WO2022107125A1 - Method for treatment of parkinson's disease - Google Patents

Method for treatment of parkinson's disease Download PDF

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Publication number
WO2022107125A1
WO2022107125A1 PCT/IL2021/051355 IL2021051355W WO2022107125A1 WO 2022107125 A1 WO2022107125 A1 WO 2022107125A1 IL 2021051355 W IL2021051355 W IL 2021051355W WO 2022107125 A1 WO2022107125 A1 WO 2022107125A1
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WIPO (PCT)
Prior art keywords
levodopa
pharmaceutical composition
patient
carbidopa
administered
Prior art date
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Ceased
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PCT/IL2021/051355
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English (en)
French (fr)
Inventor
Tal Birnberg
Liat Adar
Itay Perlstein
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Neuroderm Ltd
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Neuroderm Ltd
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Publication date
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Priority to KR1020237019830A priority Critical patent/KR20230110542A/ko
Priority to EP21894184.7A priority patent/EP4247357A4/en
Priority to CA3198748A priority patent/CA3198748A1/en
Priority to IL302826A priority patent/IL302826A/en
Priority to CN202180090972.2A priority patent/CN117120045A/zh
Priority to AU2021383322A priority patent/AU2021383322A1/en
Priority to MX2023005725A priority patent/MX2023005725A/es
Priority to JP2023529002A priority patent/JP2023552700A/ja
Publication of WO2022107125A1 publication Critical patent/WO2022107125A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays or needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention provides a method for treatment of neurological or movement disorders such as Parkinson's disease by parenteral administration of levodopa or prodrug thereof and a dopa decarboxylase inhibitor (DDCI) or prodrug thereof, such as carbidopa, benserazide, or any combination thereof, concomitantly with oral administration of levodopa or prodrug thereof, a dopa decarboxylase inhibitor (DDCI) or prodrug thereof, such as carbidopa, benserazide, or any combination thereof.
  • DDCI dopa decarboxylase inhibitor
  • Parkinson's disease is a degenerative condition characterized by reduced concentration of the neurotransmitter dopamine in the brain.
  • Levodopa (L-dopa or L-3,4- dihydroxyphenylalanine) is an immediate metabolic precursor of dopamine that, unlike dopamine, is able to cross the blood-brain barrier, and is most commonly used for restoring the dopamine concentration in the brain.
  • levodopa has remained the most effective therapy for the treatment of Parkinson’s disease.
  • levodopa has a short half-life in plasma that, even under best common current standard of care, results in pulsatile dopaminergic stimulation. Long-term therapy is therefore complicated by motor fluctuations and dyskinesia that can represent a source of significant disability for certain patients.
  • a therapeutic strategy that could ultimately deliver levodopa/dopamine to the brain in a more continuous and physiologic manner would provide the benefits of standard levodopa with reduced motor complications and is much needed by patients suffering from Parkinson’s disease and other neurological or movement disorders.
  • compositions for the treatment of a neurological or movement disorder comprising parenteral administration of levodopa, prodrugs or salts thereof (e.g., pharmaceutically acceptable prodrugs salts thereof), and compositions comprising the same (e.g., pharmaceutically acceptable compositions, for example, liquid pharmaceutical compositions) and a dopa decarboxylase inhibitor (DDCI), prodrugs or salts thereof (e.g., pharmaceutically acceptable prodrugs or salts thereof), and compositions comprising the same e.g., pharmaceutically acceptable compositions, for example, liquid pharmaceutical compositions) concomitant with oral administration of an active agent selected from the group consisting of levodopa, a levodopa salt, a levodopa prodrug, a dopa decarboxylase inhibitor (DDCI), prodrugs or salts thereof (e.g., pharmaceutically acceptable salts thereof), and compositions comprising the same (e.g.,
  • Embodiments of the invention are directed to a method for treatment of Parkinson’s disease in a patient in need thereof, said method comprising: subcutaneously administering to the patient, over a subcutaneous infusion time course of at least about 24 hours, a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in an amount to deliver about 720 mg of levodopa and about 90 mg of carbidopa to the patient over the time course of the at least about 24 hours; and orally administering to the patient, before or during the subcutaneous infusion time course, one or more immediate release tablet or capsule comprising 100 mg levodopa.
  • the pharmaceutically acceptable liquid composition further comprises arginine.
  • the pharmaceutically acceptable liquid composition further comprises at least one antioxidant.
  • the immediate release tablet or capsule further comprises carbidopa.
  • the plasma levodopa area under the curve (AUC) from time 0 to the end of the infusion time of the patient is higher as compared to the combination of i) a plasma levodopa AUC from time 0 to the end of the infusion time when a patient is subcutaneously administered over at least about 24 hours the pharmaceutically acceptable liquid composition alone; and ii) a plasma levodopa AUC of a patient administered with the oral levodopa alone.
  • FIG. 1 For embodiments of the invention, further embodiments of the invention are directed to a method for treatment of Parkinson’s disease in a patient in need thereof, said method comprising: subcutaneously administering to the patient, over a subcutaneous infusion time course of at least about 24 hours or more, a first pharmaceutically acceptable liquid composition comprising: levodopa, carbidopa, arginine, and an antioxidant, in an amount to deliver about 720 mg of levodopa and about 90 mg of carbidopa to the patient over the course of at least about 24 hours; and orally administering to the patient, before or during the subcutaneous infusion time course, at least one oral dosage form comprising levodopa.
  • a first pharmaceutically acceptable liquid composition comprising: levodopa, carbidopa, arginine, and an antioxidant, in an amount to deliver about 720 mg of levodopa and about 90 mg of carbidopa to the patient over the course of at least about 24 hours
  • the oral dosage form includes one of: 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.
  • Further embodiments of the invention are directed to a method for treatment of Parkinson’s disease in a patient currently being administered levodopa and carbidopa in the form of oral immediate release levodopa and carbidopa alone, and in need of further treatment, said method comprising: subcutaneously administering to the patient, over a subcutaneous infusion time course of 24 hours a first pharmaceutically acceptable liquid composition comprising: levodopa, carbidopa, arginine, and an antioxidant, in an amount to deliver about 720 mg of levodopa and about 90 mg of carbidopa to the patient over the course of at least about 24 hours; orally administering to the patient, before or during the subcutaneous infusion time course, at least one tablet or capsule comprising 100 mg levodopa and 25 mg carbidopa daily.
  • a method for treatment of a neurological or movement disorder in a patient in need thereof comprising: parenterally administering to the patient a first pharmaceutical composition comprising: a) levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and b) a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof; and, concomitantly, orally administering to the patient a second pharmaceutical composition comprising an active agent selected from the group consisting of levodopa, a levodopa salt, a levodopa prodrug, a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, and any combination thereof.
  • DDCI dopa decarboxylase inhibitor
  • the method described herein includes a DDCI comprising, consisting of, or consisting essentially of carbidopa, benserazide, or any combination thereof.
  • the method described herein includes the same DDCI in the first pharmaceutical composition as the DDCI in the second pharmaceutical composition.
  • the method described herein includes a different DDCI in the first pharmaceutical composition as the DDCI in the second pharmaceutical composition
  • the method described herein includes as the second pharmaceutical composition levodopa and a DDCI.
  • the method described herein includes the DDCI carbidopa.
  • the method described herein includes subcutaneous, transdermal, intradermal, intravenous, intramuscular, intratracheal, intranasal, intrathecal, intragastric or intraduodenal administration of the first pharmaceutical composition.
  • the method described herein includes subcutaneous administration of the first pharmaceutical composition.
  • the method described herein includes the administration of the pharmaceutical composition to the patient in need thereof via one or more sites.
  • the neurological or movement disorder pertaining to the method described herein includes Parkinson’s disease; secondary parkinsonism, such as drug-induced secondary parkinsonism, neuroleptic induced parkinsonism, postencephalitic parkinsonism, and vascular parkinsonism; motor fluctuations; neurodegenerative disorders; dyskinesia; reduced dopamine levels in the brain; levodopa induced dyskinesia; rapid eye movement sleep behavior disorder (RBD); dystonia; morning akinesia; tremor symptoms, such as essential tremor and drug-induced tremor; myoclonus; chorea, such as drug induced chorea; tics, such as drug induced tics and organic tics; drug induced movement disorder; drug induced akathisia; restless legs syndrome (RLS); stiff-man syndrome; benign shuddering attacks; malignant neuroleptic syndrome
  • UPDRS Unified Parkinson's Disease Rating Scale
  • H&Y Hoehn and Yahr
  • stages 1-2 are considered to be mild or early-stage Parkinson’s disease patients
  • stage 3 is considered to be moderate or mid-stage Parkinson’s disease patients
  • stages 4-5 are considered to be advanced Parkinson’s disease patients.
  • the daily levodopa dose may be defined and changed by the physician from time to time, according to, e.g., clinical findings as well as “trial and error” methods, according to the particular patient’s condition, the response of that patient to the treatment, and the like.
  • the patient may be administered a different daily dose on different days, depending on signs and symptoms, wherein the range of the administered daily dose may be set by the physician, thereby allowing the patient flexibility in treatment. It is noted that physician generally refer to signs as being objective measure and to symptoms as being subjective ones.
  • physician generally refer to signs as being objective measure and to symptoms as being subjective ones.
  • provided herein are methods of treating advancestage Parkinson’s disease patients.
  • methods of treating advanced stage and/or moderate Parkinson’s disease patients are methods for treating patients with motor fluctuations.
  • provided herein are methods for treating Parkinson’s disease patients with motor fluctuations.
  • provided herein are methods of treating Parkinson’s disease patients who require a dose of above about 300 mg levodopa/day, above about 400 mg levodopa/day, above about 500 mg levodopa/day, above about 600 mg levodopa/day, above about 700 mg levodopa/day, above about 800 mg levodopa/day, above about 900 mg levodopa/day, above about 1000 mg levodopa/day.
  • provided herein are methods of treating Parkinson’s disease patients requiring an elevated dose of levodopa at a particular timepoint, e.g. , in the morning, e.g. , towards the end (about the last hour) of a low activity/night period, e.g., in the beginning (about the first hour) of a high activity/day period.
  • a certain rate for high activity/day hours and a different rate for low activity/night hours wherein an elevated dose of levodopa may be administered towards the end of the low activity/night hours, at the end of the low activity/night hours, at the beginning of the high activity/day hours, and the like.
  • Such an elevated dose may be provided by the administration of an oral dose of the second pharmaceutical composition, e.g., at the times referred to above, provided concomitantly with the substantially continuous first pharmaceutical composition.
  • provided herein are methods of treating patients suffering from Parkinson’s disease for a period of more than about 4 years, more than about 5 years, more than about 6 years, more than about 7 years, more than about 8 years, more than about 9 years, or more than about 10 years.
  • provided herein are methods of treating Parkinson’s disease patients suffering from at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, of “off time” per day, wherein “off time” refers to the recurrence of Parkinson’s symptoms between medication doses.
  • the method described herein includes substantial continuous administration of the first pharmaceutical composition.
  • the method described herein includes administration of the second pharmaceutical composition 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times a day.
  • the method described herein includes administration of the second pharmaceutical composition when symptoms from said neurological or movement disorder require said administration.
  • the method described herein includes administration of the second pharmaceutical composition at predefined times, predefined intervals, or both.
  • the method described herein includes administration of the second pharmaceutical composition more than once, wherein the administered dose is the same at all administrations.
  • the method described herein includes administration of the second pharmaceutical composition more than once, wherein the administered dose differs in at least two administrations.
  • the method described herein includes administration of the second pharmaceutical composition in a dose of between about 25mg and about 400mg levodopa or a salt or prodrug thereof, in each administration.
  • the method described herein includes as the first pharmaceutical composition levodopa, carbidopa and arginine or any salt or prodrug thereof.
  • the method described herein includes as the first pharmaceutical composition levodopa, carbidopa, arginine, or any salt or prodrug thereof, and at least one antioxidant.
  • the method described herein includes as the first pharmaceutical composition levodopa, carbidopa, arginine, or any salt or prodrug thereof, and at least two antioxidants.
  • the method described herein includes as the first pharmaceutical composition a composition that comprises levodopa, carbidopa, or any salt or prodrug thereof, and a base selected from the group consisting of arginine, NaOH, tris(hydroxymethyl)aminomethane (TRIS), and any combination thereof.
  • a composition that comprises levodopa, carbidopa, or any salt or prodrug thereof, and a base selected from the group consisting of arginine, NaOH, tris(hydroxymethyl)aminomethane (TRIS), and any combination thereof.
  • the method described herein includes as the first pharmaceutical composition a composition with a pH in the range of between about 6 to about 10, in the range of between about 8 to about 10, in the range of between about 9 to about 10, in the range of between about 9.1 to about 9.8, or about 9.5.
  • the method described herein includes as the first pharmaceutical composition a composition that comprises between about 1 % w/v and about 40% w/v, between about 1% w/v and about 20% w/v, between about 1% w/v and about 10% w/v, between about 2% w/v and about 8% w/v, between about 4% w/v and about 8% w/v, between about 5% w/v and about 7% w/v, or about 6% w/v of levodopa, a levodopa prodrug, a levodopa salt, or any combination thereof.
  • the method described herein includes as the first pharmaceutical composition a composition that comprises between about 0.5% w/v and about 10% w/v, between about 0.5% w/v and about 6% w/v, between about 0.5% w/v and about 4% w/v, between about 0.5% w/v and about 2% w/v, between about 0.5% w/v and about 1% w/v, about 0.75% w/v of carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof.
  • the method described herein includes the antioxidant that is selected from the group consisting of ascorbic acid or a salt thereof, a cysteine, such as N- acetyl cystein, a bisulfite or a salt thereof, glutathione, a tyrosinase inhibitor, a bivalent cation, butylated hydroxy toluene (BHT), beta hydroxy acid (BHA) tocopherol, gentisic acid, tocopherol, tocopherol derivative, thioglycerol, and any combination thereof.
  • a cysteine such as N- acetyl cystein, a bisulfite or a salt thereof, glutathione, a tyrosinase inhibitor, a bivalent cation, butylated hydroxy toluene (BHT), beta hydroxy acid (BHA) tocopherol, gentisic acid, tocopherol, tocopherol derivative, thioglycerol, and any combination thereof.
  • the method described herein includes as the first pharmaceutical composition a composition that comprises between about 0.05% w/v and about 2.0% w/v, between about 0.5% w/v and about 1.5% w/v, about 0.75% w/v, about 0.9% w/v, about 1.0% w/v, about 1.1% w/v, about 1.25% w/v, of an antioxidant or a combination of antioxidants.
  • the method described herein includes as the first pharmaceutical composition a composition that comprises between about 5% w/v and about 30% w/v, between about 10% w/v and 20% w/v, between about 12.5% w/v and 17.5% w/v, about 15% w/v, or about 15.2% w/v base.
  • the method described herein includes administration of the first pharmaceutical composition via one or two sites.
  • the method described herein includes administration of the first pharmaceutical composition at a volume of between about 1ml to about 30ml per site per day, between about 2ml to about 20ml per site per day, between about 3ml to about 10ml per site per day, between about 5ml to about 7ml per site per day, or about 6ml per site per day.
  • a first pharmaceutical composition comprising: levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof; and, a second pharmaceutical composition comprising: levodopa, a levodopa salt, a levodopa prodrug, a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug; or any combination thereof, for use as a combination in the treatment of a neurological or movement disorder, wherein the first pharmaceutical composition is formulated as a parenteral composition and the second pharmaceutical composition is formulated as an oral composition.
  • DDCI dopa decarboxylase inhibitor
  • kits comprising: a first pharmaceutical composition in parenteral form comprising: levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof; a second pharmaceutical composition in oral form comprising: levodopa, a levodopa salt, a levodopa prodrug, a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug; or any combination thereof; and instructions for the concomitant administration of the first pharmaceutical composition and the second pharmaceutical composition for the treatment of a neurological or movement disorder.
  • DDCI dopa decarboxylase inhibitor
  • a method for treatment of a neurological or movement disorder in a patient in need thereof comprising: subcutaneously administering to the patient, over a subcutaneous infusion time course of about 7 to about 10 hours or more (e.g., a time course of about 8 hours), a first pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in an amount to deliver about 100 to 200 mg of levodopa and about 12 to about 50 mg of carbidopa to the patient; and orally administering to the patient, before or during the subcutaneous infusion time course, an immediate release tablet or capsule comprising levodopa and carbidopa.
  • Contemplated immediate release tablets may include for example 50mg, 75mg, lOOmg, 125mg or 150mg levodopa and/or may include 2.5mg, 18.57mg, 25 mg, 31.25mg, 37.5mg or 50mg carbidopa.
  • the method described herein includes an initial and/or concurrent oral administration of the immediate release tablet or capsule with the start of the infusion time course, for example, oral administration of the immediate release tablet or capsule may occur at substantially the same time the infusion administration begins, and/or about 1, 2, 3, 4, or 5 hours after the start of the infusion time course (e.g.
  • a method described herein includes the immediate release tablet or capsule that comprises 100 mg levodopa and 25 mg carbidopa.
  • Methods described herein may include subcutaneous administration of the first pharmaceutically acceptable liquid composition that comprises levodopa and carbidopa in an amount to deliver about 140 to 170 mg of levodopa and about 16 to about 24 mg of carbidopa to the patient.
  • Contemplated first pharmaceutically acceptable liquid composition may include a liquid composition that comprises about 6% by weight levodopa, about 0.75% by weight carbidopa, and about 10% to about 20% by weight arginine.
  • a method described herein may include the concomitant subcutaneous administration of the first composition and the oral administration of the tablet or capsule, wherein the patient’s levodopa area under the curve (AUC) from time 0 to the end of the infusion time is higher as compared to the combination of a patient’s levodopa AUC from time 0 to the end of the infusion time of a patient who is subcutaneously administered the first composition alone and a patient’s levodopa AUC when a tablet or capsule is administered alone, wherein the amount of levodopa administered concomitantly subcutaneously and orally is about the same as the combined amount of the levodopa subcutaneously alone and orally administered alone.
  • AUC area under the curve
  • Also disclosed herein is a method for treatment of a neurological or movement disorder in a patient in need thereof, said method comprising: subcutaneously administering to the patient, over a subcutaneous infusion time course of about 7 to about 10 hours or more, a first pharmaceutically acceptable liquid composition comprising about 6% by weight levodopa and about 0.75% by weight carbidopa to the patient; and orally administering to the patient, before or during the subcutaneous infusion time course, an immediate release tablet or capsule comprising 50mg, 75mg, lOOmg, 125mg, 150mg, 200mg, or 250mg levodopa, and wherein the immediate release tablet or capsule optionally further comprises carbidopa.
  • Also disclosed herein is a method for treatment of a neurological or movement disorder in a patient in need thereof, said method comprising: subcutaneously administering to the patient, over a subcutaneous infusion time course of about 24 hours or more, a first pharmaceutically acceptable liquid composition comprising levodopa and carbidopa in an amount to deliver about 720 mg of levodopa and about 90 mg of carbidopa to the patient over the course of about 24 hours; and orally administering to the patient, before or during the subcutaneous infusion time course, a tablet or capsule, e.g., an immediate release or modified release, such as an extended release, tablet or capsule, comprising levodopa and carbidopa.
  • a tablet or capsule e.g., an immediate release or modified release, such as an extended release, tablet or capsule, comprising levodopa and carbidopa.
  • the method disclosed herein includes administration of the subcutaneous infusion over the course of about 18 hours at a high activity rate and over the course of about 6 hours at a low activity rate, wherein about 691.2mg levodopa and about 86.4mg carbidopa is administered over the course of the high activity 18 hours and about 28.8mg levodopa and 3.6mg carbidopa is administered over the course of the low activity 6 hours.
  • the tablet or capsule is orally administered substantially concurrently with the start of the infusion time course.
  • the tablet or capsule may be administered during the infusion at predefined intervals, or when desired or required, based on feedback, e.g., for the patient, caregiver, physician, sensors, and the like.
  • the intervals at which the tablet or capsule are administered may be substantially the same, or different from one another.
  • a tablet or capsule is orally administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours after the start of the infusion time course, wherein any number of tablets or capsules may be administered, as detailed herein.
  • the tablet or capsule comprises 100 mg levodopa and 25 mg carbidopa.
  • the first pharmaceutically acceptable liquid composition which is administered according to the method of the invention for 24 hours or more, comprises about 6% by weight levodopa, about 0.75% by weight carbidopa, and about 10% to about 20% by weight arginine.
  • the patient’s levodopa area under the curve (AUC) from time 0 to the end of the infusion time is higher than that compared to the combination of a patient’s levodopa AUC from time 0 to the end of the infusion time when a patient is subcutaneously administered the first composition alone together with a patient’s levodopa AUC when a tablet or capsule is administered alone, and when the amount of levodopa administered concomitantly subcutaneously and orally is about the same as the combined amount of the levodopa subcutaneously alone and orally administered alone.
  • the terms “treat,” “treatment,” “treating,” and the like are used herein to generally refer to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partially or completely curing a disease and/or adverse effect attributed to the disease.
  • treatment covers any treatment of a disease in a mammal, particularly a human, and includes: (a) inhibiting the disease, i.e., preventing the disease from increasing in severity or scope; (b) relieving the disease, i.e., causing partial or complete amelioration of the disease; or (c) preventing relapse of the disease, i.e., preventing the disease from returning to an active state following previous successful treatment of symptoms of the disease or treatment of the disease.
  • Preventing includes delaying the onset of clinical symptoms, complications, or biochemical indicia of the state, disorder, disease, or condition developing in a subject that may be afflicted with or predisposed to the state, disorder, disease, or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder, disease, or condition. “Preventing” includes prophylactically treating a state, disorder, disease, or condition in, or developing in, a subject, including prophylactically treating clinical symptoms, complications, or biochemical indicia of the state, disorder, disease, or condition in or developing in a subject.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein interchangeably refer to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration.
  • compositions and “pharmaceutical formulation” as used herein refer to a composition or formulation comprising at least one biologically active compound, for example, levodopa or carbidopa, or a pharmaceutically acceptable salt thereof or a prodrug thereof, formulated together with one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be formed with the conjugates used in the compositions disclosed herein.
  • ‘Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or non-human primates, and humans.
  • the mammal treated in the methods of the invention is a human suffering from neurodegenerative condition, such as Parkinson’s disease.
  • any value provided may also be considered to cover a range of ⁇ 10% of that value, even without the use of the term “about”. This includes the values in the examples section, which may vary according to the utensils and machinery used, the purity of the compounds, etc.
  • liquid refers to any type of fluid, including gels, aqueous and non-aqueous compositions, and the like.
  • composition refers to any type of combined administration of two or more active ingredients, in the same composition, as well as the administration of those active ingredients at the same time, in separate compositions, as well as administering the two or more active ingredients sequentially, consecutively, on the same day, with a predefined period of time separating the administration of the active ingredients from one another, and the like.
  • composition may further be used herein to refer to any type of combined administration of two separate pharmaceutical compositions, wherein each composition may be administered in a different administration route, at different time intervals, doses, etc.
  • one composition may be administered parenterally, e.g., subcutaneously, substantially continuously, while a second composition, administered concomitantly with the first, by oral administration, in a non-continuous manner.
  • a second composition administered concomitantly with the first, by oral administration, in a non-continuous manner.
  • the concomitant administration of two or more separate compositions may be dependent or independent from one another.
  • the period of time during which a composition is administered may be at least about six hours, about eight hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, three days, seven days, two weeks, a month, three months, six months, a year, two years, three years, five years, ten years, etc.
  • physiologically acceptable pH value refers to pH values in the range of between about 4.5 to about 10. It is further noted that when pH values are provided, including in the examples, the values may be in the range of about ⁇ 0.1 and/or ⁇ 10% of the listed value(s), such that if the measured pH is 8.1, the same formulation may be prepared to provide a pH of about 8.0 or 8.2. Such differences may be due to temperature changes, various measuring devices, etc.
  • a neurological disorder is a disorder of the body's nervous system, and the term "movement disorder” as used herein refers to a nervous system condition that causes abnormal voluntary or involuntary movements, or slow, reduced movements.
  • the neurological or movement disorder is Parkinson’s disease; secondary parkinsonism, such as drug-induced secondary parkinsonism, neuroleptic induced parkinsonism, postencephalitic parkinsonism, and vascular parkinsonism; motor fluctuations; neurodegenerative disorders; dyskinesia; reduced dopamine levels in the brain; levodopa induced dyskinesia; rapid eye movement sleep behavior disorder (RBD); dystonia; morning akinesia; tremor symptoms, such as essential tremor and drug-induced tremor; myoclonus; chorea, such as drug induced chorea; tics, such as drug induced tics and organic tics; drug induced movement disorder; drug induced akathisia; restless legs syndrome (RLS); stiff-man syndrome;
  • dopa decarboxylase inhibitor refers to an agent capable of inhibiting the peripheral metabolism of levodopa to dopamine by aromatic L-amino acid decarboxylase, such as carbidopa and benserazide.
  • the terms “morning dose” and “morning oral dose” as used herein, unless specifically mentioned otherwise, or unless would have been understood otherwise by a person skilled in the art, are interchangeable and refer to an oral dosage form comprising levodopa, which is particularly administered in the morning hours, e.g., within 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours of the patient’s waking time, according to some embodiments, the morning dose refers to an oral dosage form comprising levodopa, which is administered within 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes of the patient’s waking hours.
  • the morning oral dose includes one of: 25 mg levodopa, 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.
  • Embodiments of the invention are directed to a method for treatment of a neurological or movement disorder, such as Parkinson’s disease, in a patient in need thereof, wherein the method comprises: parenterally administering a first pharmaceutical composition comprising: levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof; and, concomitantly, orally administering a second pharmaceutical composition comprising: levodopa, a levodopa salt, a levodopa prodrug; a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug; or any combination thereof.
  • DDCI dopa decarboxylase inhibitor
  • the concomitant administration of the first pharmaceutical composition and the second pharmaceutical composition provides a synergistic effect, such that the levodopa blood levels obtained by the concomitant administration are higher than the expected additive effect when providing the first pharmaceutical composition and the second pharmaceutical composition non- concomitantly.
  • the synergism between the first and second pharmaceutical compositions provides an elevation of between about 5% and about 50% in the levodopa blood levels, in comparison to the expected additive values.
  • the synergism between the first and second pharmaceutical compositions provides an elevation of between about 10% and 40% in the levodopa blood levels, between about 15% and 35% in the levodopa blood levels, between about 20% and 40 in the levodopa blood levels, between about 25% and 35% in the levodopa blood levels, or about 30% in the levodopa blood levels, in comparison to the expected additive values.
  • the first pharmaceutical composition comprises levodopa and carbidopa.
  • the second pharmaceutical composition comprises levodopa and carbidopa.
  • the second pharmaceutical composition comprises only levodopa.
  • the first pharmaceutical composition and/or the second pharmaceutical composition comprise (1) levodopa, a levodopa salt, and/ or a levodopa prodrug and/or (2) carbidopa, a carbidopa salt and/or a carbidopa prodrug.
  • the levodopa prodrug is any of the prodrugs disclosed in PCT/IL2020/050960 or US 63/159,236, which are incorporated herein, in their entirety, by reference.
  • the carbidopa prodrug is any prodrug disclosed in JP 2021-037959.
  • the DDCI is carbidopa, a carbidopa prodrug, a carbidopa salt, benserazide, a benserazide prodrug, a benserazide salt, or any combination thereof.
  • the DDCI is carbidopa.
  • the DDCI in the first pharmaceutical composition may be the same or different as the DDCI in the second pharmaceutical composition.
  • the levodopa component in each of the first and second pharmaceutical compositions may be the same or different.
  • both the first pharmaceutical composition and the second pharmaceutical composition comprise levodopa
  • the first pharmaceutical composition may comprise one type of levodopa component, e.g. , a levodopa prodrug and/or a levodopa salt
  • the second pharmaceutical composition comprises a different type of levodopa component, e.g., levodopa.
  • the concentration or amount of each component within the first pharmaceutical composition may be different than the concentration or amount of that component within the second pharmaceutical composition.
  • the first pharmaceutical composition may be administered by any parenteral administration route, e.g., subcutaneously, transdermally, intradermally, intravenously, intramuscularly, intratracheally, intranasally, intrathecally, intragastrically or intraduodenally.
  • the first pharmaceutical composition is administered subcutaneously.
  • the first pharmaceutical composition is liquid.
  • the first pharmaceutical composition is aqueous.
  • the first pharmaceutical composition is administered substantially continuously. According to some embodiments, the first pharmaceutical composition is administered subcutaneously via a designated pump device.
  • Embodiments of a designated pump may be, for example, any of the pump embodiments disclosed in US 62/529,784, US 62/576,362, PCT/IB2018/054962, US 16/027,804, US 16/027,710, US 10,463,787, US 10,463,572, US 10,603,430, US 16/685,364, US 2020/0093984, USD 29/655,583, USD 29/655,587, USD 29/655,589, USD 29/655,591, USD 29/655,592, USD 29/655,594, USD 29/655,597, USD 29/723,714 and US 62/851,903, all of which are incorporated herein by reference in their entirety.
  • the method of the invention comprises administering the first pharmaceutical composition at one site, two sites, or three or more sites, wherein the position of the sites may be changed at any appropriate, possibly predetermined, intervals.
  • the administration via the same site, or the vicinity of that site may be only after a, possibly predefined, period of time.
  • the position of any one of the sites is changed after 12, 24, 36, 48, 60 or 72 hours.
  • the position of the site is changed after 4, 5, 6 or 7 days.
  • the position of the site is changed after two, three or four weeks.
  • the position of the site is changed when required or desired, e.g., according to subjective data received from the patient and/or according to objective data received, e.g., from sensors located at, or in the vicinity of, the injection site(s).
  • the administrated volume and/or the administration rate is identical in all or at least two of the sites. According to other embodiments, the administration rate and/or administrated volume differ from site to site. Each site may be controlled independently or otherwise, all sites may be controlled dependently on one another.
  • the method of the invention comprises subcutaneously administrating the first pharmaceutical composition of the invention over the course of about 5 to about 24 hours or more, for example, from about 5 to about 12 hours or more, from about 7 to about 10 hours or more, or for example, about 8 hours or about 24 hours.
  • the dose of the carbidopa component in the first pharmaceutical composition is between about lOmg and about 25mg per administration, between about lOmg and about 50mg per administration, between about lOmg and about 75mg per administration, between about 12mg and about 25mg per administration, between about 12mg and about 50mg per administration, between about 12mg and about 75mg per administration, between about 15mg and about 25mg per administration, between about 15mg and about 50mg per administration, between about 15mg and about 75mg per administration, between about 25mg and about 50mg per administration, between about 25mg and about 75mg per administration, between about 50mg and about 75mg per administration.
  • the dose of the carbidopa component in the first pharmaceutical composition is about 90mg, for example, administered over the course of about 5 to about 24 hours or more. According to some embodiments, the dose of the carbidopa component in the first pharmaceutical composition is between about 46mg and about 90mg per administration. According to some embodiments, the dose of the carbidopa component in the first pharmaceutical composition is about 90mg, for example, administered over the course of about 24 hours. According to some embodiments, the dose of the carbidopa component in the first pharmaceutical composition is between about 46mg to about 90mg, for example, administered over the course of about 24 hours.
  • the dose of the levodopa component in the first pharmaceutical composition is between about lOmg and about 800mg per administration, between about lOmg and about 25mg per administration, between about 25mg and about 50mg per administration, between about 50mg and about 75mg per administration, between about 75mg and about lOOmg per administration, between about lOOmg and about 150mg per administration, between about 150mg and about 200mg per administration, between about 200mg and about 250mg per administration, between about 250mg and about 300mg per administration, between about 300mg and about 350mg per administration, between about 350mg and about 400mg per administration, between about 400mg and about 450mg per administration, between about 450mg and about 500mg per administration, between about 500mg and 800mg, between about 600mg and about 800mg, between about 700mg and about 800mg, or about 720mg.
  • the dose of the levodopa component in the first pharmaceutical composition is between about 370mg to about 720mg. In certain embodiments, the dose is administered over the course of about 5 to about 24 (e.g., about 7 to about 10, or about 8 hours, or about 24 hours) hours or more. According to some embodiments, the dose of the levodopa component in the first pharmaceutical composition is about 720mg, for example, administered over the course of about 24 hours. According to some embodiments, the dose of the levodopa component in the first pharmaceutical composition is between about 370mg about 720mg, for example, administered over the course of about 24 hours.
  • the dose of the levodopa component in the first pharmaceutical composition is between about 360mg about 720mg, for example, administered over the course of about 24 hours. According to some embodiments, the dose of the levodopa component in the first pharmaceutical composition is about 720 mg at the most.
  • the first pharmaceutical composition is administered in an amount to deliver from about 100 to about 200 mg of levodopa and about 12 to about 50 mg of carbidopa to the patient. In certain embodiments, the first pharmaceutical composition is administered in an amount to deliver from about 140 to about 170 mg of levodopa and about 16 to about 24 mg of carbidopa to the patient. In certain embodiments, the dose is administered over the course of about 5 to about 24 (e.g., about 7 to about 10) hours or more.
  • the first pharmaceutical composition is administered in an amount to deliver from about 650 mg to about 800 mg, e.g., about 720 mg of levodopa and about 80 mg to about 100 mg, e.g., about 90 mg, carbidopa to the patient over the course of about 24 hours.
  • the dose of the carbidopa component in the first pharmaceutical composition is between about 46 mg about 90 mg, for example, administered over the course of about 24 hours.
  • the dose of the carbidopa component in the first pharmaceutical composition is between about 45 mg about 90 mg, for example, administered over the course of about 24 hours.
  • the dose of the carbidopa component in the first pharmaceutical composition is about 90 mg at the most.
  • the method of the invention comprises subcutaneously administrating between about 1 to about 30 ml of the first pharmaceutical composition of the invention over the course of 24 hours.
  • the method of invention comprises subcutaneously administrating between about 1ml to about 2ml, between about 2ml to about 3ml, between about 3ml to about 4ml, between about 4ml to about 5ml, between about 5ml to about 6ml, between about 6ml to about 7ml, between about 7ml to about 8ml, between about 8ml to about 9ml, between about 9ml to about 10ml, between about 10ml to about 11ml, between about 11ml to about 12ml, between about 12ml to about 13ml, between about 13ml to about 14ml, between about 14ml to about 15ml between about 15ml to about 16ml, between about 16ml to about 17ml, between about 17ml to about 18ml, between about 18ml to about 19
  • the first pharmaceutical composition is administered at a volume of between about 1ml to about 30ml per site per day, between about 2ml to about 20ml per site per day, between about 3ml to about 10ml per site per day, between about 5ml to about 7ml per site per day, or about 6ml per site per day.
  • the first pharmaceutical composition is administered at a volume of between about 1ml to about 2.5ml per site per day, between about 2.5ml to about 5.0ml per site per day, between about 5.0ml to about 7.5ml per site per day, between about 7.5ml to about 10ml per site per day, between about 10ml to about 12.5ml per site per day, between about 12.5ml to about 15ml per site per day, between about 15ml to about 17.5ml per site per day, between about 17.5ml to about 20ml per site per day, between about 20ml to about 22.5ml per site per day, between about 22.5ml to about 25ml per site per day, between about 25ml to about 27.5ml per site per day, between about 27.5ml to about 30ml per site per day.
  • the first pharmaceutical composition is administered at a volume of about 6 ml per site per day.
  • the administration rate may be constant over the course of 24 hours or may change over the course of 24 hours.
  • the high activity/day hours may be, e.g., about 15, about 16, about 17, about 18 or about 19 hours, while the low activity night hours may be about 9, about 8, about 7, about 6 or about 5 hours, respectively.
  • the high activity/day rate is implemented for about 18 hours, while the low activity/night rate is implemented for about 6 hours.
  • the high activity/day rate is implemented for about 16 hours, while the low activity/night rate is implemented for about 8 hours.
  • the administration rate is at least partially determined by input received from the patient, a caregiver, at least one sensor and the like.
  • the administration rate may be elevated when necessary or decreased when necessary according to a predefined pattern that may be set periodically, e.g., by a caregiver or the patient.
  • the administration rate may be altered, e.g., elevated or decreased, in an on-line manner, for example, according input received from the patient, a caregiver, or at least one sensor, indicating that a change in administration rate is required or beneficial. For instance, if the patient wishes to rest at a certain point during the day, the rate may be decreased from day to night rate, e.g., by a command provided by the patient.
  • a caregiver may give a command to the system in view of the patient, e.g., resting during the day.
  • a sensor may alert the system that the patient has gone to sleep (or fallen asleep) and decrease the administration rate accordingly.
  • Sensors may also provide sleep pattern data, allowing the system to be notified in advance of the patient awaking from sleep, and in response, e.g., elevating the administration rate.
  • the patient’s monitored condition may also cause the administration rate to be altered, e.g., lapsing into an “off episode” and the like, may cause the administration rate to be raised.
  • the administration rate may be between about 0.01 mL/site/hour to about 1 mL/site/hour. According to some embodiments, the administration rate is between about 0.01-0.02 mL/site/hour. According to some embodiments, the administration rate is between about 0.02-0.03 mL/site/hour. According to some embodiments, the administration rate is between about 0.03-0.04 mL/site/hour. According to some embodiments, the administration rate is between about 0.04-0.05 mL/site/hour. According to some embodiments, the administration rate is between about 0.05-0.06 mL/site/hour. According to some embodiments, the administration rate is between about 0.06-0.07 mL/site/hour.
  • the administration rate is between about 0.07-0.08 mL/site/hour. According to some embodiments, the administration rate is between about 0.08-0.09 mL/site/hour. According to some embodiments, the administration rate is between about 0.09-0.1 mL/site/hour. According to some embodiments, the administration rate is between about 0.1-0.15 mL/site/hour. According to some embodiments, the administration rate is between about 0.15-0.2 mL/site/hour. According to some embodiments, the administration rate is between about 0.2-0.25 mL/site/hour. According to some embodiments, the administration rate is between about 0.25-0.3 mL/site/hour.
  • the administration rate is between about 0.3-0.35 mL/site/hour. According to some embodiments, the administration rate is between about 0.35-0.4 mL/site/hour. According to some embodiments, the administration rate is between about 0.4-0.45 mL/site/hour. According to some embodiments, the administration rate is between about 0.45-0.5 mL/site/hour. According to some embodiments, the administration rate is between about 0.5-0.55 mL/site/hour. According to some embodiments, the administration rate is between about 0.55-0.6 mL/site/hour. According to some embodiments, the administration rate is between about 0.6-0.65 mL/site/hour. According to some embodiments, the administration rate is between about 0.65-0.7 mL/site/hour.
  • the administration rate is between about 0.7-0.75 mL/site/hour. According to some embodiments, the administration rate is between about 0.75-0.8 mL/site/hour. According to some embodiments, the administration rate is between about 0.8-0.85 mL/site/hour. According to some embodiments, the administration rate is between about 0.85-0.9 mL/site/hour. According to some embodiments, the administration rate is between about 0.9-0.95 mL/site/hour. According to some embodiments, the administration rate is between about 0.95-1.0 mL/site/hour. [0093] According to some embodiments, the administration rate in the low activity/night hours is between about 0.01-0.15 mL/site/hour.
  • the administration rate in the low activity/night hours is between about 0.01-0.02 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.02-0.03 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.03-0.04 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.04-0.05 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.05-0.06 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.06- 0.07 mL/site/hour.
  • the administration rate in the low activity/night hours is between about 0.07-0.08 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.08- 0.09 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.09-0.1 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.1- 0.11 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.11-0.12 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.12- 0.13 mL/site/hour.
  • the administration rate in the low activity/night hours is between about 0.13-0.14 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.14- 0.15 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is about 0.04 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is about 0.08 mL/site/hour.
  • the administration rate in the high activity/day hours is between about 0.15-1.0 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.15-0.2 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.2-0.25 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.25-0.3 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.3-0.35 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.35-0.4 mL/site/hour.
  • the administration rate in the high activity/day hours is between about 0.4-0.45 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.45-0.5 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.5-0.55 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.55-0.6 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.6-0.65 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.65-0.7 mL/site/hour.
  • the administration rate in the high activity/day hours is between about 0.7-0.75 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.75-0.8 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.8-0.85 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.85-0.9 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.9-0.95 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.95-1.0 mL/site/hour.
  • the administration rate in the high activity/day hours is about 0.32 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.32 mL/hour and about 0.64 mL/hour.
  • the low and high rates are referred to as night and day rates, respectively, they may be used irrespective of the time of day; rather, of the condition of the patient and the like, e.g. , low activity and high activity. Further, the rate may be altered gradually, and may be set at any appropriate value, not necessarily bound to one particular high rate and one particular low rate.
  • the first composition is administered over the course of about 12 to about 20 hours (e.g., about 18 hours) at a high activity rate and about 4 to about 12 hours e.g., about 6 hours) at a low activity rate, wherein about 500mg to about 800mg (e.g., about 700mg or about 691.2mg) levodopa and about 60mg to about lOOmg e.g., about 80mg or about 86.4mg) is administered over the course of the high activity and about 20mg to about 40mg (e.g., about 30mg or about 28.8mg) levodopa and about 2mg to about 5mg (e.g., about 3mg or about 3.6mg) carbidopa is administered over the course of the low activity.
  • about 500mg to about 800mg e.g., about 700mg or about 691.2mg
  • levodopa e.g., about 60mg to about l
  • the high activity rate and/or the low activity rate may be a consecutive time period in the course of 24 hours. According to other embodiments, the high activity rate and/or the low activity rate may be administered at several, non-consecutive time periods over the course of 24 hours.
  • the administrated volume and/or administration rate may be constant throughout the treatment, or may vary during different hours of the day, between different days, weeks or months of treatment, and the like.
  • the patient is monitored, e.g., independently, by a caretaker, or electronically, e.g., by sensors, possibly found in a dedicated device, e.g., a watch-like device, patch-like sensor, the administration pump, and the like.
  • the administration volume and/or rate are determined according to data received from such monitoring.
  • the bolus injection comprises between about 0.5 to about 2.0 mL/Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.5 to about 0.75 mL/Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.75 to about 1.0 mL/Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.0 to about 1.25 mL/Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.25 to about 1.5 mL/Kg of the first pharmaceutical composition.
  • the bolus injection comprises between about 1.5 to about 1.75 mL/Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.75 to about 2.0 mL/Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.75 to about 1.25 mL/Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises about 1.0 mL/Kg of the first pharmaceutical composition.
  • the bolus subcutaneous injection may be administered at any time point in relation to any possible continuous subcutaneous administrations, e.g., prior to, during, or after the continuous administration.
  • the bolus subcutaneous injection may be administered at any time point during the day.
  • the bolus subcutaneous injection may be administered once a day, once every two, three, four five or six days, once a week, or more.
  • the bolus subcutaneous injection may be administered when required/desired, according to feedback received from the patient, caretaker, physician, sensors, and the like, and/or according to a predefined regimen.
  • the bolus subcutaneous injection may be administered over between about five minutes to about 40 minutes, between about five minutes to about 10 minutes, between about 10 minutes to 15 minutes, between about 15 minutes to 20 minutes, between about 20 minutes to 25 minutes, between about 25 minutes to 30 minutes, between about 30 minutes to 35 minutes, between about 35 minutes to 40 minutes.
  • the administered dose may be doubled, tripled or more, by using more than one pump, more than one injection site for each pump, and the like.
  • the first pharmaceutical composition is administered for a defined period of time, e.g., days, weeks, months, or years. According to some embodiments, the first pharmaceutical composition is administered endlessly, for the treatment of a chronic condition.
  • the first pharmaceutical composition comprises between about 1 % w/v and about 40% w/v of levodopa, a levodopa prodrug, a levodopa salt, or any combination thereof.
  • the first pharmaceutical composition comprises between about 1% w/v and about 5% w/v, between about 5% w/v and about 10% w/v, between about 10% w/v and about 15% w/v, between about 15% w/v and about 20% w/v, between about 20% w/v and about 25% w/v, between about 25% w/v and about 30% w/v, between about 30% w/v and about 35% w/v, between about 35% w/v and about 40% w/v, between about 2% w/v and about 10% w/v, between about 4% w/v and about 8% w/v, between about 5% w/v and about 7% w/v, about 6% w/v of levodopa, a levodopa prodrug, a levodopa salt, or any combination thereof.
  • the first pharmaceutical composition comprises between about 0.5% w/v and about 10% w/v of carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof.
  • the first pharmaceutical composition comprises between about 0.5% w/v and about 1% w/v, between about 1% w/v and about 1.5% w/v, between about 1.5% w/v and about 2% w/v, between about 2% w/v and about 2.5% w/v, between about 2.5% w/v and about 3% w/v, between about 3% w/v and about 3.5% w/v, between about 3.5% w/v and about 4% w/v, between about 4% w/v and about 4.5% w/v, between about 4.5% w/v and about 5% w/v, between about 5% w/v and about 5.5% w/v, between about 5.5% w/v and about 6%
  • a first pharmaceutical composition suitable for parenteral (e.g., subcutaneous) administration includes about 4-10% by weight levodopa, about 0.5 to about 2% by weight carbidopa, and about 10% to about 20% by weight arginine.
  • Another exemplary first pharmaceutical composition provided herein includes about 6% by weight levodopa, about 0.75% by weight carbidopa, and about 10% to about 20% by weight arginine.
  • the first pharmaceutical composition comprises between about 0.05% w/v and about 2.0% w/v, between about 0.05% w/v and about 0.1% w/v, between about 0.1% w/v and about 0.2% w/v, between about 0.2% w/v and about 0.3% w/v, between about 0.3% w/v and about 0.4% w/v, between about 0.4% w/v and about 0.5% w/v, between about 0.5% w/v and about 0.6% w/v, between about 0.6% w/v and about 0.7% w/v, between about 0.7% w/v and about 0.8% w/v, between about 0.8% w/v and about 0.9% w/v, between about 0.9% w/v and about 1.0% w/v, between about 1% w/v and about 1.1% w/v, between about 1.1% w/v and about 1.2% w/v, between about 1.2% w/v and about 1.3% w/v,
  • the antioxidant is selected from the group consisting of ascorbic acid or a salt thereof, a cysteine, such as N-acetyl cysteine, a bisulfite or a salt thereof, glutathione, a tyrosinase inhibitor, a bivalent cation, butylated hydroxy toluene (BHT), beta hydroxy acid (BHA) tocopherol, gentisic acid, tocopherol, tocopherol derivative, thioglycerol, and any combination thereof.
  • the antioxidant is ascorbic acid.
  • the antioxidant is N-acetyl cysteine (NAC).
  • the first pharmaceutical composition comprises a combination of ascorbic acid and NAC.
  • a first pharmaceutical composition suitable for e.g., subcutaneous administration, that includes about 0.1% to about 10% by weight ascorbic acid or a pharmaceutically acceptable salt thereof, about 0.01% to about 1% by weight of a component selected from the group consisting of: NAC, L-cysteine and pharmaceutically acceptable salts thereof; about 2% to about 16% by weight levodopa or an ester thereof; and about 0.6% to about 2% by weight carbidopa or an ester thereof.
  • the first pharmaceutical composition comprises a base.
  • the base is selected from the group consisting of arginine, NaOH, tris(hydroxymethyl)aminomethane (TRIS), NH4OH, ethylendiamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof.
  • the base is arginine.
  • the first pharmaceutical composition comprises between about 5% w/v and about 30% w/v or a base. According to some embodiments, the first pharmaceutical composition comprises between about 5% w/v and about 10% w/v, between about 10% w/v and about 15% w/v, between about 15% w/v and about 20% w/v, between about 20% w/v and about 25% w/v, between about 25% w/v and about 30% w/v, between about 12.5% w/v and 17.5% w/v, or about 15% w/v, or about 15.2% w/v base. [00109] According to some embodiments, the first pharmaceutical composition comprises a surfactant.
  • the surfactant is selected from Tween-80, Tween-60, Tween-40, Tween-20, Tween-65, Tween-85, Span 20, Span 40, Span 60, Span 80, Span 85, polyoxyl 35 castor oil (Cremophor EL), polyoxyethylene-660- hydroxystearate (macrogol 660), or Poloxamer 188 (Pluronic® F-68), or any combination thereof.
  • the first pharmaceutical composition of the invention may include between about 0.1 to about 3.0 % w/v of a surfactant or combination of two or more surfactants.
  • the first pharmaceutical composition comprises between about 0.1 to about 0.2 % w/v, between about 0.2 to about 0.3 % w/v, between about 0.3 to about 0.4 % w/v, between about 0.4 to about 0.5 % w/v, between about 0.5 to about 0.6 % w/v, between about 0.6 to about 0.7 % w/v, between about 0.7 to about 0.8 % w/v, between about 0.8 to about 0.9 % w/v, between about 0.9 to about 1.0 % w/v, between about 1.0 to about 1.5 % w/v, , between about 1.5 to about 2.0 % w/v, between about 2.0 to about 2.5 % w/v, between about 2.5 to about 3.0 % w/v of a surfactant or combination of two or more surfactants.
  • the first pharmaceutical composition may further comprise an additional pharmaceutically acceptable excipient, such as N-methylpyrrolidone (NMP), polyvinylpyrrolidone (PVP), propylene glycol, a preservative, a pharmaceutically acceptable vehicle, a stabilizer, a dispersing agent, a suspending agent, an amino sugar, a calcium chelator, protease inhibitors, or any combination thereof.
  • NMP N-methylpyrrolidone
  • PVP polyvinylpyrrolidone
  • propylene glycol a preservative
  • a pharmaceutically acceptable vehicle such as NMP
  • PVP polyvinylpyrrolidone (PVP)
  • PVP polyvinylpyrrolidone
  • propylene glycol such as propylene glycol
  • a preservative such as N-methylpyrrolidone (NMP), polyvinylpyrrolidone (PVP), propylene glycol
  • a preservative such as N-methylpyrrolidone (N
  • a pharmaceutically acceptable first composition that includes about 6% by weight levodopa, about 0.75% by weight carbidopa, about 10% to about 20% by weight arginine, about 0.5% by weight of L-cysteine or NAC, and /or about 0.5% by weight ascorbic acid or a salt thereof.
  • An exemplary pharmaceutical first composition e.g., formulation A) may include about 6% by weight levodopa, about 0.75% by weight carbidopa, and about 14% to about 16% by weight arginine.
  • the first pharmaceutical composition of the invention comprises between about 5.0 to about 10.0 % w/v, between about 10.0 to about 15.0 % w/v, between about 15.0 to about 20.0 % w/v, between about 20.0 to about 25.0 % w/v, between about 25.0 to about 30.0 % w/v, between about 30.0 to about 35.0 % w/v, between about 35.0 to about 40.0 % w/v, between about 40.0 to about 45.0 % w/v, between about 45.0 to about 50.0 % w/v, between about 50.0 to about 55.0 % w/v, between about 55.0 to about 60.0 % w/v, between about 60.0 to about 65.0 % w/v,
  • the first pharmaceutical composition further comprises a buffer.
  • the buffer is selected from citrate buffer, citric acid buffer, sodium acetate buffer, acetic acid buffer, tartaric acid buffer, phosphate buffer, succinic acid buffer, Tris buffer, glycine buffer, hydrochloric acid buffer, potassium hydrogen phthalate buffer, sodium buffer, sodium citrate tartrate buffer, sodium hydroxide buffer, sodium dihydrogen phosphate buffer, disodium hydrogen phosphate buffer, tromethamine (TRIS), or any combination thereof.
  • the first pharmaceutical composition may comprise between about 0.1 to about 30.0 % w/v of a buffer.
  • the first pharmaceutical composition comprises between about 0.1 to about 1.0 % w/v, between about 1.0 to about 2.0 % w/v, between about 2.0 to about 3.0 % w/v, between about 3.0 to about 4.0 % w/v, between about 4.0 to about 5.0 % w/v, between about 5.0 to about 6.0 % w/v, between about 6.0 to about 7.0 % w/v, between about 8.0 to about 9.0 % w/v, between about 9.0 to about 10.0 % w/v, between about 10.0 to about 15.0 % w/v, between about 15.0 to about 20.0 % w/v, between about 20.0 to about 25.0 % w/v, between about 25.0 to about 30.0 % w/v of a buffer.
  • the first pharmaceutical compositions further comprises an acid or a base, e.g., in order to provide a composition with a pre-defined pH.
  • the acid is selected from HC1, HBr, methanesulfonic acid, ascorbic acid, acetic acid, citric acid, or any combination thereof.
  • the base is selected from NaOH, Ca(OH)2, ammonium hydroxide, arginine, magnesium hydroxide, potassium hydroxide, meglumine, tromethamine (TRIS), triethylamine, diisopropylethylamine, diazabicycloundecene or any combination thereof.
  • the first pharmaceutical compositions may comprise between about 0.1 to about 30.0 % w/v of a base or acid.
  • the first pharmaceutical composition comprises between about 0.1 to about 1.0 % w/v, between about 1.0 to about 2.0 % w/v, between about 2.0 to about 3.0 % w/v, between about 3.0 to about 4.0 % w/v, between about 4.0 to about 5.0 % w/v, between about 5.0 to about 6.0 % w/v, between about 6.0 to about 7.0 % w/v, between about 8.0 to about 9.0 % w/v, between about 9.0 to about 10.0, between about 10.0 to about 11.0, between about 11.0 to about 12.0, between about 12.0 to about 13.0, between about 13.0 to about 14.0, between about 14.0 to about 15.0, between about 15.0 to about 16.0, between about 16.0 to about 17.0, between about 17.0 to about 18.0, between about 18.0 to about 19.0, between about 19.0 to about 20.0
  • the pH of the first pharmaceutical composition of the invention may be between about 4.5 to about 10 at about 25°C. According to some embodiments, the pH of the first pharmaceutical compositions is between about 4.5 to about 5 at about 25 °C. According to some embodiments, the pH of the first pharmaceutical compositions is between about 5 to about 6 at about 25°C. According to some embodiments, the pH of the first pharmaceutical compositions is between about 6 to about 7 at about 25 °C. According to some embodiments, the pH of the first pharmaceutical compositions is between about 7 to about 8 at about 25°C. According to some embodiments, the pH of the first pharmaceutical compositions is between about 8 to about 9 at about 25 °C.
  • the pH of the first pharmaceutical compositions is between about 9 to about 10 at about 25°C. According to some embodiments, the pH of the first pharmaceutical compositions is between about 4.5 to about 5.5 at about 25°C. According to some embodiments, the pH of the first pharmaceutical compositions is between about 5.5 to about 6.5 at about 25°C. According to some embodiments, the pH of the first pharmaceutical compositions is between about 6.5 to about 7.5 at about 25°C. According to some embodiments, the pH of the first pharmaceutical compositions is between about 7.5 to about 8.5 at about 25°C. According to some embodiments, the pH of the first pharmaceutical compositions is between about 8.5 to about 9.5 at about 25°C.
  • the pH of the first pharmaceutical compositions is between about 9.5 to about 10 at about 25 °C. According to some embodiments, the pH of the first pharmaceutical compositions is about 9.5 at about 25°C.
  • an acid or a base is added to the first pharmaceutical composition in order to provide a composition with a predefined pH value.
  • the acid is selected from HC1, HBr, methanesulfonic acid, ascorbic acid, acetic acid, citric acid, or any combination thereof.
  • the base is selected from NaOH, arginine, an amine base, any of the bases mentioned herein, and any combination thereof.
  • the second pharmaceutical composition is administered when desired and/or required, e.g., when symptoms from said neurological or movement disorder require such administration, or according to a predefined treatment protocol.
  • the assessment of the timing for administering the second pharmaceutical composition may be performed by a caretaker, a physician, the patient to whom the composition is being administered, or any combination thereof, resulting from consultation and/or joint decision making, and the like.
  • a system supported by any type of sensors may provide data for determining the need for administering the second pharmaceutical composition. That data may be delivered to a caretaker, a physician, the patient, or any combination thereof, via any means, such as an electronic device, e.g., a smartphone, dedicated console, tablet, email, dedicated or known application, and the like.
  • the second pharmaceutical composition is administered at predefined times, predefined intervals, or both, set, e.g., according to treatment protocols or according to data received from the patient, caregiver, physician, sensors, and the like.
  • the predetermined times and/or intervals may be reset at any time point, e.g., in view of data received from the patient, caretaker, sensors, physician assessment, and the like.
  • the second pharmaceutical composition is orally administered substantially concurrently with the start of the infusion time course.
  • the second pharmaceutical composition is orally administered about 1, 2, 3, 4, or 5 hours after the start of the infusion time course.
  • start of the infusion time course may be a daily time, wherein the cycle of the infusion, e.g., when new vials are introduced into the system, when a cartridge is replaced, when an infusion set is replaced, and the like.
  • the orally administered second pharmaceutical composition is a morning oral dose.
  • the morning oral dose comprises levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof.
  • the morning oral dose includes one of: 25 mg levodopa, 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.
  • the morning oral dose comprises (a) levodopa, a levodopa salt, a levodopa prodrug; (b) a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or (c) any combination thereof
  • the second pharmaceutical composition is administered up to 20 times a day. According to some embodiments, the second pharmaceutical composition is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 times a day. According to some embodiments, the second pharmaceutical composition is administered between about 3 and 7 times a day. According to some embodiments, the second pharmaceutical composition is administered between about 4 and 6 times a day. According to some embodiments, the second pharmaceutical composition is administered at a frequency of between about 30 minutes to about 24 hours.
  • the second pharmaceutical composition is administered at a frequency of between about 30 minutes to about one hour, between about one hour to two hours, between about two hours to three hours, between about three hours to about four hours, between about four hours to about five hours, between about five hours to about six hours, between about six hours to seven five hours, between about seven hours to about eight hours, between about eight hours to about nine hours, between about nine hours to about 10 hours, between about 10 hours to about 11 hours, between about 11 hours to about 12 hours, between about 12 hours to about 13 hours, between about 13 hours to about 14 hours, between about 14 hours to about 15 hours, between about 15 hours to about 16 hours, between about 16 hours to about 17 hours, between about 17 hours to about 18 hours, between about 18 hours to about 19 hours, between about 19 hours to about 20 hours, between about 20 hours to about 21 hours, between about 21 hours to about 22 hours, between about 22 hours to about 23 hours, between about 23 hours to about 24 hours.
  • intervals between one administration to the next may differ as well, depending, e.g., on the patient’ s/caretaker’s/physician’s observations and assessment, on data received from any type of appropriate sensor, on a predefined treatment protocol, any combination thereof, and the like.
  • the administered dose of the levodopa component in the second pharmaceutical composition is the same each time it is administered. According to some embodiments, the dose of the levodopa component in the second pharmaceutical composition may differ between different administrations.
  • the dose of the levodopa component in the second pharmaceutical composition is between about lOmg per day and about 3000mg per day, between about lOmg per day and about 50mg per day, between about 50mg per day and about lOOmg per day, between about lOOmg per day and about 150mg per day, between about 150mg per day and about 250mg per day, between about 250mg per day and about 350mg per day, between about 350mg per day and about 500mg per day, between about 500mg per day and about 750mg per day, between about 750mg per day and about lOOOmg per day, between about lOOOmg per day and about 1250mg per day, between about 1250mg per day and about 1500mg per day, between about 1500mg per day and about 1750mg per day, between about 1750mg per day and about 2000mg per day, between about 2000mg per day and about 2250mg per day,
  • the dose of the levodopa component in the second pharmaceutical composition is between about lOOmg per day to about 1800 mg per day. According to some embodiments, the dose of the levodopa component in the second pharmaceutical composition is between about 350mg per day to about 700 mg per day.
  • an administered dose is defined according to the time in which the composition is administered to the patient, and therefore, if several tablets, e.g., 4 tablets, each comprising lOOmg of levodopa are administered to the patient at practically the same time, the administered dose of the levodopa in the second pharmaceutical composition would be considered to be 400mg in such an instance.
  • the dose per day may consist of several administered doses, not necessarily identical to one another, e.g., a patient may be administered 100 mg at 8am, 200mg at 10am, lOOmg at 3pm and 75mg at 7pm, such that the dose of the levodopa component in the second pharmaceutical composition would be considered to be 475mg per day.
  • the dose of the levodopa component in the second pharmaceutical composition is between about lOmg and about 500mg per administration, between about lOmg and about 25mg per administration, between about 25mg and about 50mg per administration, between about 50mg and about 75mg per administration, between about 75mg and about lOOmg per administration, between about lOOmg and about 150mg per administration, between about 150mg and about 200mg per administration, between about 200mg and about 250mg per administration, between about 250mg and about 300mg per administration, between about 300mg and about 350mg per administration, between about 350mg and about 400mg per administration, between about 400mg and about 450mg per administration, between about 450mg and about 500mg per administration.
  • the dose differs between different administrations.
  • the dose remains constant for at least two administrations, e.g., over the course of 24 hours, three days, one
  • the dose of the levodopa component in the second pharmaceutical composition is about 50mg, 75mg, lOOmg, 125mg, 150mg, 200mg, or 250mg levodopa, e.g., in an immediate release tablet or capsule.
  • the dose of the levodopa component in the second pharmaceutical composition is about 95mg, about 145mg, about 195 mg, or about 245 mg levodopa, e.g., in an extended release form, e.g., a tablet or capsule.
  • the levodopa component may be levodopa, a levodopa salt, a levodopa prodrug or any combination thereof. According to some embodiments, the levodopa component is levodopa.
  • the dose of the carbidopa component in the second pharmaceutical composition is between about 2.5mg and about 50mg per administration, between about 2.5mg and about 20mg per administration, between about 2.5mg and about 25mg per administration, between about 2.5mg and about 35mg per administration, between about 2.5mg and about 40mg per administration, between about 15mg and about 20mg per administration, between about 15mg and about 25mg per administration, between about 15mg and about 35mg per administration, between about 15mg and about 40mg per administration, between about 15mg and about 50mg per administration, between about 20mg and about 25mg per administration, between about 20mg and about 35mg per administration, between about 20mg and about 40mg per administration, between about 20mg and about 50mg per administration, between about 25mg and about 35mg per administration, between about 25mg and about 40mg per administration, between about 25mg and about 35mg per administration, between about 25mg and about 40mg per administration, between about 25m
  • the second pharmaceutical composition may be in any appropriate oral form, such as a pill, hard or soft capsule, tablet, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups or elixirs.
  • the second pharmaceutical composition may an immediate release form, or any type of controlled release form, such as sustained release, extended release, delayed release, prolonged release, and the like.
  • the second pharmaceutical composition may comprise at least two active ingredients, e.g., levodopa and carbidopa.
  • each one of the active ingredients in the second pharmaceutical composition may be formulated in a different release form, for instance, the levodopa may be in a controlled release form, while the carbidopa is in an immediate release form, or vice versa.
  • the second pharmaceutical formulation is administered only during high activity/waking hours, e.g., during the day, such that the administration intervals are smaller during high activity/waking hours than during other parts of the day, e.g. , low activity/night hours.
  • the doses of the second pharmaceutical formulation provided during high activity/waking hours are higher than the doses administered during other parts of the day, e.g., low activity/night hours.
  • a dosing regimen over 24 hours is devised and may remain constant for a certain number of days, while, within the same day the regimen may be different based on wakefulness, activity, and the like. According to some embodiments, the dosing regimen may change from day to day, as well as within the same day.
  • Embodiments of the invention are further directed to a method for treatment of a neurological or movement disorder, such as Parkinson’s disease, in a patient in need thereof, wherein the method comprises: parenterally administering a first pharmaceutical composition comprising: levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof; and, concomitantly, orally administering a morning oral dose composition comprising: levodopa, a levodopa salt, a levodopa prodrug; a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug; or any combination thereof.
  • a neurological or movement disorder such as Parkinson’s disease
  • FIG. 1 For embodiments of the invention are directed to a first pharmaceutical composition comprising: levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof; and, a second pharmaceutical composition comprising: levodopa, a levodopa salt, a levodopa prodrug; a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug; or any combination thereof, for use as a combination in the treatment of a neurological or movement disorder, for example, Parkinson’s disease, wherein the first pharmaceutical composition is formulated as a parenteral composition and the second pharmaceutical composition is formulated as an oral composition.
  • DDCI dopa decarboxylase inhibitor
  • kits comprising: a first pharmaceutical composition in parenteral form comprising: levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof; a second pharmaceutical composition in oral form comprising: levodopa, a levodopa salt, a levodopa prodrug; a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug; or any combination thereof; and instructions for the concomitant administration of the first pharmaceutical composition and the second pharmaceutical composition for the treatment of a neurological or movement disorder, such as Parkinson’s disease.
  • a neurological or movement disorder such as Parkinson’s disease.
  • kits comprising: a first pharmaceutical composition in parenteral form comprising: levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof; and instructions for the concomitant administration of the first pharmaceutical composition and a second pharmaceutical composition for the treatment of a neurological or movement disorder, such as Parkinson’s disease, wherein the second pharmaceutical composition is provided separately.
  • DDCI dopa decarboxylase inhibitor
  • Further embodiments of the invention are directed to a method of treating Parkinson’s disease in a patient in need thereof, wherein the patient was previously administered a previous form of levodopa other than immediate release carbidopa-levodopa tablets in a ratio of 1:4, and wherein the method comprises: converting the patient from the previous form of levodopa to oral immediate release levodopa-carbidopa 100/25mg tablets; subcutaneously administering to the patient, over a subcutaneous infusion time course of at least about 24 hours or more, a first pharmaceutically acceptable liquid composition comprising levodopa; and orally administering to the patient, before or during the subcutaneous infusion time course, at least one oral dosage form comprising levodopa.
  • Further embodiments of the invention are directed to a method of treating Parkinson’s disease in a patient in need thereof, wherein the patient was previously administered a previous form of levodopa, and wherein the method comprises: converting the patient from the previous form of levodopa to an oral immediate release levodopa form, thus administering an amount of oral immediate release levodopa to said patient; following said conversion, subcutaneously administering to the patient, over a subcutaneous infusion time course of at least about 24 hours or more, a first pharmaceutically acceptable liquid composition comprising a subcutaneous amount of levodopa, wherein if the amount of oral immediate release form of levodopa is higher than the subcutaneous amount of levodopa, the amount of oral immediate release form of levodopa is reduced by about the amount of the subcutaneous amount of levodopa and the patient is administered a remaining amount of oral immediate release levodopa; and if the amount of oral immediate release form of levo
  • Further embodiments of the invention are directed to a method of treating Parkinson’s disease in a patient in need thereof, wherein the patient was previously administered with a previous form of levodopa, and wherein the method comprises: converting the patient from the previous form of levodopa to an oral immediate release levodopa form, thus administering an initial daily amount of oral immediate release levodopa to said patient; following said conversion, subcutaneously administering to the patient, over a subcutaneous infusion time course of at least about 24 hours or more, a first pharmaceutically acceptable liquid composition in an amount to deliver about 720 mg of levodopa to the patient over the course of at least about 24 hours, wherein if the initial daily amount of oral immediate release form of levodopa is higher than about 700mg, the amount oral immediate release form of levodopa is reduced by about 700mg and the patients is administered with a remaining amount of oral immediate release levodopa, equal to the initial daily amount of oral immediate release levo
  • the concomitant administration of the first composition (parenteral, e.g., subcutaneous administration) and the second composition e.g., oral tablet) to the patient results in a higher area under the curve (AUC) for levodopa from time 0 to the end of the parenteral, e.g., subcutaneous, infusion as compared to the combined AUC for levodopa in the patient when the first composition and the second composition are not concomitantly administered, wherein the total amount of levodopa administered is the same, whether administered concomitantly or non-concomitantly.
  • AUC area under the curve
  • Treatment A A total dose of 180/22.5mg LD/CD (formulation A) was administered by SC infusion over the course of 8 hours, at a steady infusion rate.
  • Treatment B An immediate release (IR) tablet of 100/25mg LD/CD was administered orally at time Oh.
  • Treatment C A dose of 153.6/19.2 LD/CD (formulation A) was administered by SC infusion over the course of 8 hours, at a steady infusion rate, combined with a single coadministration of an oral IR LD/CD 100/25 mg tablet, 4 hours after the initiation of the infusion.
  • Treatment A 0 (prior to treatment initiation), 0.5h, Ih, 2h, 3h, 4h, 5h, 5.5h, 6h, 7h, 8h (prior to the end of the infusion).
  • Treatment B 0 (prior to treatment initiation), 0.5h, Ih, 2h, 3h, 4h.
  • Treatment C 0 (prior to treatment initiation), 0.5h, Ih, 2h, 3h, 4h, 4.5h, 5h, 5.5h, 6h, 7h, 8h (prior to the end of the infusion).
  • the ratio of the LD normalized AUCs resulting from Treatment C, compared to those obtained in Treatments A+B (addition of both to simulate the SC + oral administration in Treatment C) for each individual was above 1.0, with a mean ratio of 1.245, and a range of from 1.057 to 1.402.
  • the ratio of the CD normalized AUCs resulting from Treatment C, compared to those obtained in Treatments A+B, for most individuals was below 1.0, with a mean ratio of 0.869 and a range of from 0.773 to 1.080.
  • the combined SC+oral treatment provides LD levels higher than expected from the addition of the two types of administrations, when each is provided separately.
  • the CD levels obtained from the combined SC+oral treatment are lower than expected from the addition of the two types of administrations, when each is provided separately.
  • the low CD results obtained in the combined treatment render the higher than expected LD levels even more surprising - even though the amount of CD is reduced, the amount of LD actually rises, which is opposite than what would have been expected, since generally, the CD inhibits the peripheral metabolism of LD and therefore, the lower the amount of CD, the lower the expected amount of LD would be.

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