WO2020014072A1 - Association pharmaceutique de néostigmine pour le traitement de la myasthénie grave - Google Patents

Association pharmaceutique de néostigmine pour le traitement de la myasthénie grave Download PDF

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WO2020014072A1
WO2020014072A1 PCT/US2019/040548 US2019040548W WO2020014072A1 WO 2020014072 A1 WO2020014072 A1 WO 2020014072A1 US 2019040548 W US2019040548 W US 2019040548W WO 2020014072 A1 WO2020014072 A1 WO 2020014072A1
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neostigmine
antagonist
dose
unit form
pharmaceutically acceptable
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PCT/US2019/040548
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Kathleen Clarence-Smith
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Gt Biopharma, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings

Definitions

  • This invention pertains to the field of the treatment of myasthenia gravis in patients suffering from this disease.
  • the invention describes a new combination for safely treating myasthenia gravis.
  • the present invention provides a new composition and method to enable the safe administration of neostigmine to mammalian subjects with myasthenic syndromes, including myasthenia gravis, which comprises administering to a patient in need of said treatment an effective daily dose of a NK1 -antagonist in combination with an effective daily dose of a pharmaceutically acceptable salt of neostigmine.
  • MG Myasthenia Gravis.
  • MG is a chronic neuromuscular autoimmune disease, characterized by muscle weakness.
  • the basic abnormality in MG is a reduction in the acetylcholine nicotinic receptors (AChRs) at neuromuscular junctions due to the effects of autoantibodies.
  • AChRs acetylcholine nicotinic receptors
  • Antibodies to other proteins at the neuromuscular junction are present in some cases of MG, such as antibodies to muscle-specific kinase, or to low density lipo-protein 4, or to agrin.
  • Myasthenic syndrome refers to conditions associated with muscle weakness in which the cholinergic transmission at the neuromuscular junction is decreased either because of a decrease in the number and/or dysfunction of post-synaptic nicotinic receptors or to a decrease in the amount of acetylcholine (“Ach”) available at the neuromuscular junction due to gene mutations in the presynaptic proteins involved in the synthesis, storage and release of ACh, or to degeneration of cholinergic nerves that innervate muscles.
  • An emerging myasthenic syndrome (with or without auto antibodies to nicotinic receptors) has been reported in association with immune-therapies used for the treatment of certain malignancies.
  • Myasthenic syndromes are sometimes loosely referred to as MG in the medical literature but herein, all MG-like conditions which do not involve autoantibodies to nicotinic receptors will be referred to as myasthenic syndromes.
  • MG itself is a myasthenic syndrome and is considered as such herein, although, as the most prominent myasthenic syndrome it is often mentioned specifically (as in the phrase "MG and other myasthenic syndromes").
  • NK1 -antagonist an antagonist of the neurokinin receptor subtype- 1, in the literature also referred to as NK1 receptor antagonist or NK1 receptor inhibitor.
  • NK1 -antagonist refers to a daily dose of said NK1 -antagonist of from 1 pg to 600 mg.
  • Neostigmine refers to a pharmaceutically acceptable salt of neostigmine (“neostigmine pharmaceutically acceptable salt”), the daily doses and the amounts per unit form thereof being expressed as equivalents of neostigmine bromide per oral unit forms, and equivalents of neostigmine methylsulfate per injectable unit forms.
  • Effective daily dose of neostigmine refers to a neostigmine pharmaceutically acceptable salt daily dose, including doses used in the titration period, equivalent to at least 15 mg of neostigmine bromide administered orally or to at least 0.5 mg of neostigmine methylsulfate administered parenterally.
  • “Maximally effective (daily) dose” or“Maximal effective (daily) dose”, as used herein for neostigmine, refers to any neostigmine daily dose allowing the expression of significantly greater neostigmine efficacy, heretofore hindered by the typical gastro-intestinal neostigmine adverse effects.
  • Effective amount per unit form is a neostigmine amount per unit form equivalent to at least 0.2 mg of neostigmine methylsulfate in a parenteral lml-solution unit form or as released from a transdermal drug delivery system; or, respectively, a neostigmine amount per unit form equivalent to at least 15 mg of neostigmine bromide in an oral unit form.
  • Neostigmine bromide or “neostigmine methylsulfate”: these expressions, or equivalent ones, as used herein in connection with neostigmine doses, refer to a neostigmine dose per unit form or to a neostigmine daily dose (range) equivalent of either neostigmine bromide, in the case of an oral dose, or to neostigmine methyl sulfate, in the case of a parenteral dose.
  • mammalian subject refers to any class of warm blooded higher vertebrates (such as placentals, marsupials, or monotremes) that nourish their young with milk secreted by mammary glands, have the skin usually more or less covered with hair; and include, but are not limited to, a human, a dog, and a cat.
  • MG Myasthenia gravis
  • NMJ neuromuscular junction
  • Muscular weakness can be generalized or localized to certain muscle groups, and involvement of the bulbar and respiratory muscles can be life threatening (Phillips and Vincent, 2016). Groups of muscles are often involved in typical patterns. Certain muscles such as those that control eye and eyelid movement, facial expression, chewing, talking, and swallowing are often, but not always, involved in the disorder. The muscles that control breathing and neck and limb movements may also be affected.
  • MG occurs in all ethnic groups and both genders. It most commonly affects young adult women (under 40) and older men (over 60), but it can occur at any age (Myasthenia Gravis Fact Sheet; National Institute of neurological Disorders and Stroke, 2016). In neonatal myasthenia, the fetus may acquire immune proteins (antibodies) from a mother affected with myasthenia gravis. Generally, cases of neonatal MG are temporary and the child's symptoms usually disappear within 2-3 months after birth (Myasthenia Gravis Fact Sheet; National Institute of neurological Disorders and Stroke, 2016). Other children develop MG indistinguishable from adults. MG in juveniles is uncommon (Myasthenia Gravis Fact Sheet; National Institute of neurological Disorders and Stroke, 2016).
  • the basic abnormality in MG is a reduction in acetylcholine receptors (AChRs) at neuromuscular junctions due to the effects of autoantibodies that are directed against the AChRs in most patients, or against neighboring proteins involved in the clustering of AChRs, such as MuSK, LRP-4, or agrin (Drachman, 2016).
  • AChRs acetylcholine receptors
  • the diagnosis may be missed during the early stages of the disease, and depends on the recognition of clinical manifestations, the measurement of autoantibodies, and/or electrophysiol ogical features (Drachman, 2016).
  • CMS congenital myasthenia or congenital myasthenic syndrome
  • a myasthenic syndrome is due to bi-allelic variants in the gene encoding the vesicular acetylcholine transporter (VAChT) located in the presynaptic terminal (O’ Grady et al, 2016). ).
  • VAChT vesicular acetylcholine transporter
  • degeneration of the nerves that innervate muscles such as occurs with aging (Lex ell, 1997) leads to a myasthenic syndrome.
  • Recently (Makarious et al, 2017), have reported on a myasthenic syndrome involving an emerging toxicity of checkpoint inhibitors used for the treatment of certain malignancies.
  • Ocular myasthenia gravis is a localized form of myasthenia gravis in which autoantibodies directed against acetylcholine receptors block or destroy these receptors at the postsynaptic neuromuscular junction.
  • OMG Ocular myasthenia gravis
  • the hallmark of OMG is a history of painless weakness or fatigability of the extraocular muscles and ptosis with normal pupillary function and visual acuity.
  • Clinical, laboratory, electrophysiologic, and pharmacologic tests are available for diagnosis. Treatment can begin with symptom management; there is no cure (Smith and Lee, 2017).
  • the treatment of myasthenic syndromes involves treatment of the symptoms through the enhancement of cholinergic transmission at the neuromuscular junction by acetylcholine esterase inhibitors (AChEIs) that do not appreciably cross the Blood-Brain-Barrier (BBB), such as neostigmine.
  • AChEIs acetylcholine esterase inhibitors
  • BBB Blood-Brain-Barrier
  • Patients with autoimmune-related myasthenic syndromes may also benefit from immunotherapy to slow disease progression.
  • Options for immunosuppression include corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, methotrexate, rituximab, cyclophosphamide, intravenous immunoglobulin, plasmapheresis, and thymectomy (Gotterer and Li, 2016).
  • Neostigmine treat the symptoms by retarding the enzymatic hydrolysis of acetylcholine at cholinergic synapses, so that acetylcholine concentrations increase at the neuromuscular junction and the effect of acetylcholine is both increased and prolonged. ChE inhibitors have been shown to cause considerable improvement in some patients and little to none in others (Howard, 2015). Strength rarely returns to normal. Neostigmine bromide (Prostigmin), iodide or methyl sulfate, all of which do not appreciably cross the BBB, are commonly used for the treatment of MG. No fixed dosage schedule suits all patients.
  • Neostigmine is commercially available as a brand or generic drug, for example as oral Prostigmin ® , consisting of tablets comprising 15 mg neostigmine bromide and vials for parenteral injection comprising 0.5 mg of neostigmine methyl sulfate, a 15 mg of neostigmine bromide oral dose being equivalent to 0.5 mg of neostigmine methylsulfate parenteral dose.
  • oral Prostigmin ® consisting of tablets comprising 15 mg neostigmine bromide and vials for parenteral injection comprising 0.5 mg of neostigmine methyl sulfate, a 15 mg of neostigmine bromide oral dose being equivalent to 0.5 mg of neostigmine methylsulfate parenteral dose.
  • Neostigmine bromide slow release preparation which can be taken once every day for treating myasthenia gravis is described in CN 102258492, the contents of which are incorporated herein in their entirety for reference. Neostigmine is also described in combination with some plant extracts according to traditional Chinese medicine (CN 102552381), for treating myasthenia gravis.
  • Neostigmine methylsulfate has been disclosed as a remedy for eye diseases, in an eye drop preparation, consisting of a neostigmine methylsulfate aqueous solution, also containing other chemicals, emulsified with an oily higher fatty acid solution obtained from olive oil and isopropyl myristate (JPS 56104814, the contents of which are incorporated herein in their entirety for reference).
  • Neostigmine methylsulfate has also been disclosed, in combination with naphazoline hydrochloride and chlorpheniramine maleate, for the treatment of conjunctivitis (CN 105708838, the contents of which are incorporated herein in their entirety for reference).
  • neostigmine used to treat MG are dose-limiting and used typically consist of gastrointestinal complaints, queasiness, loose stools, nausea, vomiting, abdominal cramps, and diarrhea (Howard, 2015).
  • Gastro-intestinal side effects are an important source of discomfort for the patient, may be a source of non-compliance, or may result in the need to decrease the daily dose of neostigmine to mitigate these side effects whereupon these side effects become dose-limiting. As a consequence, efficacy is reduced.
  • gastro-intestinal side effects in particular when using neostigmine methylsulfate intravenous injection (0.5mg/ml vials or lmg/ml in lO-ml multiple dose vials), are counteracted by a previous or concurrent administration of glycopyrrolate ad recommended in the label for injectable neostigmine (Bloxyberz Prescribing Information, revised May 2013).
  • a neurokinin-l receptor antagonist also referred to as NK1 receptor inhibitor or simply NK1 -antagonist
  • NK1 receptor inhibitor or simply NK1 -antagonist
  • the constant combination of a NK1 -antagonist with neostigmine enables for the first time greater or complete efficacy of neostigmine in the treatment of symptoms of muscle weakness associated with MG and other myasthenic syndromes.
  • the present invention provides a method for treating symptoms of muscle weakness associated with MG and other myasthenic syndromes, which comprises administering to a mammalian subject in need of said treatment a combination of a NK1 -antagonist with an effective dose of neostigmine.
  • NK1 -antagonists disclosed in the literature may be used in combination with a dose of neostigmine that is generally at least as high as that currently used for treating myasthenia gravis.
  • the chronic use of this combination improves the symptoms of myasthenia gravis by concurrently mitigating or even eliminating the gastro-intestinal dose-limiting adverse effects induced by neostigmine, thus enabling the safe administration of the recommended or even higher than recommended dose of neostigmine (maximally effective dose), leading to greater efficacy and safety of neostigmine.
  • the NK1 -antagonists used are those shown to be effective for preventing or treating nausea and vomiting following cancer chemotherapy.
  • NK1 receptor inhibitors known to block nausea, vomiting, and diarrhea induced by chemotherapeutic drugs, have been shown, in particular when administered at high doses, to also block the gastro- intestinal side effects of neostigmine without affecting its efficacy in treating symptoms of muscle weakness associated with MG or other myasthenic syndromes, thus allowing the administration of neostigmine maximally effective doses.
  • the present invention provides a method for treating symptoms of muscle weakness associated with MG and other myasthenic syndromes, which comprises administering to mammalian subjects, and in particular, humans, dogs, and cats, in need of said treatment an effective daily dose of a NK1 -antagonist in combination with an effective daily dose of a pharmaceutically acceptable salt of neostigmine.
  • the invention provides a pharmaceutical combination comprising a NK1 -antagonist, at a dose that is at least as high as the pediatric or adult dose shown to be effective for the prevention or treatment of chemotherapy-induced nausea and vomiting, and a maximally effective dose of a neostigmine pharmaceutically acceptable salt.
  • the invention provides a NK1 -antagonist, in a pharmaceutical composition comprising, as an active ingredient, said NK1- antagonist in an amount at least as high as the pediatric or adult dose shown to be effective for the prevention or treatment of chemotherapy-induced nausea and vomiting, in admixture with a pharmaceutical carrier, for use for preventing or attenuating the dose-limiting gastrointestinal adverse effects of neostigmine in the treatment of symptoms of muscle weakness associated with MG and other myasthenic syndromes in a mammalian subject in need of said treatment.
  • the invention includes the use of a NK 1- antagonist for the preparation of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said NK1 -antagonist, in an amount per unit form at least as high as the pediatric or adult dose shown to be effective for the prevention or treatment of chemotherapy-induced nausea and vomiting (effective amount per unit form), in admixture with a pharmaceutical carrier, for preventing, attenuating or even abrogating the gastrointestinal adverse effects of neostigmine in the treatment of MG and other myasthenic syndromes, in a mammalian subject in need of said treatment.
  • the amount per unit form of the NK1 -antagonist is at least as high as the pediatric or adult dose shown to be effective for the prevention or treatment of chemotherapy-induced nausea and vomiting and may be up to 4 times and even up to 6 times said dose.
  • composition comprising said NK1 -antagonist, for the first time allows the administration of maximally effective neostigmine doses to mammalian subjects suffering from symptoms of muscle weakness associated with MG or other myasthenic syndromes, with the consequent expression of the neostigmine greater efficacy.
  • the invention provides a pharmaceutical fixed-dose combination consisting of a pharmaceutical composition in dosage unit form comprising a NK1 -antagonist, in an amount per unit form that is at least as high as the pediatric or adult dose shown to be effective for the prevention and treatment of chemotherapy-induced nausea and vomiting, as Component (a) and an effective amount per unit form of a neostigmine pharmaceutically acceptable salt, as Component (b), in admixture with a pharmaceutical carrier or vehicle.
  • the invention provides a pharmaceutical combination comprising an approved NK1 -antagonist, at a dose that is at least as high as the pediatric or adult dose approved for the prevention or treatment of chemotherapy -induced nausea and vomiting, and an effective, especially maximally effective, dose of a neostigmine pharmaceutically acceptable salt.
  • the invention provides an approved NK1 -antagonist, in a pharmaceutical composition comprising, as an active ingredient, said NK1 -antagonist in an amount at least as high as the pediatric or adult dose approved for the prevention or treatment of chemotherapy-induced nausea and vomiting, in admixture with a pharmaceutical carrier, for use for preventing, attenuating or even abrogating the gastrointestinal adverse effects of neostigmine in the treatment of myasthenia gravis and other myasthenic syndromes.
  • the invention includes the use of an approved NK1 -antagonist for the preparation of a medicament consisting of a pharmaceutical composition comprising, as an active ingredient, said NK1 -antagonist, in an amount at least as high as the pediatric or adult dose approved for the prevention or treatment of chemotherapy-induced nausea and vomiting, in admixture with a pharmaceutical carrier, for preventing, attenuating or even abrogating the gastrointestinal adverse effects of neostigmine in the treatment of myasthenia gravis and other myasthenic syndromes.
  • the amount of the NK1 -antagonist is at least as high as the pediatric or adult dose approved for the prevention or treatment of chemotherapy- induced nausea and vomiting and may be up to 6 times said dose.
  • said amount per unit form of said NK1 -antagonist administered orally Component (a) in said composition normally is from 1 pg to 600 mg.
  • the unit dose of neostigmine is equivalent to a range of from 0.1 mg to 800 mg of neostigmine bromide or methyl sulfate, including unit doses (in the case of multidose systems) and unit forms, for their use in the titration period.
  • the oral dose per unit form of neostigmine, normally as bromide, in an IR tablet will range from 15 mg to 75 mg or from 15 mg to 150 mg, depending on safety and tolerability (per day the dose normally is from 15 mg to 375 mg or from 15 mg to 1500 mg).
  • the NK1 -antagonist is aprepitant or a pharmaceutically acceptable salt thereof, its dose per IR unit form, in combination with neostigmine, will correspond to from 10 mg to 125 mg of aprepitant.
  • the NK1 -antagonist is rolapitant
  • the dose/unit form in combination with neostigmine at the above doses/unit form will range from 15 mg to 270 mg in an IR formulation.
  • neostigmine normally as methyl sulfate
  • administered by intravenous injection is 0.03 mg/kg to 0.07 mg/kg administered as an intravenous bolus, the recommended maximum total dose normally being 0.07 mg/kg or up to a total of 5 mg, whichever is less.
  • the present invention allows the improvement of the conditions of mammalian subjects suffering from MG and other myasthenic syndromes and treated with neostigmine by chronically administering to said patients a NK1 -antagonist.
  • the present invention provides, according to its aspects,
  • NK1 -antagonist for use in the treatment of MG and other myasthenic syndromes in combination with neostigmine;
  • a NK1 -antagonist for the preparation of a medicament for the treatment of symptoms of muscle weakness associated with MG and other myasthenic syndromes in combination with neostigmine;
  • a fixed-dose combination consisting of a pharmaceutical composition in dosage unit form comprising, as active ingredients, a NK1 -antagonist Component (a) and neostigmine Component (b).
  • the present invention also relates to the use of a NK1 -antagonist for the preparation of a medicament for the treatment of symptoms of muscle weakness associated with MG and other myasthenic syndromes comprising, as an active ingredient, said NK1 -antagonist Component (a) and, as a second active ingredient, said neostigmine Component (b), in a pharmaceutical composition in dosage unit form in admixture with a pharmaceutically acceptable carrier or vehicle.
  • NKl-antagonist may be used for allowing the safe treatment of MG and other myasthenic syndromes with normal, but also with high and very high, fully effective neostigmine doses.
  • Antagonists of the NK1 receptor that are shown to be effective for the prevention or treatment of chemotherapy-induced nausea and vomiting are particularly useful according to the present invention.
  • the NK1 -antagonist is preferably selected from the group consisting of
  • Illustrative examples of pharmaceutically acceptable salts of basicthese advantageous NK1 -antagonists include acid addition salts with mineral or organic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, sulfamic acid, nitric acid, carbonic acid, phosphoric acid, formic acid, acetic acid, propionic acid, stearic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, hydroxymaleic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, phenylacetic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic (isethionic) acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-amino-benzenesulfonic (
  • Illustrative examples of pharmaceutically acceptable salts of acidic NK 1- antagonists such as fosaprepitant include salts with inorganic bases such as alkaline metal or alkaline-earth metal salts, and salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine (meglumine) salts, and salts with amino acids, as described in US 5,691,336, the contents of which are incorporated herein in their entirety by reference.
  • Aprepitant, fosaprepitant meglumine, fosaprepitant di(cyclohexylamine), rolapitant, rolapitant hydrochloride, netupitant-300/palonosetron-0.5 and fosnetupitant-235/palonosetron-0.25 are particularly advantageous NK 1- antagonists.
  • Antagonists of the NK1 receptor that are approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting are particularly useful according to the present invention.
  • aprepitant is commercially available (Emend ® ) in capsules containing 40 mg, 80 mg, or 125 mg aprepitant, in one l50-mg powder in single-dose glass vial, for reconstitution for intravenous injection, or, as fosaprepitant dimeglumine (Emend ® Injection, Ivemend ® ), in vials containing 115 mg or 150 mg fosaprepitant; rolapitant is available (Varubi ® ) in 90-mg tablets; and netupitant- 300/palonostron-0.5, available (Akynzeo ® ) in a fixed-dose combination in capsules containing 300 mg of netupitant and 0.5 mg of the NK1 -antagonist palonosetron (as hydrochloride); and fosnetup
  • said NK1 -antagonist is selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; rolapitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 15 mg to 270 mg of rolapitant, netupitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 300 mg to 600 mg; netupitant-300/palonosetron-0.5; and fosnetupitant-235/palonosetron-0.25.
  • each of the above NK1 -antagonists is formulated in a pharmaceutical composition in dosage unit form comprising, as an active ingredient, said NK1 -antagonist, in admixture with a pharmaceutical carrier or vehicle.
  • said NK1 -antagonist active ingredient of said pharmaceutical composition is selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; rolapitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 15 mg to 270 mg of rolapitant; netupitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 300 mg to 600 mg; netupitant- 300/palonosetron-0.5; and fosnetupitant-235/palonosetron-0.25.
  • said NK1 -antagonist is aprepitant, in an amount per unit form of from 10 mg to 250 mg; fosaprepitant meglumine, in an amount per unit form equivalent to from 10 mg to 250 mg of aprepitant; or rolapitant, in an amount per unit form of from 15 mg to 270 mg or from 30 mg to 270 mg.
  • a NK1 -antagonist in combination with neostigmine it is possible to treat a patient suffering from MG or a myasthenic syndrome by maintaining a therapeutically effective neostigmine daily dose with minimal adverse effect.
  • the present invention provides a fixed-dose combination consisting of a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said NK1 -antagonist and an effective amount per unit form of said neostigmine, in admixture with a pharmaceutical carrier or vehicle.
  • NKl-antagonist/neostigmine fixed-dose combinations are illustrated in “The Pharmaceutical Compositions” section below.
  • Neostigmine is currently indicated for the oral treatment of MG, as neostigmine bromide, in particular in l5-mg tablets for IR administration; and, as parenteral treatment for the reversal of the effects of non-depolarizing neuromuscular blocking agents (NMBAs) after surgery as neostigmine methyl sulfate, in 0.5 mg/ml and 1 mg/ml in 10 ml multiple-dose vials.
  • NMBAs non-depolarizing neuromuscular blocking agents
  • neostigmine bromide oral doses up to 375 mg/day should be administered. However, as set forth above, said doses are not tolerated in most patients.
  • neostigmine doses than the currently recommended doses should provide further improvement and even a near-to-complete response, i.e., the complete alleviation of symptoms.
  • neostigmine bromide or neostigmine methylsulfate with a NK1 -antagonist, said treatment becomes safe, and greatly increased effective oral doses, up to 1500 mg/day, and even more, or parenteral doses up to 240 mg/day, and even higher, up to 500 mg/day by continuous 24h-infusion, may be attained without appreciable gastrointestinal adverse effects.
  • a pharmaceutically acceptable salt of neostigmine is administered at a unit dose equivalent to from 0.03 mg/kg to 6.25 mg/kg of neostigmine bromide or neostigmine methylsulfate.
  • This unit dose includes an oral unit form comprising an amount of said neostigmine equivalent to from 0.2 mg to 200 mg of neostigmine bromide and a parenteral unit form comprising a neostigmine amount equivalent to from 0.09 mg to 500 mg.
  • unit dose is intended as both a unit form and daily dose.
  • neostigmine is administered to a mammal at an unit dose, including titration doses, equivalent to from 0.25mg/kg to 2.5 mg/kg of body weight of neostigmine bromide by oral route, or equivalent to from 0.03 mg/kg to 6.25 mg/kg, normally from 0.03 mg/kg to 4 mg/kg of body weight of neostigmine methylsulfate by parenteral route.
  • the parenterally administered neostigmine unit dose is equivalent to from 0.03 mg/kg to 0.28 mg/kg of neostigmine methylsulfate by intravenous bolus injection and from 0.03 mg to 8.33 mg/kg, normally from 0.2 mg/kg to 4 mg/kg of neostigmine methylsulfate by subcutaneous continuous 24h- infusion.
  • the neostigmine oral unit dose normally corresponds to an unit form comprising said neostigmine in an amount per unit form equivalent to from 1 mg to 200 mg of neostigmine bromide;
  • neostigmine is in a parenteral unit dose equivalent to from 0.16 mg/24 hours (“mg/24h”) to 500 mg/24h of neostigmine methylsulfate; and
  • neostigmine is in an unit form (ampoule or vial) comprising a parenteral unit dose corresponding to an unit form comprising a neostigmine amount equivalent to from 0.09 mg to 0.28 mg of neostigmine methylsulfate.
  • the amount of neostigmine, normally as bromide, in an oral Immediate Release (“IR”) unit form (“amount per unit form”) will range from 1 mg to 200 mg, normally from 15 mg to 200 mg, advantageously from 17.5 mg to 200 mg, from 35 mg to 200 mg, from 45 mg to 200 mg, from 62.5 mg to 200 mg, from 70 mg to 200 mg, or from 100 mg to 200 mg, depending on safety and tolerability (per day the oral dose is from 15 mg to 1500 mg, and even more, normally from 17.5 mg to 1500 mg, from 17.5 mg to 1125 mg, from 17.5 mg to 750 mg, or from 17.5 mg to 375 mg).
  • One appropriate neostigmine bromide IR-tablet or IR-capsule comprises 3 mg, 8 mg, 15 mg, 17.5 mg, 35 mg, 50 mg, 62.5 mg, 70 mg, 100 mg, or 200 mg of neostigmine bromide.
  • the present invention provides appropriate unit forms, normally a pharmaceutical composition in tablets or capsules comprising, as an active ingredient, a pharmaceutically acceptable salt of neostigmine, in an amount per unit form equivalent to from 17.5 mg to 200 mg, from 35 mg to 200 mg, from 50 mg to 200 mg, from 62.5 mg to 200 mg, from 70 mg to 200 mg or from 100 mg to 200 mg of neostigmine bromide, in admixture with a pharmaceutical carrier or vehicle.
  • Said unit forms may be safely administered to a mammalian subject suffering from symptoms of muscle weakness associated with MG and other myasthenic syndromes, constantly and concurrently with a NK1 -antagonist.
  • Tablets each comprising a neostigmine pharmaceutically acceptable salt in an amount per tablet equivalent to 17.5 mg, 35 mg, 50 mg, 62.5 mg, 70 mg, 100 mg and 200 mg of neostigmine bromide are particularly appropriate.
  • Said unit forms are given several times per day at given intervals depending on the patient’s response.
  • the normal, maximally effective neostigmine oral daily dose is equivalent to 1200 mg/day of neostigmine bromide, but some patients may need more (up to 1500 mg or more) and some may need less.
  • such an oral unit form is destined to be administered from two to seven times per day to mammalian subjects, and particularly, humans, dogs, and cats, suffering from conditions or symptoms of muscle weakness associated with MG or other myasthenic syndromes, in combination with a NK1 -antagonist.
  • two unit forms may be simultaneously administered from two to seven times per day to said mammalian subjects in combination with a NKl-antagonist.
  • the unit dose thus administered does not correspond to an unit form.
  • the maximally effective daily dose in combination with a NKl-antagonist is equivalent to from 0.2 mg (to neonates) daily to 500 mg daily of neostigmine methylsulfate.
  • Said infusion is in unit doses normally corresponding to the 24-hour dose, preferably in unit doses comprising an amount of neostigmine equivalent to from 0.2 mg to 10 mg, from 10 mg to 50 mg, from 50 mg to 100 mg.
  • neostigmine methylsulfate When administered by continuous subcutaneous injection, neostigmine methylsulfate is normally administered at single ampoule doses of from 0.09 mg (to neonates) to 500 mg, to be administered once every 24 hours in order to supply a maximally effective daily dose of from 1 mg (neonates) to 500 mg.
  • a safer administration is assured by combining, in the same oral unit form, a NKl-antagonist, in an amount per oral unit form of from 1 pg to 600 mg; and neostigmine, in an amount per unit form equivalent to from 0.2 mg to 200 mg, normally from 15 mg to 200 mg, advantageously from 17.5 mg to 200 mg of neostigmine bromide.
  • said MK1 -antagonist is one of the approved 5HT3-antgonists illustrated in“The NKl-antagonist” section, in an amount per unit form as illustrated in the same section and said neostigmine is neostigmine bromide or neostigmine methylsulfate.
  • the present invention provides a method for safely improving the conditions or symptoms of muscle weakness associated with mammalian subjects, and particularly, humans, dogs, and cats, suffering from MG or other myasthenic syndromes by treating said mammalian subject with a NKl- antagonist in combination with neostigmine.
  • the present invention proposes a method to safely improve the conditions of patients suffering from MG or other myasthenic syndromes and treated with neostigmine by chronically administering to said patients a NK1 -antagonist.
  • the present invention provides a method for treating symptoms of muscle weakness associated with MG and other myasthenic syndromes, which comprises administering to a patient in need of said treatment an effective daily dose of a NK1 -antagonist in combination with an effective daily dose of neostigmine.
  • the daily dose of these NK1 -antagonists is at least as high as that preventing or treating nausea and vomiting in pediatric or adult patients undergoing a surgical operation or cancer chemotherapy according to the current protocols for said treatment or prevention
  • Said daily dose is from 1 pg to 600 mg, normally from 1 mg to 600 mg, or from 1 mg to 300 mg.
  • the NK1 -antagonists allowing the safe treatment of neostigmine, in particular at heretofore intolerable doses and even at high doses, are illustrated in “The NK1 -antagonist” section.
  • said NK1 -antagonist is selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, fosaprepitant and pharmaceutically acceptable salts and solvates thereof, rolapitant and pharmaceutically acceptable salts and solvates thereof, netupitant and pharmaceutically acceptable salts and solvates thereof, each at a daily dose illustrated in“The NK1 -antagonist” section, netupitant-300/palonosetron-0.5 administered once a day; and fosnetupitant-235/palonosetron-0.25 , administered once a day; and
  • neostigmine is selected from the group consisting of pharmaceutically acceptable salts of neostigmine, at a daily dose as illustrated above in “The neostigmine Component (b)” section.
  • said daily dose of said NK1 -antagonist is from 1 pg to 600 mg normally from 1 mg to 600 mg, or from 1 mg to 300 mg; and said daily dose of said neostigmine is equivalent to up to 1500 mg/day of neostigmine bromide orally (including the low doses used in the titration period), or up to 240 mg/day , and even higher, up to 500 mg/day (in neostigmine methyl sulfate), by continuous 24h- infusion,
  • a NK1 -antagonist selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof and rolapitant and pharmaceutically acceptable salt and solvate thereof is a particularly advantageous NK1 -antagonist.
  • said NK1 -antagonist is aprepitant and neostigmine is neostigmine bromide or neostigmine methylsulfate.
  • said NK1 -antagonist in said combination is aprepitant, at an effective daily dose of from 10 mg to 250 mg and said effective daily dose, for example, allows the safe treatment of adult patients suffering from MG or other myasthenic syndromes with a neostigmine oral daily maximally effective dose equivalent to from 375 mg to 1500 mg, normally from 375 mg to 1200 mg, from 375 mg to 1125 mg, from 375 mg to 750 mg or from 375 mg to 450 mg of neostigmine bromide.
  • NK1 antagonists also allows the safe administration to a mammalian subject of parenteral doses of neostigmine, normally as methylsulfate.
  • aprepitant at a daily dose of from 10 mg to 250 mg allows the safe, continuous 24-hour/day subcutaneous neostigmine infusion, at a maximally effective daily dose equivalent to from 10 mg to 500 mg, advantageously from 30 mg to 400 mg, normally from 120 mg to 240 mg of neostigmine methylsulfate.
  • said NK1 -antagonist is formulated in a pharmaceutical composition in dosage unit form comprising an effective amount per unit form of said NK1 -antagonist, normally from 1 pg to 600 mg, in admixture with a pharmaceutical carrier or vehicle.
  • Said composition is administered to said patient at the above daily doses, in combination with neostigmine, also in a pharmaceutical composition comprising or delivering an effective amount per unit dose of neostigmine, normally equivalent to from 0.1 mg to 800 mg of neostigmine bromide, or neostigmine methylsulfate, at the aforementioned daily doses.
  • said NK1 -antagonist active ingredient of said pharmaceutical composition is selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; rolapitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 15 mg to 270 mg of rolapitant; netupitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 300 mg to 600 mg; netupitant- 300/palonosetron-0.5; and fosnetupitant-235/palonosetron-0.25.
  • Said NK1 -antagonist and said meostigmine may also be co-formulated in a pharmaceutical composition, in admixture with a pharmaceutical carrier or vehicle as illustrate herein below.
  • the method of the present invention allows a safe treatment of symptoms of muscle weakness associated with MG or other myasthenic disorders in a mammalian subject.
  • the invention provides a NK1 -antagonist for use in the treatment of symptoms of muscle weakness associated with MG and other myasthenic syndromes in combination with neostigmine.
  • NK1 -antagonist in particular those that are shown to be effective for the prevention or treatment of chemotherapy-induced nausea and vomiting may be used, in a combination, including fixed-dose combinations, with neostigmine according to this aspect of the present invention.
  • said NK1 -antagonists are those approved for the prevention or treatment of chemotherapy-induced nausea and vomiting.
  • said NK1 -antagonist single dose is formulated in a pharmaceutical or veterinary composition in dosage unit form comprising an effective amount per unit form of said NK1 -antagonist, in admixture with a pharmaceutical carrier or vehicle.
  • the NK1 -antagonist is administered to a mammalian subject in a pharmaceutical or veterinary composition comprising said NKl-antaagonist in an effective amount per unit form of from 1 pg to 600 mg to be administered once a day, in combination with neostigmine, also in a pharmaceutical or veterinary composition in dosage unit form comprising a neostigmine amount per unit form equivalent to from 2 mg to 200 mg of neostigmine bromide, to be administered at a daily dose as illustrated below.
  • NK1 -antagonists The amounts per unit form of said NK1 -antagonists and the daily doses to be administered to a mammal such as a cat or a dog, or a human patient suffering from symptoms of muscle weakness associated with MG or another myasthenic syndrome in combination with neostigmine are illustrated in“The NK1 -antagonist” section.
  • NK1 -antagonists to be used in combination with 6- propylamino-4,5,6,7-tetrahydro-l,3-benzothiazole-2-amine is selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, fosaprepitant and pharmaceutically acceptable salts and solvates thereof, casopitant and pharmaceutically acceptable salts and solvates thereof, maropitant and pharmaceutically acceptable salts and solvates thereof, ezlopitant and pharmaceutically acceptable salts and solvates thereof, lanepitant and pharmaceutically acceptable salts and solvates thereof, netupitant and pharmaceutically acceptable salts and solvates thereof, fosnetupitant and pharmaceutically acceptable salts and solvates thereof: orvapitant and pharmaceutically acceptable salts and solvates thereof, rolapitant and pharmaceutically acceptable salts and solvates thereof, serlopitant and pharmaceutically acceptable salts and solvates thereof, vestipitant and pharmaceutically acceptable salts and solvates thereof, vofopitant and
  • said NK1 -antagonist is selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; rolapitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 15 mg to 270 mg of rolapitant, netupitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 300 mg to 600 mg; netupitant-300/palonosetron-0.5; and fosnetupitant-235/palonosetron-0.25and netupitant-300/palonosetron-0.5.
  • Said NK1 -antagonist and said neostigmine may also be co-formulated in a pharmaceutical composition, in admixture with a pharmaceutical carrier or vehicle as illustrate herein below, in the fourth aspect of the invention.
  • composition comprising said NK1 -antagonist allows a safe treatment of symptoms of muscle weakness associated with MG and other myasthenic syndromes, in combination with neostigmine.
  • the invention provides a NK1 -antagonist for use in the treatment of symptoms of muscle weakness associated with MG and other myasthenic syndromes in combination with neostigmine.
  • NK1 -antagonist in particular those that are shown to be effective for the prevention or treatment of chemotherapy-induced nausea and vomiting may be used, in a combination, including fixed-dose combinations, with neostigmine according to this aspect of the present invention.
  • said NK1 -antagonists are those approved for the prevention or treatment of chemotherapy-induced nausea and vomiting.
  • said NK1 -antagonist single dose is formulated in a pharmaceutical or veterinary composition in dosage unit form comprising an effective amount per unit form of said NK1 -antagonist, in admixture with a pharmaceutical carrier or vehicle.
  • the NK1 -antagonist is administered to a mammalian subject in a pharmaceutical or veterinary composition comprising said NKl-antaagonist in an effective amount per unit form of from 1 pg to 600 mg to be administered once a day, in combination with neostigmine, also in a pharmaceutical or veterinary composition in dosage unit form comprising a neostigmine amount per unit form equivalent to a range of from 0.1 mg to 800 mg of neostigmine bromide or methyl sulfate, including unit doses (in the case of multidose systems) and unit forms, for their use in the titration period, and extended-release formulation.
  • a pharmaceutical or veterinary composition comprising said NKl-antaagonist in an effective amount per unit form of from 1 pg to 600 mg to be administered once a day, in combination with neostigmine, also in a pharmaceutical or veterinary composition in dosage unit form comprising a neostigmine amount per unit form equivalent to a range of
  • the neostigmine dose per unit form is equivalent to from 2 mg to 200 mg of neostigmine bromide, to be administered at a daily dose as illustrated in “The neostigmine Component (b)” section.
  • NK1 -antagonists The amounts per unit form of said NK1 -antagonists and the daily doses to be administered to a mammal such as a cat or a dog, or a human patient suffering from symptoms of muscle weakness associated with MG or another myasthenic syndrome in combination with neostigmine are illustrated in“The NK1 -antagonist” section.
  • NK1 -antagonists to be used in combination with 6- propylamino-4,5,6,7-tetrahydro-l,3-benzothiazole-2-amine is selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, fosaprepitant and pharmaceutically acceptable salts and solvates thereof, casopitant and pharmaceutically acceptable salts and solvates thereof, maropitant and pharmaceutically acceptable salts and solvates thereof, ezlopitant and pharmaceutically acceptable salts and solvates thereof, lanepitant and pharmaceutically acceptable salts and solvates thereof, netupitant and pharmaceutically acceptable salts and solvates thereof, fosnetupitant and pharmaceutically acceptable salts and solvates thereof: orvapitant and pharmaceutically acceptable salts and solvates thereof, rolapitant and pharmaceutically acceptable salts and solvates thereof, serlopitant and pharmaceutically acceptable salts and solvates thereof, vestipitant and pharmaceutically acceptable salts and solvates thereof, vofopitant and
  • said NK1 -antagonist is selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; rolapitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 15 mg to 270 mg of rolapitant, netupitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 300 mg to 600 mg; netupitant-300/palonosetron-0.5 once a day; and fosnetupitant-235/palonosetron-0.25 once a day.
  • Said composition is for use for safely improving the conditions or symptoms of muscle weakness associated with mammalian subjects, and particularly, humans, dogs, and cats, suffering from MG or other myasthenic syndromes, in combination with a neostigmine pharmaceutically acceptable salt at a daily dose equivalent to from 375 mg to 1500 mg, and even more, of neostigmine bromide or neostigmine methyl sulfate. .
  • composition comprising said NK1 -antagonist at the above dose per unit form and daily dose allows a safe ,
  • Said composition allows a safe treatment of MG or other myasthenic syndromes, in combination with neostigmine daily oral doses equivalent to from 15 mg to 1500 mg, especially of maximally effective daily oral doses of from 375 mg to 1500 mg, normally from 450 mg to 1200 mg, of neostigmine bromide.
  • Said composition also allows the safe administration to a mammalian subject of parenteral doses of neostigmine, normally as methyl sulfate, for example a continuous 24-hour/day subcutaneous neostigmine infusion, at a maximally effective daily dose equivalent to from 10 mg to 500 mg, advantageously from 30 mg to 400 mg, normally from 120 mg to 240 mg of neostigmine methylsulfate.
  • parenteral doses of neostigmine normally as methyl sulfate
  • a maximally effective daily dose equivalent to from 10 mg to 500 mg, advantageously from 30 mg to 400 mg, normally from 120 mg to 240 mg of neostigmine methylsulfate.
  • the invention provides the use of a NK 1- antagonist for the preparation of a medicament for the treatment of a mammal such as a cat or a dog, or a human patient suffering from symptoms of muscle weakness associated with MG or other myasthenic syndromes in combination with neostigmine.
  • Said medicament for the treatment of symptoms of muscle weakness associated with MG and other myasthenic syndromes comprises a NK1 -antagonist formulated in a pharmaceutical or veterinary composition wherein said NK 1- antagonist is in admixture with a pharmaceutical carrier or vehicle, to be administered, concurrently or sequentially, in combination with neostigmine.
  • said NK1 -antagonist is in admixture with a pharmaceutical carrier and formulated in unit forms for oral, intravenous, transcutaneous, transdermal administration, as described in “The formulations” section below.
  • any of the NK 1- antagonists described in“The NK1 -antagonist Component (a)” section may be used as an active ingredient of the pharmaceutical or veterinary composition indicated as a medicament for the treatment of a mammalian subject suffering from symptoms of muscle weakness associated with MG or other myasthenic syndromes, in combination with neostigmine doses as described in“The neostigmine Component (b)” section.
  • said medicament is a pharmaceutical or veterinary composition in dosage unit form comprising, as an active ingredient, said NK1 -antagonist, in an amount per unit form of from 1 pg to 600 mg, normally from 1 mg to 600 mg or from 1 mg to 300 mg, in admixture with a pharmaceutical carrier or vehicle.
  • Said medicament in the above dose per unit form is destined to be administered to said mammalian subject at a daily dose of from 1 pg to 600 mg, normally from 1 mg to 600 mg or from 1 mg to 300 mg, in combination with neostigmine, also in pharmaceutical or veterinary composition in dosage unit form comprising a neostigmine amount per unit form equivalent to from 0.1 mg to 300 mg of neostigmine bromide or neostigmine methylsulfate, said unit form being administered from three times per day to six times per day.
  • compositions of the present invention are formulated with the classic excipients suitable for different ways of administration. Particularly advantageous are the formulations in the form of tablets, multi-score tablets, coated tables, orally disintegrating tablets, extended release tablets, hard or soft capsules, extended-release capsules, patches for transdermal administration, liquid oral solutions, syrups or suspensions in a predetermined unit form, and vials for the intravenous or subcutaneous administration.
  • the aforementioned pharmaceutical composition comprising said 5HT3- antagonist, in the aforesaid amounts per unit form, is administered to a patient suffering from MG or another myasthenic syndrome in combination with neostigmine, also in a pharmaceutical composition in dosage unit form, comprising an effective amount of neostigmine in admixture with a pharmaceutical carrier.
  • Said effective amounts, in unit forms for oral, intravenous, or subcutaneous for continuous infusion administration as well as the neostigmine daily doses are illustrated in“The Neostigmine” section.
  • said effective amount per unit form for oral administration is in the range of from 0.2 mg to 200 mg, preferably from 17.5 mg to 200 mg.
  • said neostigmine is neostigmine bromide.
  • said effective amount per unit form for continuous subcutaneous infusion administration is from 10 mg to 500 mg, preferably from 60 mg to 240 mg.
  • said neostigmine for continuous subcutaneous infusion is neostigmine methylsulfate.
  • said medicament includes a pharmaceutical or veterinary composition
  • a pharmaceutical or veterinary composition comprising a NK1 -antagonist active ingredient selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 10 mg to 250 mg of aprepitant; rolapitant and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 15 mg to 270 mg of rolapitant; netupitant and pharmaceutically acceptable salts and solvates thereof, in an amount per unit form equivalent to from 300 mg to 600 mg; netupitant-300/palonosetron-0.5; and fosnetupitant-235/palonosetron-0.25.
  • a NK1 -antagonist active ingredient selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, in an
  • said NK1 -antagonist is preferably selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 10 mg to 250 mg of aprepitant; rolapitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 15 mg to 270 mg of rolapitant, netupitant and pharmaceutically acceptable salts and solvates thereof, at a daily dose equivalent to from 300 mg to 600 mg; netupitant-300/palonosetron-0.5 once a day; and fosnetupitant-235/palonosetron-0.25 once a day.
  • said medicament is destined to be administered to said mammalian subject, at the above daily dose, in combination with neostigmine.
  • said neostigmine is neostigmine bromide for oral administration or neostigmine methylsulfate for parenteral administration.
  • the NK1 -antagonist and the neostigmine are used in combination and the two active components may be co-administered simultaneously or sequentially, or in a fixed dose combination comprising a pharmaceutical composition comprising the NK1 -antagonist and neostigmine, in admixture with a pharmaceutically acceptable carrier or vehicle.
  • the NK1 -antagonist Component (a) and the neostigmine Component (b) can be administered separately or together in any conventional oral or parenteral dosage unit form such as capsule, tablet, powder, sachet, suspension, solution, or transdermal device.
  • the amount of NK1 -antagonist per unit form in preferred embodiments will be in the range of from 1 pg to 600 mg.
  • the amount of neostigmine per unit form in preferred embodiments will be in the range of from 1 mg to 200 mg.
  • each of them can be packaged in a kit comprising said NK1 -antagonist, in admixture with a pharmaceutical carrier or vehicle, in a container; and said neostigmine, in admixture with a pharmaceutical carrier or vehicle, in another, separate container.
  • the two active principles can be formulated together and with a pharmaceutical carrier or vehicle, in a pharmaceutical composition.
  • the present invention provides the use of a NK1 -antagonist for the preparation of a medicament for the treatment of symptoms of muscle weakness associated with MG and other myasthenic syndromes in combination with neostigmine, said medicament including a pharmaceutical composition in dosage unit form comprising said NK1 -antagonist and said neostigmine pharmaceutically acceptable salt, in admixture with a pharmaceutical carrier or vehicle.
  • the pharmaceutical composition comprising a NK1 -antagonist may contain another active ingredient, in particular neostigmine, co-formulated with said NK1 -antagonist, in admixture with a pharmaceutical carrier or vehicle.
  • the present invention further provides a fixed-dose combination including a pharmaceutical or veterinary composition in dosage unit form comprising, as active ingredients,
  • the NK1 -antagonist Component (a) is present in an amount per unit form of from 1 pg to 600 mg and the neostigmine Component (b) for oral administration is present in an amount equivalent to from 0.2 mg to 200 mg, normally to from 17.5 mg to 200 mg of neostigmine bromide or for subcutaneous 24-hour continuous administration is present in an amount equivalent to 10 mg to 500 mg, or 30 mg to 400 mg, preferably 60 mg to 240 mg neostigmine methyl sulfate.
  • Said fixed-dose combination is useful for the treatment of MG and other myasthenic disorders in a mammal such as a cat, a dog or a human being.
  • Said treatment safely provides said mammal with a NK1 -antagonist dose of from 1 pg to 600 mg and a single neostigmine dose equivalent to from 0.2 mg to 200 mg of neostigmine bromide or neostigmine methylsulfate.
  • the above fixed-dose combination may be safely used for the treatment of infants, including neonates, and also includes neostigmine doses for titration.
  • said NK1 -antagonist Component (a) active ingredient is selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; fosaprepitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 10 mg to 250 mg of aprepitant; rolapitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 15 mg to 270 mg of rolapitant; netupitant and pharmaceutically acceptable salts and solvates thereof, in an amount, per unit form, equivalent to from 300 mg to 600 mg of netupitant; and
  • neostigmine pharmaceutically acceptable salt Component (b) is in an amount per unit form equivalent to from 0.2 mg to 200 mg of neostigmine bromide or 10 mg to 240 mg neostigmine methyl sulfate;
  • the fixed-dose combination is a pharmaceutical composition in dosage unit form comprising
  • a NK1 -antagonist Component (a) selected from the group consisting of aprepitant, in an amount per unit form of from 10 mg to 250 mg; and rolapitant, in an amount per unit form of from 15 mg to 270 mg; and
  • neostigmine bromide Component (b) in an amount per unit form of from 15 mg to 200 mg, from 17.5 mg to 200 mg, from 35 mg to 200 mg, from 50 mg to 200 mg, from 62.5 mg to 200 mg, from 70 mg to 200 mg and from 100 mg to 200 mg, in admixture with a pharmaceutical carrier or vehicle in an oral formulation.
  • the fixed-dose combination is a pharmaceutical composition in dosage unit form comprising
  • a NK1 -antagonist Component (a) selected from the group consisting of aprepitant, in an amount per unit form of from 25 mg to 200 mg; and fosaprepitant dimeglumine, in an amount per unit form of 25 mg to 200 mg; and
  • neostigmine methyl sulfate Component (b) in an amount per unit form of from 0.2 mg to 200 mg, from 17.5 mg to 200 mg, from 35 mg to 200 mg, from 50 mg to 200 mg, from 62.5 mg to 200 mg, from 70 mg to 200 mg and from 100 mg to 200 mg,
  • said Component (a) is a mixture of the NK1 -antagonist netupitant, in an amount per unit form of 300 mg, and of the 5HT3 -antagonist palonosetron hydrochloride, in an amount per unit form equivalent to 0.5 mg of palonosetron base;
  • said neostigmine Component (b) is neostigmine bromide in an amount per unit form of from 15 mg to 200 mg, from 17.5 mg to 200 mg, from 35 mg to 200 mg, from 50 mg to 200 mg, from 62.5 mg to 200 mg, from 70 mg to 200 mg and from 100 mg to 200 mg;
  • said Component (a) is a mixture of the NK1 -antagonist fosnetupitant, in an amount per unit form of 235 mg, and of the 5HT3 -antagonist palonosetron hydrochloride, in an amount per unit form equivalent to 0.25 mg of palonosetron base;
  • said neostigmine Component (b) is neostigmine methylsulfate in an amount per unit form of from 0.2 mg to 200 mg, from 17.5 mg to 200 mg, from 35 mg to 200 mg, from 50 mg to 200 mg, from 62.5 mg to 200 mg, from 70 mg to 200 mg and from 100 mg to 200 mg;
  • compositions are mixed together and with a pharmaceutical carrier or vehicle for parenteral administration or for reconstitution in a solution for parenteral, normally intravenous, administration.
  • the above-illustrated pharmaceutical compositions in dosage unit form are preferably administered to a pediatric or adult patient suffering from symptoms of muscle weakness associated with MG or another myasthenic syndrome to provide a neostigmine oral daily dose equivalent to from 1 mg to 1500 mg, and even more, normally from 15 mg to 1200 mg, from 17.5 mg to 1200 mg, from 270 mg to 1200 mg, from 375 mg to 1200 mg or from 450 mg to 1200 mg of neostigmine bromide or for continuous subcutaneous infusion from 10 mg to 500 mg, or 30 mg to 500 mg, or 60 mg to 240 mg of neostigmine methylsulfate.
  • the NK1 -antagonist is formulated in a pharmaceutical composition in dosage unit form, wherein said NK1 -antagonist is in admixture with a pharmaceutical carrier or vehicle.
  • neostigmine is formulated in a pharmaceutical composition in dosage unit form, wherein said neostigmine is in admixture with a pharmaceutical carrier or vehicle.
  • the pharmaceutical compositions are formulated in admixture with a pharmaceutical carrier or vehicle for any administration route.
  • said pharmaceutical compositions are in a pharmaceutical dosage unit form for oral, intravenous (including infusion), intramuscular, intranasal, intraperitoneal, subcutaneous, transdermal, or rectal administration.
  • Transdermal drug delivery system provides transdermal delivery using transdermal drug formulations and transdermal patches incorporating such transdermal drug formulations.
  • the transdermal drug delivery system may include a composition in form of a patch, a cream, a gel, a lotion or a paste comprising a NK1 -antagonist, neostigmine or both the active ingredients.
  • Said unit forms are manufactured according to conventional technologies. Particularly advantageous are the formulations in the form of tablets, multi-score tablets, multi-layer tablets, coated tables, orally disintegrating tablets, extended release tablets, hard or soft capsules, multi-compartment capsules, extended-release capsules, patches for transdermal administration, liquid oral solutions, syrups or suspensions in a predetermined unit form, apparatus for intravenous infusion, and vials for the intravenous or subcutaneous administration.
  • the pharmaceutical compositions may be formulated in oral forms such as tablets or gelatin capsules wherein the NK 1- antagonist or neostigmine or both the active ingredients are in admixture with a carrier or vehicle that may include a diluent, such as cellulose, dextrose, lactose, mannitol, sorbitol or sucrose; a lubricant, such as stearic acid, calcium or magnesium stearate, polyethylene glycol, silica, or talc; and if needed, a binder such as magnesium aluminum silicate, gelatin, methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone.
  • a carrier or vehicle may include a diluent, such as cellulose, dextrose, lactose, mannitol, sorbitol or sucrose; a lubricant, such as stearic acid, calcium or magnesium stearate, polyethylene glycol, silica, or talc; and
  • Said oral forms may be tablets coated with sucrose or with various polymers; or, alternatively, the tablets can be manufactured by using carriers such as acrylic and methacrylic acid polymers and copolymers; cellulose derivatives such as hydroxypropylethylcellulose; or other appropriate materials, to have a prolonged or delayed activity by progressively releasing a predetermined quantity of NK 1- antagonist or of neostigmine, or of both the active ingredients.
  • the oral formulations can also be in form of capsules allowing the extended release of the NK1 -antagonist, or of neostigmine, or of both the active ingredients.
  • the unit forms may be formulated in tablets in which Component (b) is in Extended Release (“ER”)-formulation, for example in admixture with hydroxypropyl methyl cellulose or in a film-coated microgranule.
  • Carriers and vehicles for ER tablets include retardant materials such as acrylic and methacrylic acid polymers and copolymers; the aforementioned cellulose derivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, or sodium carboxymethylcellulose; gums; waxes; glycerides or aliphatic alcohols or a mixture thereof.
  • each unit form may also be a vial containing the pharmaceutical composition a solution, an emulsion, a powder for reconstitution or also an apparatus for continuous infusion of a solution or an emulsion, wherein the active ingredient is dissolved in or mixed with a pharmaceutical carrier for parenteral use.
  • compositions may also be formulated in a TDDS, such as a patch formulation wherein the active ingredient or the mixture of the active ingredients may comprise adjuvants such as D-sorbitol, gelatin, kaolin, methyl paraben, polysorbate 80, propylene glycol, propyl paraben, povidone, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water.
  • a patch formulation may also contain skin permeability enhancer such as lactate esters (e.g., lauryl lactate), triacetin or diethylene glycol monoethyl ether.
  • the preferred NK1 -antagonist active ingredient is aprepitant, fosaprepitant, rolapitant, netupitant-300/palonosetron- 0.5; or fosnetupitant-235/palonosetron-0.25, and the preferred neostigmine is neostigmine bromide.
  • the unit form may be a stratified, bi-layer tablet wherein the NK1 -antagonist, formulated with a pharmaceutical carrier, normally in IR- formulation, is in one of the layers and neostigmine, formulated with a pharmaceutical carrier, is the other layer, preferably in ER-formulation.
  • the NK1 -antagonist and neostigmine active ingredients are in a pill containing one of the active ingredients, admixed with a pharmaceutical carrier, in the core and the other active ingredient, admixed with a pharmaceutical carrier, is in the outer part of the pill, the core and the outer part being optionally separated by an inert film or carrier.
  • capsules made of two separated parts, one containing Component (a), in IR-formulation and the other containing Component (b), in ER- formulation may be manufactured.
  • the NK1 -antagonist daily dose may be decided on the basis of the body weight.
  • aprepitant may be administered at a daily dose of 0.16 mg/kg to 4.2mg/kg and rolapitant may be administered at a daily dose of 0.25 mg/kg to 4.5 mg/kg.
  • neostigmine in combination with a NK1 -antagonist neostigmine is administered by oral route at a dose, including titration doses, equivalent to from 0.25 mg/kg to 2.5 mg/kg of body weight of neostigmine bromide, or by parenteral route at dose equivalent to from 0.03 mg/kg to 6.25 mg/kg, normally from 0.03 mg/kg to 4 mg/kg, of body weight of neostigmine methylsulfate.
  • a dose including titration doses, equivalent to from 0.25 mg/kg to 2.5 mg/kg of body weight of neostigmine bromide, or by parenteral route at dose equivalent to from 0.03 mg/kg to 6.25 mg/kg, normally from 0.03 mg/kg to 4 mg/kg, of body weight of neostigmine methylsulfate.
  • NK1 -antagonists for preventing the adverse effects of orally administered neostigmine bromide in humans was tested.
  • a Phase I study was conducted in six human subjects receiving a single oral dose of neostigmine bromide with or without a single oral dose of aprepitant hydrochloride dihydrate, as a representative NK1 -antagonist. The study was a single center, single-blind, placebo-controlled study.
  • the objective of the study was to demonstrate that aprepitant could safely attenuate the gastro-intestinal side effects of neostigmine given in doses demonstrated to be effective for the treatment of Myasthenia Gravis.
  • Electrolyte abnormalities e.g., hypokalemia or hypomagnesemia
  • congestive heart failure e.g., bradyarrhythmias or other conditions that lead to QT prolongation
  • participants Following a wash-out, participants then received their first intolerable dose of neostigmine plus a single oral dose of aprepitant, (in doses of aprepitant up to l25mg as necessary to prevent or attenuate dose-limiting gastro-intestinal adverse events) or aprepitant placebo.
  • neostigmine On each study day, participants received one single dose of neostigmine. When a subject experienced dose-limiting side effects, the subject was washed out for 7 days, and then received the first intolerable dose of neostigmine together with oral aprepitant, (in doses of aprepitant up to 125 mg as necessary to prevent or attenuate dose-limiting gastro-intestinal adverse events) or aprepitant placebo.
  • Results showed that the co-administration of aprepitant with neostigmine at FID prevented or attenuated gastro-intestinal AEs reported with neostigmine alone at FID.
  • Drachman DB Drachman DB. “ Myasthenia Gravis”. Semin Neurol. 2016; 36:419-424. Epub 2016 Sep 23.

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Abstract

La présente invention concerne l'utilisation d'un antagoniste de NK1, en association constante avec la néostigmine, pour faciliter le traitement d'un patient souffrant de myasthénie grave en fournissant une dose quotidienne de bromure ou de méthylsulfate de néostigmine thérapeutiquement efficace sans effets secondaires gastro-intestinaux limitant la dose.
PCT/US2019/040548 2018-07-09 2019-07-03 Association pharmaceutique de néostigmine pour le traitement de la myasthénie grave WO2020014072A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2023104163A1 (fr) * 2021-12-08 2023-06-15 首都医科大学宣武医院 Système de sélection précise de la dose thérapeutique de tacrolimus pour une myasthénie grave et son utilisation
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