WO2017184531A1 - Traitement de troubles liés au mouvement au moyen de la noribogaïne - Google Patents

Traitement de troubles liés au mouvement au moyen de la noribogaïne Download PDF

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WO2017184531A1
WO2017184531A1 PCT/US2017/028007 US2017028007W WO2017184531A1 WO 2017184531 A1 WO2017184531 A1 WO 2017184531A1 US 2017028007 W US2017028007 W US 2017028007W WO 2017184531 A1 WO2017184531 A1 WO 2017184531A1
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substituted
alkyl
group
hydrogen
pharmaceutically acceptable
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PCT/US2017/028007
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Holger Weis
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Demerx, Inc.
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • Neurodegenerative diseases arise as a result of progressive loss of neuron structure and/or function.
  • Neurodegenerative diseases include, without limitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), prion diseases (e.g., Creutzfeldt- Jakob Disease), ataxia, spinocerebellar ataxia, spinal muscular atrophy, Friedreich's ataxia, Lewy body disease, and motor neuron diseases.
  • Neurodegeneration may also occur as a result of aging or trauma. These diseases have no known cure, and are marked by progressive degeneration and/or death of neurons.
  • Movement-related disorders are neurologic disorders that result in excessive or movement (hyperkinetic), or reduced movement (hypokinetic).
  • Several neurodegenerative diseases including Parkinson's disease, Huntington's disease, and ALS, may also be classified as movement-related disorders.
  • Other movement disorders include, without limitation, bradykinesia, Hallevorden-Spatz disease, progressive supranuclear palsy, multiple system atrophy, dystonia, spasmodic torticollis, essential tremor, other types of tremor, various choreas and diskenesias, tic disorders, Tourette's syndrome, stereotypic movement disorder, paroxysmal nocturnal limb movement, restless leg syndrome, and stiff person syndrome. Movement disorders may interfere with daily functioning and activity. Many movement disorders have no known cure and/or treatment available. [0005] There remains an acute need for effective strategies for treating and preventing movement disorders and neurodegenerative diseases, including symptoms thereof.
  • the current invention is predicated, in part, on the surprising discovery that treatment with a low, narrow dosage range of an iboga alkaloid or pharmaceutically acceptable salt and/or solvate thereof, provides a therapeutic alleviation of at least some symptoms and/or progression of neurodegenerative disease and/or movement disorders.
  • the dose provides both therapeutic results and an acceptable QT interval prolongation of less than about 60 milliseconds (ms) in humans, and more preferably less than about 20 ms.
  • this invention relates to methods of treating or preventing neurodegenerative disease and/or symptoms and/or progression thereof by administering a therapeutic amount (or prophylactic amount) of an iboga alkaloid or a pharmaceutically acceptable salt or solvate thereof.
  • the treatment does results in a QT interval prolongation of less than 60 ms, preferably less than 50 ms, more preferably less than 30 ms, even more preferably less than 20 ms.
  • the neurodegenerative disease and/or at least one symptom thereof is prevented. In one embodiment, the neurodegenerative disease and/or at least one symptom thereof is treated. In one embodiment, the iboga alkaloid or pharmaceutically acceptable salt and/or solvate thereof is administered prior to on-set of the disease or symptoms thereof, e.g., to a patient at risk of having the disease (e.g., having a genetic predisposition for the disease, exposed to a substance that may cause the disease or disorder, etc.).
  • the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), a prion disease (e.g., Creutzfeldt- Jakob Disease), spinocerebellar ataxia, spinal muscular atrophy, Friedreich's ataxia, Lewy body disease, and a motor neuron disease.
  • the neurodegenerative disease is Parkinson's disease.
  • the neurodegenerative disease is not Alzheimer's disease.
  • the ALS amyotrophic lateral sclerosis
  • a prion disease e.g., Creutzfeldt- Jakob Disease
  • spinocerebellar ataxia e.g., Spinocerebellar ataxia
  • spinal muscular atrophy e.g., Friedreich's ataxia
  • Friedreich's ataxia e.g., Friedreich's ataxia
  • Lewy body disease e.g., Lewy body disease
  • neurodegenerative disease is a result of aging or brain trauma (e.g., traumatic brain injury, concussion, stroke).
  • the patient is co-administered a therapeutic amount of an agent known to treat the neurodegenerative disease or a symptom(s) thereof in addition to the iboga alkaloid.
  • both compounds are administered at the same time.
  • the compounds are administered at different times (e.g., sequentially).
  • this invention provides a method for treating or preventing a movement disorder and/or symptoms thereof in a patient in need thereof by administering to the patient a therapeutic amount (or prophylactic amount) of an iboga alkaloid or a pharmaceutically acceptable salt or solvate thereof.
  • the treatment results in a QT interval prolongation of less than 60 ms, preferably less than 50 ms, more preferably less than 30 ms, even more preferably less than 20 ms.
  • the movement disorder is a hyperkinetic disorder. In one embodiment, the movement disorder is a hypokinetic disorder. In one embodiment, the movement disorder is bradykinesia, Hallevorden-Spatz disease, progressive supranuclear palsy, multiple system atrophy, dystonia, spasmodic torticollis, essential tremor, other types of tremor, various choreas and diskenesias, tic disorders, Tourette's syndrome, stereotypic movement disorder, paroxysmal nocturnal limb movement, restless leg syndrome, or stiff person syndrome.
  • the patient is co-administered a therapeutic amount of an agent known to treat the movement disorder or a symptom(s) thereof in addition to the iboga alkaloid.
  • both compounds are administered at the same time.
  • the compounds are administered at different times (e.g., sequentially).
  • the therapeutic amount or prophylactic amount of iboga alkaloid is between about 0.1 milligrams (mg) and about 180 mg per day. In one embodiment, the therapeutic amount or prophylactic amount of iboga alkaloid is between about 0.1 mg and about 100 mg per day. In one embodiment, the therapeutic amount or prophylactic amount of iboga alkaloid is between about 1 mg and about 50 mg per day. In one embodiment, the therapeutic amount or prophylactic amount of iboga alkaloid is between about 1 mg and about 30 mg per day. In another embodiment, the therapeutic amount or prophylactic amount of iboga alkaloid is between about 1 mg and about 20 mg per day.
  • the iboga alkaloid is noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. More preferably, the iboga alkaloid is noribogaine or a pharmaceutically acceptable salt and/or solvate thereof.
  • the therapeutically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is administered once a day, twice a day, or more than twice a day.
  • this invention provides a composition for treating and/or preventing a neurodegenerative disease or a movement disorder, which composition contains a therapeutic or prophylactic amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof, at least one agent that is known to treat and/or prevent the diease or disorder, and optionally a pharmaceutically acceptable excipient.
  • the iboga alkaloid is noribogaine or a pharmaceutically acceptable salt and/or solvate thereof.
  • FIG. 1 represents mean noribogaine concentration-time profiles in healthy patients after single oral dosing with 3 mg ( ⁇ ), 10 mg (o), 30 mg ( ⁇ ) or 60 mg ( ⁇ ) doses.
  • Inset Individual concentration-time profiles from 0-12 h after a 10 mg dose.
  • FIG. 3 illustrates the mean noribogaine concentration-time profile in opioid- addicted patients after a single oral 60 mg ( ⁇ ), 120 mg ( ⁇ ), or 180 mg (A) dose of noribogaine.
  • FIG. 4A illustrates the average change in QT interval (AQTcl) for each cohort (60 mg, ⁇ ; 120 mg, ⁇ ; 180 mg, ⁇ ; or placebo, ⁇ ) over the first 24 hours post administration.
  • FIG. 4B illustrates the relationship between noribogaine concentrations and AAQTcI with 90% CI.
  • FIG. 4C is a goodness-of-fit plot for observed and predicted relation between noribogaine plasma levels.
  • FIG. 5 illustrates the effect of acute noribogaine treatment on cylinder test performance of rats.
  • FIG. 6A illustrates the effect of L-Dopa/benserazide in combination with noribogaine on cylinder test performance of rats.
  • FIG. 6B illustrates the effect of L-Dopa/benserazide in combination with noribogaine on semi-quantitative dyskinesia score in rats.
  • FIG. 7 illustrates the effect of sub-chronic, once-daily noribogaine on cylinder test performance of rats.
  • the term "about” when used with regard to a dose amount means that the dose may vary by +/- 20%.
  • "about 2 mg/kg noribogaine” indicates that a patient may be administered a dose of noribogaine between 1.6 mg/kg and 2.4 mg/kg.
  • about 120 mg per unit dose of noribogaine indicates that the unit dose may range from 96 mg to 144 mg.
  • administering refers to introducing an agent, such as an iboga alkaloid, into a patient.
  • an effective amount is administered, which amount can be determined by the treating physician or the like.
  • Any route of administration such as oral, topical, subcutaneous, peritoneal, intra-arterial, inhalation, vaginal, rectal, nasal, introduction into the cerebrospinal fluid, or instillation into body compartments can be used.
  • the agent, such as an iboga alkaloid may be administered by direct blood stream delivery, e.g. sublingual, buccal, intranasal, or intrapulmonary administration.
  • administration is oral.
  • administration which may be the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
  • Periodic administration refers to multiple treatments that occur on a daily, weekly, or monthly basis. Periodic administration may also refer to administration of an agent, such as iboga alkaloid or salt or solvate thereof one, two, three, or more times per day. Administration may be via transdermal patch, gum, lozenge, sublingual tablet, intranasal, intrapulmonary, oral administration, or other administration.
  • compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
  • alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 12 carbon atoms, 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms.
  • C x alkyl refers to an alkyl group having x carbon atoms, wherein x is an integer, for example, C 3 refers to an alkyl group having 3 carbon atoms.
  • Carboxy or “carboxyl” refers to -COOH or salts thereof.
  • Carboxyl ester or “carboxy ester” refers to the
  • Substituted cycloalkenyloxy refers to -0-(substituted cycloalkenyl).
  • Heteroaryloxy refers to -0-heteroaryl.
  • Substituted heteroaryloxy refers to the group -0-(substituted heteroaryl).
  • Heteroarylthio refers to the group -S-heteroaryl.
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl).
  • Substituted heterocyclylthio refers to the group -S -(substituted heterocycyl).
  • thiamorpholinyl 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.
  • Spiro ring systems refers to bicyclic ring systems that have a single ring carbon atom common to both rings.
  • Substituted sulfonyl refers to the group -SC ⁇ -alkyl, -S0 2 -substituted
  • (substituted sulfonyl)aminocarbonyl refers to -C(0)NH(substituted sulfonyl), wherein substituted sulfonyl is as defined herein.
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S -(substituted alkyl) wherein substituted alkyl is as defined herein.
  • phosphate ester refers to any one of the mono-, di- or triphosphate esters of noribogaine, wherein the mono-, di- or triphosphate ester moiety is bonded to the 12-hydroxy group and/or the indole nitrogen of noribogaine.
  • phosphate ester refers to any one of the mono-, di- or triphosphate esters of noribogaine, wherein the mono-, di- or triphosphate ester moiety is bonded to the 12-hydroxy group and/or the indole nitrogen of noribogaine.
  • diphosphate refers to the group -P(0)(OH)-OP(0)(OH) 2 .
  • esters of the monophosphate refers to the group -P(0)(OH)- (OP(0)(OH)) 2 OH.
  • esters of the monophosphate can be represented by the formula - P(0)(OR 45 ) 2 , where each R 45 is independently hydrogen, C1-C12 alkyl, C3-C10 cycloalkyl, C 6 - Ci4 aryl, heteroaryl of 1 to 10 carbon atoms and 1 to 4 optionally oxidized heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and the like, provided that at least one R 45 is not hydrogen.
  • exemplary esters of the di- or triphosphate can be represented by the formulas -P(0)(OR 45 )-OP(0)(OR 45 ) 2
  • hydrolyzable group refers to a group that can be hydrolyzed to release the free hydroxy group under hydrolysis conditions.
  • hydrolysable group include, but are not limited to those defined for R above.
  • Preferred hydrolysable groups include carboxyl esters, phosphates and phosphate esters.
  • the hydrolysis may be done by chemical reactions conditions such as base hydrolysis or acid hydrolysis or may be done in vivo by biological processes, such as those catalyzed by a phosphate hydrolysis enzyme.
  • Nonlimiting examples of hydrolysable group include groups linked with an ester-based linker (-C(O)O- or -OC(O)-), an amide-based linker (-C(O)NR 46 - or -NR 46 C(0)-), or a phosphate-linker (-P(0)(OR 46 )-0-, -0-P(S)(OR 46 )-0-, -0-P(S)(SR 46 )- 0-, -S-P(0)(OR 46 )-0-, -0-P(0)(OR 46 )-S-, -S-P(0)(OR 46 )-S-, -0-P(S)(OR 46 )-S-, -S- P(S)(OR 46 )-0-, -0-P(0)(R 46 )-0-, -0-P(S)(R 46 )-0-, -S-P(0)(R 46 )-0-, -S-P(S)(R 46 )-0-, -S- P(0)
  • Substituted groups of this invention do not include polymers obtained by an infinite chain of substituted groups. At most, any substituted group can be substituted up to five times.
  • ibogaine is mentioned herein, one or more polymorphs of ibogaine can be utilized and are contemplated. Ibogaine is isolated from Tabernanth iboga, a shrub of West Africa. Ibogaine can also be synthesized using known methods. See, e.g., Buchi, et al. (1966), J. Am. Chem Society, 88(13), 3099- 3109. Non-limiting examples of ibogaine derivatives encompassed by this invention are given in more detail in the "Compositions of the Invention" section below.
  • Noribogaine can be prepared by demethylation of naturally occurring ibogaine. Demethylation may be accomplished by conventional techniques such as by reaction with boron tribromide/methylene chloride at room temperature followed by conventional purification. See, for example, Huffman, et al, J. Org. Chem. 50: 1460 (1985), which incorporated herein by reference in its entirety.
  • Noribogaine can be synthesized as described, for example in U.S. Patent Pub. Nos. 2013/0165647, 2013/0303756, and 2012/0253037, PCT Patent Publication No. WO 2013/040471 (includes description of making noribogaine polymorphs), and U.S. PatentNo. 9,617,274, each of which is incorporated herein by reference in its entirety.
  • Nonibogaine derivatives refer to, without limitation, esters or O-carbamates of noribogaine, or solvates of each thereof, or pharmaceutically acceptable salts of each thereof. Also encompassed within this invention are derivatives of noribogaine that act as prodrug forms of noribogaine.
  • a prodrug is a pharmacological substance administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolized in vivo into an active metabolite.
  • Noribogaine derivatives include, without limitation, those compounds set forth in US Patent Nos. 6,348,456, 8,362,007, and 8,741,891; as well as in US Patent Application Publication Nos.
  • the methods of the present disclosure entail the
  • a prodrug of noribogaine refers to a compound that metabolizes, in vivo, to noribogaine.
  • the prodrug is selected to be readily cleavable either by a cleavable linking arm or by cleavage of the prodrug entity that binds to noribogaine such that noribogaine is generated in vivo.
  • the prodrug moiety is selected to facilitate binding to the ⁇ and/or ⁇ receptors in the brain either by facilitating passage across the blood brain barrier or by targeting brain receptors other than the ⁇ and/or ⁇ receptors. Examples of prodrugs of noribogaine are provided in United States Patent No. 8,741,891, the entire content of which is incorporated herein by reference.
  • composition refers to a composition that is suitable for administration to a mammal, particularly, a human.
  • Such compositions include various excipients, diluents, carriers, and such other inactive agents well known to the skilled artisan.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts, including pharmaceutically acceptable partial salts, of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, thalic acid, embonic acid, enanthic acid, oxalic acid and the like, and when the molecule contains an acidic functionality, include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.
  • a "pharmaceutically acceptable solvate” or "hydrate” of a compound of the invention means a solvate or hydrate complex that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound, and includes, but is not limited to, complexes of a compound of the invention with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
  • solvate can be referred to as a hydrate.
  • the compounds of the present invention may absorb moisture, may include one or more molecules of water in the formed crystal, and thus become a hydrate. Even when such hydrates are formed, they are included in the term "solvate".
  • Solvate also is meant to include such compositions where another compound or complex co-crystallizes with the compound of interest.
  • solvate refers to complexes with solvents in which the iboga alkaloid (e.g., noribogaine) is reacted or from which the iboga alkaloid is precipitated or crystallized.
  • a complex with water is known as a "hydrate”.
  • Solvates of the iboga alkaloid are within the scope of the invention. It will be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary based on the solvate used. Thus, all crystalline forms of the iboga alkaloid or the pharmaceutically acceptable salts or solvates thereof are within the scope of the present invention.
  • Therapeutically effective amount refers to an amount of a drug or an agent that, when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient.
  • the therapeutically effective amount will vary depending upon the patient and the condition being treated, the weight and age of the subject, the severity of the condition, the salt, solvate, or derivative of the active drug portion chosen, the particular composition or excipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art.
  • a therapeutically effective amount may be administered in one or more administrations.
  • a therapeutically effective amount of an agent in the context of treating a neurodegenerative disease or a movement disorder and/or symptoms thereof, refers to an amount of the agent that attenuates the disease or disorder; attenuates, reverses, or reduces the severity of a symptom or symptoms thereof; and/or prevents, delays, or reduces the severity of progression of the disease or disorder.
  • the therapeutically effective amount of the compound may be higher or lower, depending on the route of administration used. For example, when direct blood
  • a lower dose of the compound may be administered.
  • a therapeutically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is from about 50 ng to less than 100 ⁇ g per day. Where other routes of administration are used (e.g., oral), a higher dose of the compound may be administered.
  • the therapeutically effective amount of the compound is from about 0.1 mg to about 180 mg per day. In one embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 100 mg per day.
  • a “therapeutic level” of a drug is an amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof that is sufficient to treat or prevent the disease or disorder and/or symptoms thereof, but not high enough to pose any significant risk to the patient.
  • Therapeutic levels of drugs can be determined by tests that measure the actual concentration of the compound in the blood of the patient. This concentration is referred to as the "serum concentration.”
  • a prophylactically effective amount of a drug is an amount, typically less than the therapeutically effective amount, that provides prevention of the disease or disorder and/or symptoms thereof in a patient.
  • the prophylactically effective amount of the compound maybe less than the therapeutically effective amount because the level of inhibition may not need to be as high in a patient who is not currently experiencing the disease or disorder.
  • a prophylactically effective amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount.
  • the prophylactically effective amount of the compound is the same as the therapeutically effective amount.
  • Treatment covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the condition but not yet diagnosed as having the condition, (b) impeding the development of the condition, and/or (c) relieving the condition, i.e. , causing regression of the condition and/or relieving one or more symptoms of the condition.
  • Treating” or “treatment of a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results such as the reduction of symptoms.
  • beneficial or desired clinical results include, but are not limited to: treating or preventing the neurodegenerative disease or movement disorder; treating or preventing a symptom or symptoms thereof; treating, preventing, or reversing progression of the disease or disorder; and the like.
  • the term "patient” refers to mammals and includes humans and non-human mammals. Preferably, the patient is a human.
  • QT interval refers to the measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart. Prolongation of the QT interval refers to an increase in the QT interval.
  • dose refers to a range of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof that provides a therapeutic serum level of the iboga alkaloid or pharmaceutically acceptable salt or solvate thereof when given to a patient in need thereof.
  • the dose is recited in a range, for example from about 20 mg to about 120 mg, and can be expressed either as milligrams or as mg/kg body weight.
  • the attending clinician will select an appropriate dose from the range based on the patient's weight, age, degree of addiction, health, and other relevant factors, all of which are well within the skill of the art.
  • unit dose refers to a dose of drug that is given to the patient to provide therapeutic results, independent of the weight of the patient.
  • the unit dose is sold in a standard form (e.g., 10 mg or 20 mg tablet).
  • the unit dose may be administered as a single dose or a series of subdoses.
  • the unit dose provides a standardized level of drug to the patient, independent of weight of patient.
  • Many medications are sold based on a dose that is therapeutic to all patients based on a therapeutic window. In such cases, it is not necessary to titrate the dosage amount based on the weight of the patient.
  • compositions for treating or preventing a neurodegenerative disease and/or symptoms and/or progression thereof in a subject comprising iboga alkaloid or
  • composition further comprises at least one agent known to treat or prevent the
  • compositions for treating or preventing a movement disorder and/or symptoms and/or progression thereof in a subject comprising iboga alkaloid or
  • composition further comprises at least one agent known to treat or prevent the movement disorder and/or symptoms and/or progression thereof.
  • the iboga alkaloid is ibogaine, noribogaine, an ibogaine derivative, noribogaine derivative, or prodrug, salt or solvate thereof.
  • the noribogaine derivative is represented by Formula I:
  • R is hydrogen or a hydrolyzable group such as hydrolyzable esters of from about 1 to 12 carbons.
  • R is hydrogen or a group of the formula: wherein X is a Cr-C 12 group, which is unsubstituted or substituted.
  • X may be a linear alkyl group such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n- octyl, n-nonyl, n -decyl, n-undecyl or n-dodecyl, or a branched alkyl group, such as i-propyl or sec-butyl.
  • X may be a phenyl group or benzyl group, either of which may be substituted with lower alkyl groups or lower alkoxy groups.
  • the lower alkyl and/or alkoxy groups have from 1 to about 6 carbons.
  • the group R may be acetyl, propionyl or benzoyl. However, these groups are only exemplary.
  • C1-C12 groups include C1-C12 alkyl, C3-C12 cycloalkyl, C6-C12 aryl, C7-C12 arylalkyl, wherein C x indicates that the group contains x carbon atoms.
  • Lower alkyl refers to C1-C4 alkyl and lower alkoxy refers to C1-C4 alkoxy.
  • the noribogaine derivative is represented by Formula II:
  • R 1 is halo, OR 2 , or C1-C12 alkyl optionally substituted with 1 to 5 R ;
  • R 2 is hydrogen or a hydrolysable group selected from the group consisting of -
  • each R x is selected from the group consisting of C1-C6 alkyl optionally substituted with 1 to 5 R 10
  • each R y is independently selected from the group consisting of hydrogen, C1-C6 alkyl optionally substituted with 1 to 5 R 10 , C6-C14 aryl optionally substituted with 1 to 5 R 10 , C3-C10 cycloalkyl optionally substituted with 1 to 5 R 10 , C1-C10 heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 , C1-C1 0 heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R , and where each R y , together with the nitrogen atom bound thereto form a C1-C6 heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 or a C1-C
  • R 3 is selected from the group consisting of hydrogen, C1-C12 alkyl optionally
  • R 4 is selected from the group consisting of hydrogen, -(CH 2 ) m OR 8 , -
  • L is a bond or Ci-Ci 2 alkylene
  • R 5 is selected from the group consisting of hydrogen, Ci-Ci 2 alkyl substituted with 1 to 5 R 10 , Ci-Ci 2 alkenyl substituted with 1 to 5 R 10 , -X x -R 7 , -(X'-YVX 1 - R 7 , -S0 2 NR 7 R 8 , -0-C(0)R 9 , -C(0)OR 8 , -C(0)NR 7 R 8 , -NR 7 R 8 , -NHC(0)R 9 , and -NR 7 C(0)R 9 ;
  • each R 6 is independently selected from the group consisting of hydrogen, Ci-Ci 2 alkyl, C 2 -Ci 2 alkenyl, C 2 -Ci 2 alkynyl, C6-Cio aryl, C1-C6 heteroaryl having 1 to 4 heteroatoms, and C1-C6 heterocycle having 1 to 4 heteroatoms, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R 10 ;
  • n 1, 2, or 3;
  • R 10 is selected from the group consisting of C1-C4 alkyl, phenyl, halo, -OR 11 , -
  • R 11 is independently hydrogen or C1-C12 alkyl
  • R 5 is not hydrogen
  • R 1 when is a double bond, R 1 is an ester hydrolyzable group, R 3 and R 4 are both hydrogen, then -L-R 5 is not ethyl;
  • R 1 when is a double bond, R 1 is -OH, halo or C1-C12 alkyl optionally substituted with 1 to 5 R 10 , then R 4 is hydrogen;
  • R 1 when is a double bond, R 1 is OR 2 , R 4 is hydrogen, -L-R 5 is ethyl, then R 2 is not a hydrolyzable group selected from the group consisting of an ester, amide, carbonate and carbamate.
  • the noribogaine derivative is represented by Formula III:
  • R 12 is halo, -OH, -SH, -NH 2 , -S(0) 2 N(R 17 ) 2 , -R z -L x -R 18 , -R z -L x -R 19 , -R'-I ⁇ -R 20 or -R z - I ⁇ -CHR ⁇ R 19 , where R z is O, S or NR 17 ;
  • L 1 is alkylene, arylene, -C(0)-alkylene, -C(0)-arylene, -C(0)0-arylene, -C(0)0- alkylene, -C(O)NR 20 -alkylene, -C(O)NR 20 -arylene, -C(NR 20 )NR 20 -alkylene or -C(NR 20 )NR 20 -arylene, wherein L 1 is configured such that -O-I ⁇ -R 18 is - OC(0)-alkylene-R 18 , -OC(0)0-arylene-R 18 , -OC(0)0-alkylene-R 18 , -OC(O)- arylene-R , -OC(0)NR 2U -alkylene-R , -OC(0)NR 2U -arylene-R , - OC(NR 20 )NR 20 -alkylene-R 18 or -OC(NR 20 )NR 20 -arylene-R 18 , and wherein the alkylene and ary
  • R 13 is hydrogen, -S(0) 2 OR 2 °, -S(0) 2 R 2 °, -C(0)R 15 , -C(0)NR 15 R 15 , -C(0)OR 15 , C 1 -C 12 alkyl optionally substituted with 1 to 5 R 16 , C 1 -C 12 alkenyl optionally substituted with 1 to 5 R 16 , or aryl optionally substituted with 1 to 5 R 16 ;
  • R 14 is hydrogen, halo, -OR 17 , -CN, C 1 -C 12 alkyl, Ci-C ⁇ alkoxy, aryl or aryloxy, where the alkyl, alkoxy, aryl, and aryloxy are optionally substituted with 1 to 5 R 16 ; each R 15 is independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, and heterocycle, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R 16 ;
  • R 16 is selected from the group consisting of phenyl, halo, -OR 17 , -
  • R 100 is H, halo, C1-C3 alkyl, substituted C1-C3 alkyl, OR 110 , NH 2 , NHR 110 , NR 110 R i n ,
  • NHC(0)R 110 or NR 110 C(O)R i n ;
  • R 101 is H, C1-C3 alkyl, substituted C1-C3 alkyl, C1-C3 alkoxy, CH 2 -X-CH 3 , or
  • R 102 is H, COOH, COOR 104 , (CH 2 ) n OH, CH(OH)R 105 , CH 2 OR 105 , C(0)NH 2 ,
  • R 103 is C1-C3 alkyl, benzyl, substituted C1-C3 alkyl, YH, YR 108 , YC(0)R 108 ,
  • X is O or NH
  • Y is O or S
  • n is an integer selected from 0-8;
  • r 0, 1 or 2.
  • R 100 is hydrogen or C1-C3 alkoxy
  • R 102 is hydrogen
  • R 102 is CH 2 OH and CH(OH)R 105 . In one embodiment, R 102 is CH 2 OR 105 . In one embodiment, R 102 is C0 2 R 105 . In one embodiment, R 102 is C(0)NH 2 , C(0)NHR 105 , or C(O)NR 105 R 106 . In one embodiment, R 102 is C(0)NHNH 2 , C(O)NHNHR 105 i C(O)NR 105 NH 2 , C(O)NHNR 105 R 106 C(O)NHR 105 NHR 106 , or C(O)NR 105 NR 106 R 107 . In one embodiment, R 102 is C(0)NHNH(C(0)R 105 ), C(O)NHNR 105 (C(O)R 106 ),
  • R 102 is C(0)R 105 .
  • Agents known to treat and/or prevent neurodegenerative diseases and/or movement disorders and/or symptoms and/or progression thereof include, without limitation, an anti- epilectic drug (e.g., ethosuximide, carbamazepine, valproate), an anti-seizure medication (e.g., primidone, gabapentin), a beta-blocker (e.g., propranolol), levo-3,4- dihydroxyphenylalanine (1-DOPA) or other dopamine agonist (e.g., pramipexole, ropinirole, rotigotine, apomorphine, bromocriptine, pergolide) or dopamine precursor (e.g., levodopa with or without carbidopa), a cholinesterase inhibitor, choline, an anticholinergic (e.g., benztropine or trihexyphenidyl), an anti-inflammatory, a cannabinoid,
  • the composition is formulated for administration once per day. In some aspects, the composition is formulated for administration two or more times per day.
  • the composition is formulated for oral, sublingual, intranasal, buccal, or intrapulmonary delivery.
  • the composition is formulated for oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery. Routes of administration are discussed in further detail below in the subsection titled "Dosages and Routes of Administration.”
  • this invention in one aspect, provides a method for treating or preventing a neurodegenerative disease and/or symptoms and/or progression thereof in a subject, comprising administering to the patient in need thereof a therapeutically effective amount of an iboga alkaloid or
  • the method further comprises administering at least one agent known to treat or prevent the neurodegenerative disease and/or symptoms and/or progression thereof.
  • the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), a prion disease (e.g., Creutzfeldt- Jakob Disease), spinocerebellar ataxia, spinal muscular atrophy, Friedreich's ataxia, Lewy body disease, and a motor neuron disease.
  • the neurodegenerative disease is Parkinson's disease.
  • the neurodegenerative disease is not Alzheimer's disease.
  • the ALS amyotrophic lateral sclerosis
  • a prion disease e.g., Creutzfeldt- Jakob Disease
  • spinocerebellar ataxia e.g., Spinocerebellar ataxia
  • spinal muscular atrophy e.g., Friedreich's ataxia
  • Friedreich's ataxia e.g., Friedreich's ataxia
  • Lewy body disease e.g., Lewy body disease
  • neurodegenerative disease is a result of aging or brain trauma.
  • Current treatments include treatment of one or more symptoms of the disease by medication, surgery, deep brain stimulation, botulism toxin injections, etc.
  • abetalipoproteinaemia Some drug treatments that have been used to control ataxia include, without limitation, 5-hydroxytryptophan (5-HTP), idebenone, amantadine, physostigmine, L- carnitine or derivatives, trimethoprimsulfamethoxazole, vigabatrin, phosphatidylcholine, acetazolamide, 4-aminopyridine, buspirone, and a combination of coenzyme Q10 and vitamin E.
  • 5-hydroxytryptophan 5-HTP
  • idebenone idebenone
  • amantadine physostigmine
  • L- carnitine or derivatives trimethoprimsulfamethoxazole
  • vigabatrin trimethoprimsulfamethoxazole
  • vigabatrin trimethoprimsulfamethoxazole
  • phosphatidylcholine acetazol
  • Huntington's disease is an inherited disease that causes movement, cognitive and psychiatric disorders. Treatments for Huntington's disease include, withut limitation, tetrabenazine, antipsychotic drugs, amantadine, levetiracetam, and clonazepam, as well as anti-depressants and mood stabilizers. Patients with this disease also frequently undergo speech, physical, and/or occupational therapy to improve some symptoms.
  • ALS also known as Lou Gehrig's disease
  • Lou Gehrig's disease is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord which affects muscle movement and control. Voluntary muscle action worsens progressively and may result in total paralysis. ALS is inherited in only about 10% of cases (familial ALS). Treatment for ALS includes riluzole, baclofen, diazepam, trihexyphenidyl or amitriptyline, as well as other medications that address one or more symptoms of the disease.
  • Prion diseases are caused by misfolded proteins (prions) in the brain.
  • Human prion diseases include Creutzfeldt- Jakob Disease (CJD) and its variant (vCJD), Gerstmann- Straussler-Scheinker syndrome, Fatal Familial Insomnia, kuru, and multiple system atrophy.
  • Prions cause neurodegenerative disease via extracellular aggregation within the central nervous system to form amyloid plaques, which disrupt the normal tissue structure.
  • Neurodegenerative symptoms can include convulsions, dementia, ataxia (balance and coordination dysfunction), and behavioural or personality changes. There are no known cures or treatments for prion diseases.
  • [0177] provides a method for treating or preventing a movement disorder and/or symptoms and/or progression thereof in a subject, comprising administering to the patient in need thereof a therapeutically effective amount of an iboga alkaloid or
  • the method further comprises administering at least one agent known to treat or prevent the disorder and/or symptoms and/or progression thereof.
  • agent known to treat and/or prevent a particular disease or disorder is discussed throughout the specification, it is to be understood that such an agent may optionally be administered in conjunction with (e.g., before, after, or concurrently with) the iboga alkaloid or pharmaceutically acceptable salt or solvate thereof.
  • treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof results in a QT interval prolongation of less than about 60 ms. In one embodiment, treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof results in a QT interval prolongation of less than about 50 ms. In one embodiment, treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof results in a QT interval prolongation of less than about 40 ms. In a preferred embodiment, treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof results in a QT interval prolongation of less than about 30 ms.
  • treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof results in a QT interval prolongation of less than about 20 ms. In one embodiment, treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof results in a QT interval prolongation of less than about 10 ms.
  • the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 470 ms during treatment.
  • the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 450 ms during treatment.
  • the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 420 ms during treatment.
  • the dosage or aggregate dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is from about 1 mg to about 50 mg per day. In one embodiment, the dosage or aggregate dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is from about 1 mg to about 40 mg per day. In one embodiment, the dosage or aggregate dosage of iboga alkaloid or
  • pharmaceutically acceptable salt or solvate thereof is from about 1 mg to about 10 mg per day.
  • the therapeutically effective amount of the compound may be any amount or subrange within any of these ranges, including endpoints.
  • the therapeutically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is administered once a day. In some embodiments, the therapeutically effective amount is administered twice per day. In some embodiments, the therapeutically effective amount is administered more than two times per day.
  • compositions suitable for administration in accordance with the methods provided herein, can be suitable for a variety of delivery modes including, without limitation, oral, sublingual, buccal, intrapulmonary, or intranasal delivery.
  • Compositions suitable for internal, rectal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes may also be used.
  • Other dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).
  • Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration.
  • Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, poly glycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like.
  • Parenteral compositions containing iboga alkaloid or pharmaceutically acceptable salt or solvate thereof may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, poly glycols mixed with water, Ringer's solution, etc.
  • compositions utilized herein may be formulated for aerosol administration, particularly to the respiratory tract and including intrapulmonary or intranasal administration.
  • the compound will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • the active ingredient may be provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), (for example,
  • compositions utilized herein may be formulated for sublingual administration, for example as sublingual tablets.
  • Sublingual tablets are designed to dissolve very rapidly.
  • the formulations of these tablets contain, in addition to the drug, a limited number of soluble excipients, usually lactose and powdered sucrose, but sometimes dextrose and mannitol.
  • microencapsulation numbing of taste buds; multiple emulsion; modification of viscosity; prodrug or salt formation; inclusion or molecular complexes; ion exchange resins; and solid dispersion. Any method of masking the bitterness of the compound of the invention may be used.
  • the patient is administered periodically, such as once, twice, three times, four times or five times daily with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof.
  • the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week.
  • the dosage and frequency of the administration depends on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made by a qualified clinician.
  • a unit dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof which is about 50 mg to about 200 mg per dose. In one embodiment, the unit dose is about 50 to about 120 mg per dose. In one embodiment, the unit dose is about 120 mg per dose. It is to be understood that the term "unit dose" means a dose sufficient to provide therapeutic results whether given all at once or serially over a period of time.
  • a patient receiving a therapeutic dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is monitored in a clinical setting.
  • a “clinical setting” refers to an inpatient setting (e.g., inpatient clinic, hospital, rehabilitation facility) or an outpatient setting with frequent, regular monitoring (e.g., outpatient clinic that is visited daily to receive dose and monitoring). Monitoring includes monitoring of QT interval. Methods for monitoring of QT interval are well-known in the art, for example by ECG.
  • a patient receiving iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is not monitored in a clinical setting. In one embodiment, a patient receiving iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is monitored periodically, for example daily, weekly, monthly, or occasionally.
  • this invention relates to a method for treating, preventing, or attenuating a disease or disorder or symptoms of a disease or disorder described herein who is prescreened to evaluate the patient's expected tolerance for prolongation of QT interval, administering to the patient a dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof that is sufficient to inhibit or ameliorate said disease or disorder or symptoms/progression thereof, while maintaining a QT interval of less than about 500 ms during said treatment.
  • the dosage maintains a QT interval of less than about 470 ms during treatment.
  • the co dosage maintains a QT interval of less than about 450 ms during treatment.
  • the dosage maintains a QT interval of less than about 420 ms during treatment.
  • prescreening of the patient comprises ascertaining that iboga alkaloid or pharmaceutically acceptable salt or solvate thereof treatment will not result in a maximum QT interval over about 500 ms. In one embodiment, prescreening of the patient comprises ascertaining that iboga alkaloid or pharmaceutically acceptable salt or solvate thereof treatment will not result in a maximum QT interval over about 470 ms. In one embodiment, prescreening comprises ascertaining that iboga alkaloid or pharmaceutically acceptable salt or solvate thereof treatment will not result in a maximum QT interval over about 450 ms.
  • prescreening comprises ascertaining that iboga alkaloid or pharmaceutically acceptable salt or solvate thereof treatment will not result in a maximum QT interval over about 420 ms. In one embodiment, prescreening comprises determining the patient's pre-treatment QT interval.
  • patients may be selected based on any criteria as determined by the skilled clinician.
  • criteria may include, by way of non-limiting example, pre-treatment QT interval, pre-existing cardiac conditions, risk of cardiac conditions, age, sex, general health, and the like.
  • selection criteria for disallowing iboga alkaloid or pharmaceutically acceptable salt or solvate thereof treatment or restricting dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof administered to the patient: high QT interval before treatment (e.g., such that there is a risk of the patient's QT interval exceeding about 500 ms during treatment);
  • the methods can include selecting and/or
  • this invention relates to monitoring a patient who is
  • the dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is reduced if the patient has serious adverse side effects.
  • the iboga alkaloid or pharmaceutically acceptable salt or solvate thereof treatment is discontinued if the patient has serious adverse side effects.
  • the adverse side effect is a QT interval that is prolonged beyond a safe level.
  • kits of parts for the treatment, prevention, or attenuation of a disease or disorder or symptoms of a disease or disorder described herein wherein the kit comprises a composition comprising iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and a means for administering the composition to a patient in need thereof.
  • the invention is directed to a kit of parts for administration of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and optionally an agent for treatment of the disease or disorder, the kit comprising multiple delivery vehicles, wherein each delivery vehicle contains a discrete amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and further wherein each delivery vehicle is identified by the amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and/or agent provided therein; and optionally further comprising a dosing treatment schedule in a readable medium.
  • the dosing treatment schedule includes the amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof required to achieve each average serum level is provided.
  • the kit of parts includes a dosing treatment schedule that provides an attending clinician the ability to select a dosing regimen of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof based on the sex of the patient, mass of the patient, and the serum level that the clinician desires to achieve.
  • the dosing treatment schedule further provides information corresponding to the volume of blood in a patient based upon weight (or mass) and sex of the patient.
  • the storage medium can include an accompanying pamphlet or similar written information that accompanies the unit dose form in the kit.
  • the storage medium can include electronic, optical, or other data storage, such as a nonvolatile memory, for example, to store a digitally-encoded machine-readable representation of such information.
  • delivery vehicle refers to any formulation that can be used for administration of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and optionally agent to treat the disease or disorder to a patient.
  • Non-limiting, exemplary delivery vehicles include caplets, pills, capsules, tablets, powder, liquid, or any other form by which the drug can be administered. Delivery vehicles may be intended for administration by oral, inhaled, injected, or any other means.
  • the machine-readable medium is a Quick Response Code (QR Code) or other matrix barcode.
  • the machine-readable medium comprises software that contains information regarding dosing schedules for the unit dose form of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and optionally other drug information.
  • the software may be interactive, such that the attending clinician or other medical professional can enter patient information.
  • the medical professional may enter the weight and sex of the patient to be treated, and the software program provides a recommended dosing regimen based on the information entered. The amount and timing of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof recommended to be delivered will be within the dosages that result in the serum
  • the kit of parts comprises multiple delivery vehicles in a variety of dosing options.
  • the kit of parts may comprise pills or tablets in multiple dosages, such as 120 mg, 90 mg, 60 mg, 30 mg, 20 mg, 10 mg, and/or 5 mg of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof per pill.
  • Each pill is labeled such that the medical professional and/or patient can easily distinguish different dosages. Labeling may be based on printing or embossing on the pill, shape of the pill, color of pill, the location of the pill in a separate, labeled compartment within the kit, and/or any other distinguishing features of the pill.
  • all of the delivery vehicles within a kit are intended for one patient.
  • the delivery vehicles within a kit are intended for multiple patients.
  • the unit dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is from 0.1 mg to 100 mg. In one embodiment, the unit dose is 0.1 mg. In one embodiment, the unit dose is 1 mg. In one embodiment, the unit dose is 2 mg. In one embodiment, the unit dose is 3 mg. In one embodiment, the unit dose is 4 mg. In one embodiment, the unit dose is 5 mg. In one embodiment, the unit dose is 6 mg. In one embodiment, the unit dose is 10 mg. In one embodiment, the unit dose is 20 mg. In one embodiment, the unit dose is 25 mg. In one embodiment, the unit dose is 30 mg. In one embodiment, the unit dose is 40 mg. In one embodiment, the unit dose is 50 mg.
  • the unit dose is 60 mg. In one embodiment, the unit dose is 70 mg. In one embodiment, the unit dose is 80 mg. In one embodiment, the unit dose is 90 mg. In one embodiment, the unit dose is 100 mg. Unit doses may include any range or subrange between any of these doses, as well as any value therebetween, including endpoints.
  • the unit dose form comprises one or multiple dosages to be administered periodically, such as once, twice, three times, four times or five times daily with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and optionally the agent to treat the disease or disorder.
  • the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week.
  • the dosage and frequency of the administration depends on criteria including the route of administration, content of composition, age and body weight of the patient, condition of the patient, sex of the patient, without limitation, as well as by the severity of the addiction. Determination of the unit dose form providing a dosage and frequency suitable for a given patient can readily be made by a qualified clinician.
  • the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week.
  • the dosage and frequency of the administration depends on criteria including the route of administration, content of composition, age and body weight of the patient, condition of the patient, sex of the patient, without limitation, as well as by the severity of the addiction. Determination of the unit dose form providing a dosage and frequency suitable for a given patient can readily be made by a qualified clinician.
  • iboga alkaloid or pharmaceutically acceptable salt or solvate thereof in unit dose form.
  • Such unit dose form may conveniently be provided in transdermal patch, tablet, caplet, liquid or capsule form.
  • the iboga alkaloid is noribogaine provided as noribogaine HC1, with dosages reported as the amount of free base noribogaine.
  • the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients.
  • iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is provided in saline for intravenous administration. VII. Formulations
  • This invention further relates to pharmaceutically acceptable formulations comprising a unit dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and an agent known to treat the neurodegenerative disease or movement disorder or a symptom and/or progression thereof, and optionally a pharmaceutically acceptable excipient.
  • the formulation is a controlled release formulation.
  • controlled release formulation includes sustained release and time-release formulations. Controlled release formulations are well-known in the art. These include excipients that allow for sustained, periodic, pulse, or delayed release of the drug. Controlled release formulations include, without limitation, embedding of the drug into a matrix; enteric coatings; microencapsulation; gels and hydrogels; implants; transdermal patches; and any other formulation that allows for controlled release of a drug.
  • the formulation is designed for periodic administration, such as once, twice, three times, four times or five times daily with iboga alkaloid or
  • the formulation is designed for oral administration, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form.
  • the iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is noribogaineprovided as noribogaine HC1, with dosages reported as the amount of free base noribogaine.
  • the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients.
  • the scales measure the intensity of withdrawal symptoms, based on clinical, subjective, and objective indicia.
  • the unilateral 6-OHDA model is the traditional model for testing Parkinson's disease therapies, especially those intended to increase dopamine levels in the striatum.
  • the toxin 6-OHDA is injected into the rats unilaterally (i.e., into one hemisphere of the brain), while the opposite hemisphere serves as an intra-animal control.
  • the injection produces dopamine neuron loss on the 6-OHDA-inj ected side while sparing the contralateral dopamine neurons.
  • the number of left and right forepaw contacts with the cylinder were counted.
  • Forelimb contact was defined as the placement of the whole palm on the wall of the cylinder, and indicated its use during supported rearing. The percentage of use of the left paw was calculated.
  • Example 4 Acute effect of noribogaine in combination with L-dopa on motor
  • Figure 6 A illustrates the effect of vehicle, L-Dopa and benzerazide, or L-Dopa/benzerazide and noribogaine on the percent of left forepaw use.
  • Figure 6B shows a semi-quantitative dyskinesia score, where a score of 0 indicates no dyskinesia behavior; 1 indicates mild dyskinesia behavior; 2 indicates moderate dyskinesia behavior; and 3 indicates severe dyskinesia behavior.
  • the rats were administered noribogaine for a total of 11 weeks, and the plasma and brain concentrations determined, as shown in Table 4.
  • a male patient, age 60, with Parkinson's disease is treated with noribogaine hydrochloride at an initial dose of about 6 mg per day (administered as 3 mg twice per day). Improvement in one or more symptoms is expected. Prolonged (e.g. 6 months or more) administration of between 6 mg and 20 mg per day is expected to delay progression of the disease and/or symptoms thereof.

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Abstract

La présente invention concerne des procédés et des compositions pour traiter ou prévenir une maladie neurodégénérative ou un trouble du mouvement et/ou des symptômes de ceux-ci chez un sujet. Le procédé comprend l'administration au sujet en ayant besoin d'une quantité thérapeutiquement efficace d'un alcaloïde d'iboga ou un sel ou solvate pharmaceutiquement acceptable de celui-ci.
PCT/US2017/028007 2016-04-18 2017-04-17 Traitement de troubles liés au mouvement au moyen de la noribogaïne WO2017184531A1 (fr)

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CN110483515A (zh) * 2019-09-02 2019-11-22 中国科学院昆明植物研究所 依波加生物碱或其药学上可接受的盐以及制备方法和应用、依波加生物碱药物组合物及应用
WO2021003467A1 (fr) * 2019-07-04 2021-01-07 Sw Holdings, Inc. Compositions de dosage et procédés d'utilisation de composés psychédéliques
WO2021011462A1 (fr) * 2019-07-15 2021-01-21 Demerx, Inc. Méthodes pour le traitement non toxique de sevrage de médicament opioïde combinant la noribogaïne et les cannabinoïdes
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
WO2024059717A1 (fr) * 2022-09-14 2024-03-21 The Board Of Trustees Of The Leland Stanford Junior University Méthodes de traitement à l'aide d'un alcaloïde iboga

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