophrenia.
PCT/US2017/047897 2016-08-22 2017-08-22 Muscarinic m2-antagonist combination WO2018039159A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113164424A (en) * 2018-09-25 2021-07-23 才思治疗公司 Compositions and uses for treating parkinson's disease and related disorders
CN113329747A (en) * 2018-12-27 2021-08-31 才思治疗公司 Domperidone compositions and methods for treating depression
CN114630669A (en) * 2020-10-14 2022-06-14 参天制药株式会社 Stable pharmaceutical composition
WO2023190653A1 (en) * 2022-03-30 2023-10-05 参天製薬株式会社 Sterilization method of pharmaceutical preparation and packaging
EP4385497A1 (en) * 2022-12-12 2024-06-19 Alfred E. Tiefenbacher (GmbH & Co. KG) Antioxidant-free fixed dose combination of netupitant and palonosetron
EP4385500A1 (en) * 2022-12-12 2024-06-19 Alfred E. Tiefenbacher (GmbH & Co. KG) Fixed dose combination comprising netupitant and palonosetron
WO2024126398A1 (en) 2022-12-12 2024-06-20 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Fixed dose combination comprising netupitant and palonosetron
WO2024126408A1 (en) 2022-12-12 2024-06-20 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Antioxidant-free fixed dose combination of netupitant and palonosetron

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6297262B1 (en) * 1997-05-29 2001-10-02 H. Lundbeck A/S Treatment of schizophrenia and psychosis
US20120202819A1 (en) * 2009-10-07 2012-08-09 Merck Sharp & Dohme Corporation Combination therapy using a beta 3 adrenergic receptor agonists and an antimuscarinic agent
US20160143890A1 (en) * 2009-09-18 2016-05-26 Chase Pharmaceuticals Corporation Method and composition for treating alzheimer-type dementia

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6297262B1 (en) * 1997-05-29 2001-10-02 H. Lundbeck A/S Treatment of schizophrenia and psychosis
US20160143890A1 (en) * 2009-09-18 2016-05-26 Chase Pharmaceuticals Corporation Method and composition for treating alzheimer-type dementia
US20120202819A1 (en) * 2009-10-07 2012-08-09 Merck Sharp & Dohme Corporation Combination therapy using a beta 3 adrenergic receptor agonists and an antimuscarinic agent

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PRIEN, D ET AL.: "Enantioselective Biotransformation of the Chiral Antihistaminic Drug Dimethindene in Humans and Rats", ARZNEIMITTELFORSCHUNG, vol. 47, no. 5, 1997, pages 653 - 658 *
STOLL, C ET AL.: "Functional Characterization of Muscarinic Autoreceptors in Rat and Human Neocortex", J NEUROCHEM., vol. 110, no. 3, August 2009 (2009-08-01), pages 837 - 847, XP055465498 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113164424A (en) * 2018-09-25 2021-07-23 才思治疗公司 Compositions and uses for treating parkinson's disease and related disorders
EP3856168A4 (en) * 2018-09-25 2022-07-06 Chase Therapeutics Corporation Composition and use for the treatment of parkinson's disease and related disorders
CN113329747A (en) * 2018-12-27 2021-08-31 才思治疗公司 Domperidone compositions and methods for treating depression
EP3902540A4 (en) * 2018-12-27 2022-11-02 Chase Therapeutics Corporation Domperidone compositions and methods for treating depression
CN114630669A (en) * 2020-10-14 2022-06-14 参天制药株式会社 Stable pharmaceutical composition
CN114630669B (en) * 2020-10-14 2023-03-24 参天制药株式会社 Stable pharmaceutical composition
WO2023190653A1 (en) * 2022-03-30 2023-10-05 参天製薬株式会社 Sterilization method of pharmaceutical preparation and packaging
EP4385497A1 (en) * 2022-12-12 2024-06-19 Alfred E. Tiefenbacher (GmbH & Co. KG) Antioxidant-free fixed dose combination of netupitant and palonosetron
EP4385500A1 (en) * 2022-12-12 2024-06-19 Alfred E. Tiefenbacher (GmbH & Co. KG) Fixed dose combination comprising netupitant and palonosetron
WO2024126398A1 (en) 2022-12-12 2024-06-20 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Fixed dose combination comprising netupitant and palonosetron
WO2024126408A1 (en) 2022-12-12 2024-06-20 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Antioxidant-free fixed dose combination of netupitant and palonosetron

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