EP3606530A2 - Dihydrotetrabenazine for use in the treatment a movement disorder - Google Patents

Dihydrotetrabenazine for use in the treatment a movement disorder

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Publication number
EP3606530A2
EP3606530A2 EP18718398.3A EP18718398A EP3606530A2 EP 3606530 A2 EP3606530 A2 EP 3606530A2 EP 18718398 A EP18718398 A EP 18718398A EP 3606530 A2 EP3606530 A2 EP 3606530A2
Authority
EP
European Patent Office
Prior art keywords
dihydrotetrabenazine
pharmaceutically acceptable
combination
subject
odihydrotetrabenazine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP18718398.3A
Other languages
German (de)
French (fr)
Inventor
Andrew John Duffield
Anant Pandya
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Adeptio Pharmaceuticals Ltd
Original Assignee
Adeptio Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB1705306.7A external-priority patent/GB201705306D0/en
Priority claimed from GBGB1705305.9A external-priority patent/GB201705305D0/en
Priority claimed from GBGB1705304.2A external-priority patent/GB201705304D0/en
Application filed by Adeptio Pharmaceuticals Ltd filed Critical Adeptio Pharmaceuticals Ltd
Publication of EP3606530A2 publication Critical patent/EP3606530A2/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4747—Quinolines; Isoquinolines spiro-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia

Definitions

  • This invention relates to the use of (+)-3-dihydrotetrabenazine and combinations of (+)-odihydrotetrabenazine, (-)-odihydrotetrabenazine and/or (+)- ⁇ - dihydrotetrabenazine, for the treatment of movement disorders, such as Tourette's syndrome.
  • Movement disorders can generally be classified into two categories: hyperkinetic movement disorders and hypokinetic movement disorders.
  • Hyperkinetic movement disorders are caused by an increase in muscular activity and can cause abnormal and/or excessive movements, including tremors, dystonia, chorea, tics, myoclonus and stereotypies.
  • Hyperkinetic movement disorders often are often psychological in nature and arise through improper regulation of amine neurotransmitters in the basal ganglia.
  • a particular hyperkinetic movement disorder is Tourette's syndrome, which is an inherited neurological condition characterised by multiple physical and vocal tics.
  • the tics are usually repetitive, but random, physical movements or vocal noises.
  • the vocal tics can be of various forms and include repeating one's own words, the words of others or other sounds. Onset usually occurs in children and continues through to adolescence and adulthood. While the tics associated with Tourette's syndrome are temporarily suppressible, those affected can usually only suppress their tics for limited time periods. There is yet to be an effective treatment to cover all types of tics in all patients, but certain medicaments for tic suppression have been developed.
  • dopamine receptor antagonists display an ability to supress tics in Tourette's syndrome patients and a number dopamine receptor antagonists are currently used in the suppression of Tourette's tics, such as fluphenazine, haloperidol and pimozide.
  • Type 2 vesicular monoamine transporter (VMAT2) is a membrane protein responsible for the transportation of monoamine neurotransmitters, such as dopamine, serotonin and histamine, from cellular cytosol into synaptic vesicles. Inhibition of this protein hinders presynaptic neurons from releasing dopamine, resulting in a depletion of dopamine levels in the brain.
  • VMAT2 inhibitors can be used to treat the symptoms of Tourette's syndrome.
  • Tetrabenazine (Chemical name: 1 ,3,4,6,7,1 1 b-hexahydro-9,10-dimethoxy-3-(2- methylpropyl)-2H-benzo(a)quinolizin-2-one) has been in use as a pharmaceutical drug since the late 1950s. Initially used as an anti-psychotic, tetrabenazine is currently used for treating hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic, tardive dyskinesia and Tourette's syndrome, see for example Jankovic et al., Am. J. Psychiatry. (1999) Aug;
  • tetrabenazine The primary pharmacological action of tetrabenazine is to reduce the supply of monoamines (e.g. dopamine, serotonin, and norepinephrine) in the central nervous system by inhibiting the human vesicular monoamine transporter isoform 2 (hVMAT2).
  • monoamines e.g. dopamine, serotonin, and norepinephrine
  • hVMAT2 human vesicular monoamine transporter isoform 2
  • the central effects of tetrabenazine closely resemble those of reserpine, but it differs from reserpine in that it lacks activity at the VMAT1 transporter.
  • Tetrabenazine has less peripheral activity than reserpine and consequently does not produce VMAT1 -related side effects such as hypotension.
  • Tetrabenazine is an effective and safe drug for the treatment of a variety of hyperkinetic movement disorders and, in contrast to typical neuroleptics, has not been demonstrated to cause tardive dyskinesia. Nevertheless, tetrabenazine does exhibit a number of dose-related side effects including causing depression, parkinsonism, drowsiness, nervousness or anxiety, insomnia and, in rare cases, neuroleptic malignant syndrome, see for example the introductory section of WO2016/127133 (Neurocrine Biosciences).
  • the compound has chiral centres at the 3 and 1 1 b carbon atoms and hence can, theoretically, exist in a total of four isomeric forms, as shown below.
  • tetrabenazine is a racemic mixture of the RR and SS isomers and it would appear that the RR and SS isomers are the most
  • Tetrabenazine has somewhat poor and variable bioavailability. It is extensively metabolised by first-pass metabolism, and little or no unchanged tetrabenazine is typically detected in the urine. It is known that at least some of the metabolites of tetrabenazine are dihydrotetrabenazines formed by reduction of the 2-keto group in tetrabenazine.
  • Dihydrotetrabenazine (Chemical name: 2-hydroxy-3-(2-methylpropyl)- 1 ,3,4,6,7,1 1 b-hexahydro-9,10-dimethoxy-benzo(a)quinolizine) has three chiral centres and can therefore exist in any of the following eight optical isomeric forms:
  • alpha isomers are characterised by a trans relative orientation of the hydroxyl and 2- methylpropyl substituents at the 2- and 3-positions - see for example, Kilbourn et al., Chirality, 9:59-62 (1997) and Brossi et al., Helv. Chim. Acta., vol. XLI, No. 193, pp1793-1806 (1958.
  • the SRR and RSS isomers are commonly referred to as "beta ( ⁇ )” isomers and can be referred to individually as (+)-3-dihydrotetrabenazine and (-)- ⁇ - dihydrotetrabenazine respectively.
  • the beta isomers are characterised by a c/ ' s relative orientation of the hydroxyl and 2-methylpropyl substituents at the 2- and 3- positions.
  • dihydrotetrabenazine is responsible for its biological activity. More specifically, there have been no published studies demonstrating which of the stereoisomers is responsible for the ability of tetrabenazine to treat movement disorders such as Tourette's syndrome.
  • Schwartz et al. (Biochem. Pharmacol. (1966), 15: 645-655) describes metabolic studies of tetrabenazine carried out in rabbits, dogs and humans.
  • Schwartz et al. identified nine metabolites, five of which were unconjugated and the other four of which were conjugated with glucuronic acid.
  • the five unconjugated metabolites were the alpha- and beta-dihydrotetrabenazines, their two oxidised analogues in which a hydroxyl group has been introduced into the 2-methylpropyl side chain, and oxidised tetrabenazine in which a hydroxyl group has been introduced into the 2-methylpropyl side chain.
  • the four conjugated metabolites were all compounds in which the 9-methoxy group had been demethylated to give a 9-hydroxy compound.
  • the chirality of the various metabolites was not studied and, in particular, there was no disclosure of the chirality of the individual a- and ⁇ -isomers.
  • Mehvar et al. ⁇ J. Pharm. Sci. (1987), 76(6), 461 -465) reported a study of the concentrations of tetrabenazine and dihydrotetrabenazine in the brains of rats following administration of either tetrabenazine or dihydrotetrabenazine. The study showed that despite its greater polarity, dihydrotetrabenazine was able to cross the blood-brain barrier. However, the stereochemistry of the dihydrotetrabenazine was not disclosed. Mehvar et al.
  • Roberts et al. ⁇ Eur. J. Clin. Pharmacol. (1986), 29: 703-708) describes the pharmacokinetics of tetrabenazine and its hydroxy-metabolite in patients treated for involuntary movement disorders. Roberts et al. reported that tetrabenazine was extensively metabolised after oral administration resulting in very low plasma concentrations of tetrabenazine but much higher concentrations of a
  • WO 201 1/153157 (Auspex Pharmaceutical, Inc.) describes deuterated forms of dihydrotetrabenazine. Many deuterated forms of dihydrotetrabenazine are depicted but the application only provides sufficient information to allow a small number of the depicted compounds to be synthesised. Although racemic mixtures of d 6 -a-dihydrotetrabenazine and d 6 -3-dihydrotetrabenazine as disclosed, these mixtures were not resolved and the properties of the individual (+) and (-) isomers are not studied.
  • WO 2014/047167 (Auspex Pharmaceutical, Inc.) describes number of deuterated forms of tetrabenazine and its derivatives. Again, the individual (+) and (-) isomers of deuterated forms of a- and ⁇ - dihydrotetrabenazine were not separated or studied.
  • AUC area under the curve
  • (+)-odihydrotetrabenazine is not primarily responsible for the therapeutic properties of tetrabenazine.
  • (+)-o dihydrotetrabenazine may be responsible for a relatively small contribution to the therapeutic properties of tetrabenazine.
  • enantiomers may have different biological properties, for example wherein one enantiomer is useful for the treatment of a specific disease or condition and wherein the other enantiomer is toxic or produces unwanted side effects.
  • thalidomide which was marketed as a sedative and also prescribed to pregnant women to treat morning sickness, but it was later found that one enantiomer caused birth defects in children of the women who had been administered thalidomide during their pregnancy.
  • dihydrotetrabenazine compounds of the invention may be used for the treatment of movement disorders and in particular hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
  • hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
  • the invention provides a pharmaceutical unit dosage form comprising (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.
  • the combination of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof is not administered with a therapeutic effective amount of amantadine.
  • the combination of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof is not administered with any amount of amantadine.
  • the invention provides a combination of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for use in medicine.
  • (+)-a-Dihydrotetrabenazine is believed to have the chemical structure (I) shown below:
  • the invention provides a combination of (+)-o
  • the invention provides a combination of (+)-o
  • dihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof for use in the treatment of a movement disorder.
  • the invention provides:
  • a method of treatment of a movement disorder in a subject in need thereof comprises administering to the subject a combination of (+)-odihydrotetrabenazine and (-)-a-dihydrotetrabenazine, or pharmaceutically acceptable salts thereof.
  • the invention provides a combination of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for use in a method of treatment of a movement disorder, wherein the method comprises administering to a subject (.e.g. a human subject) in need thereof an effective therapeutic amount of the combination sufficient to provide a dosage of from 1 mg to 20 mg of (+)-odihydrotetrabenazine per day.
  • a subject .e.g. a human subject
  • the invention provides:
  • a subject comprises administering to a subject (.e.g. a human subject) in need thereof an effective therapeutic amount of a combination of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, sufficient to provide a dosage of from 1 mg to 20 mg of (+)-odihydrotetrabenazine per day.
  • the daily dose of (+)-odihydrotetrabenazine is from 1 mg to 20 mg.
  • (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine typically forms part of a chronic treatment regime.
  • the (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine may therefore be administered to a patient for a treatment period of at least a week, more usually at least two weeks, or at least a month, and typically longer than a month. Where a patient is shown to respond well to treatment, the period of treatment can be longer than six months and may extend over a period of years.
  • the chronic treatment regime may involve the administration of the (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine every day, or the treatment regime may include days when no (+)-odihydrotetrabenazine or (-)-a- dihydrotetrabenazine is administered.
  • the dosage administered to the subject may vary during the treatment period.
  • the initial dosage may be increased or decreased depending on the subject's response to the treatment.
  • a subject may, for example, be given an initial low dose to test the subject's tolerance towards the (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine, and the dosage thereafter increased as necessary up to the maximum daily intake of 20 mg.
  • an initial daily dosage administered to the patient may be selected so as to give an estimated desired degree of VMAT2 blockage, following which a lower maintenance dose may be given for the remainder of the treatment period, with the option of increasing the dosage should the subject's response to the treatment indicate that an increase is necessary.
  • (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine required to achieve the desired therapeutic effect will be dependent on the weight of the subject to be treated.
  • the quantities of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine administered to the subject can be expressed in a number of mg/kg, where in the kg relates the weight of the subject to be treated.
  • the appropriate dosage amount can therefore be calculated by multiplying the mg/kg amount by the weight of the subject to be treated.
  • the invention provides a combination of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine or pharmaceutically acceptable salts thereof, for use in a method for the treatment of a movement disorder, wherein the treatment comprises administering to a subject an amount of the combination of from 0.01 mg/kg to 0.3 mg/kg (e.g. between 0.01 mg/kg and 0.3 mg/kg) per day provided that the total amount of (+)-odihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg.
  • the invention provides:
  • a method of treatment of a movement disorder in a subject in need thereof comprises administering to the subject a combination of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, in an amount from 0.01 mg/kg to 0.3 mg/kg (e.g. between 0.01 mg/kg and 0.3 mg/kg) per day, provided that the total amount of (+)-o dihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg.
  • dihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg.
  • dihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg.
  • dihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg.
  • the combinations of the invention are useful in the treatment of movement disorders, and in particular hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
  • hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
  • the combinations of the invention are for use in the treatment of a hyperkinetic movement disorder selected from tic disorders, Huntington's disease, tardive dyskinesia and Tourette's syndrome.
  • the combinations of the invention are for use in the treatment of tardive dyskinesia.
  • the combinations of the invention are for use in the treatment of Tourette's syndrome.
  • VMAT2 vesicular monoamine transporter 2
  • the present invention provides plasma levels of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine that are sufficient to give effective treatment of movement disorders but do not block the VMAT2 proteins to an extent that causes
  • VMAT2 blocking can be determined by competitive binding studies using Positron Emission Tomography (PET).
  • PET Positron Emission Tomography
  • the proportion of binding sites occupied can be determined (see for example, Matthews et al., "Positron emission tomography molecular imaging for drug development", Br. J. Clin. Pharmacol., 73:2, 175-186).
  • the invention provides a combination of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for use in a method for the treatment of a movement disorder, wherein the treatment comprises administering to a subject an amount of the combination sufficient to cause a level of blocking of from 20% to 90% of VMAT2 proteins in the subject.
  • the invention provides:
  • a method of treatment of a movement disorder in a subject in need thereof comprises administering to the subject a combination of (+)-odihydrotetrabenazine and (-)-a-dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, sufficient to cause a level of blocking of from 20% to 90% of the VMAT2 proteins in the subject.
  • a combination of (+)-a-dihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of a movement disorder in a subject (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 20% to 90% of VMAT2 proteins in the subject.
  • (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in combination with (-)-odihydrotetrabenazine or a pharmaceutically acceptable salt thereof for the treatment of a movement disorder in a subject (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 20% to 90% of VMAT2 proteins in the subject.
  • the combinations of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine may be racemic.
  • the combinations of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine may be scalemic (i.e. non-racemic).
  • the ratio of (+)-o dihydrotetrabenazine to (-)-odihydrotetrabenazine in the combination can be, for example, from 0.5:1 to 20:1.
  • the ratio of (+)-o dihydrotetrabenazine to (-)-odihydrotetrabenazine in the combination can be a ratio in a range selected from:
  • (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine are typically unaccompanied by other dihydrotetrabenazine isomers.
  • minor amounts of other tetrabenazine isomers may be present but these generally are present in amounts corresponding to no more than 20% by weight (i.e. 0.2:1 ), compared to the total weight of the combination. More usually, other dihydrotetrabenazine isomers are present in amounts corresponding to no more than 10% or 5%, or 2%, or 1 % by weight (i.e. 0.2:1 ), compared to the total weight of the combination. More preferably, other dihydrotetrabenazine isomers are either completely absent, or are present in amounts of less than 1 % by weight, for example less than 0.5% by weight.
  • the (+)-odihydrotetrabenazine and/or (-)-odihydrotetrabenazine can be administered as the free base or as a pharmaceutically acceptable salt.
  • one or both of the (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine are administered as pharmaceutically acceptable salts.
  • both the (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine are administered as free bases.
  • (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine are calculated as the amounts of the free base, or when the (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine is in the form of a pharmaceutically acceptable salt, the amount of (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine per se present in the pharmaceutically acceptable salt.
  • (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine or pharmaceutically acceptable salts thereof typically, the (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine or pharmaceutically acceptable salt thereof, are not administered with a therapeutically effective amount of amantadine. More particularly, the (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine, or pharmaceutically acceptable salt thereof, are not administered with any amount of amantadine.
  • the unit dosage form does not comprise a therapeutically effective amount of amantadine and, more particularly, the pharmaceutical unit dosage form does not comprise any amount of amantadine.
  • the pharmaceutical unit dosage form may be other than an extended release or delayed release dosage form.
  • (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine, or pharmaceutically acceptable salt thereof may be administered as an immediate release unit dosage form.
  • dihydrotetrabenazine does not appear to be primarily responsible for the therapeutic properties of tetrabenazine. On the contrary, it appears that (+)-o dihydrotetrabenazine may be responsible for a relatively small contribution to the therapeutic properties of tetrabenazine.
  • (+)-oisomer was 3- to 4-times more active than the (+)-3-isomer
  • (+)-3-isomer is present in the body following administration of tetrabenazine in an amount over 50 times greater suggests that (+)-3-dihydrotetrabenazine may make a major contribution to the activity of tetrabenazine.
  • (+)- ⁇ - dihydrotetrabenazine per se having the chemical name, (S,R,R,)-3-isobutyl-9,10- dimethyloxy-1 ,3,4,5,7,1 1 b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-ol, and having the formula (III) shown below
  • (III) is effective in the treatment of movement disorders, despite previous findings that it has a lower VMAT2 activity than (+)-odihydrotetrabenazine.
  • the invention provides a unit dosage form comprising (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the invention provides (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in medicine.
  • unit dosage form comprising (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, which is substantially free of other dihydrotetrabenazine isomers.
  • the unit dosage form can be one which is administered orally, for example a capsule or tablet.
  • pharmaceutically acceptable salt thereof can be administered in a non-solid dosage form such as a solution, syrup, suspension or gel.
  • a non-solid dosage form such as a solution, syrup, suspension or gel.
  • a unit dosage form comprising from 1 mg to 200 mg (e.g. between 1 mg and 200 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 1 mg to 150 mg (e.g. between 1 mg and 150 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 1 mg to 100 mg (e.g. between 1 mg and 100 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 1 mg to 80 mg (e.g. between 1 mg and 80 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 3 mg to 200 mg (e.g. between 3 mg and 200 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 3 mg to 150 mg (e.g. between 3 mg and 150 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 3 mg to 100 mg (e.g. between 3 mg and 100 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 3 mg to 80 mg (e.g. between 3 mg and 80 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 5 mg to 200 mg (e.g. between 5 mg and 200 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 5 mg to 150 mg (e.g. between 5 mg and 150 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 5 mg to 100 mg (e.g. between 5 mg and 100 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 5 mg to 80 mg (e.g. between 5 mg and 80 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 3 mg to 60 mg (e.g. between 3 mg and 60 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 5 mg to 60 mg (e.g. between 5 mg and 60 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 10 mg to 60 mg (e.g. between 10 mg and 60 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising from 15 mg to 60 mg (e.g. between 15 mg and 60 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising approximately 20 mg of (+)- ⁇ - dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising approximately 30 mg of (+)- ⁇ - dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising approximately 40 mg of (+)- ⁇ - dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising approximately 50mg of (+)- ⁇ - dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a unit dosage form comprising approximately 60 mg of (+)- ⁇ - dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the unit dosage forms defined and described above are typically for use in the treatment of a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
  • a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
  • the unit dosage forms described above are for use in the treatment of a hyperkinetic movement disorder selected from tic disorders, Huntington's disease, tardive dyskinesia and Tourette's syndrome.
  • the unit dosage forms described above are for use in the treatment of tardive dyskinesia. In another particular embodiment, the unit dosage forms described above are for use in the treatment of Tourette's syndrome.
  • (+)-3-dihydrotetrabenazine is useful in the blocking of the VMAT2 receptor in the treatment of movement disorders.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (+)- ⁇ -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the invention also provides (+)-3-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for use as a VMAT2 inhibitor.
  • (+)-3-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for use as a VMAT2 inhibitor.
  • a method of treatment of a hyperkinetic movement disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of (+)"3-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.
  • chorea tic disorders, tardive dyskinesia, dystonia or Tourette's syndrome in a subject in need thereof (e.g. a mammalian subject such as a human), which method comprises administering to the subject a therapeutically effective amount of (+)-3-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.
  • (+)-3-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a hyperkinetic movement disorder.
  • (+)-3-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a of Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia or Tourette's syndrome.
  • the treatment comprises administering to a subject an amount of (+)-3-dihydrotetrabenzine from 1 mg to 200 mg (e.g. between 1 mg and 200 mg) per day.
  • a method of treatment of a movement disorder in a subject in need thereof comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine from 1 mg to 200 mg (e.g. between 1 mg and 200 mg) per day.
  • (+)-3-dihydrotetrabenazine for the manufacture of a medicament for the treatment of a movement disorder, which treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine from 1 mg to 200 mg (e.g. between 1 mg and 200 mg) per day.
  • (+)-3-dihydrotetrabenazine, or pharmaceutically acceptable salt thereof is not administered with an effective amount of amantadine.
  • the (+)-3-dihydrotetrabenazine, or pharmaceutically acceptable salt thereof is not administered with amantadine.
  • the (+)"3-dihydrotetrabenazine, or pharmaceutically acceptable salt thereof, may be administered as an immediate release unit dosage form.
  • (+)"3-dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 1 mg to 150 mg (e.g. between 1 mg and 150) mg per day.
  • (+)"3-dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 1 mg to 100 mg (e.g. between 1 mg and 100) mg per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 3 mg to 200 mg (e.g. between 3 mg and 200) mg per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 3 mg to 150 mg (e.g. between 3 mg and 150) mg per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 3 mg to 100 mg (e.g. between 3 mg and 100) mg per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 5 mg to 200 mg (e.g. between 5 mg and 200) mg per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 5 mg to 150 mg (e.g. between 5 mg and 150) mg per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 5 mg to 100 mg (e.g. between 5 mg and 100) mg per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 1 mg to 60 mg (e.g. between 1 mg and 60 mg) per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 1 mg to 50 mg (e.g. between 1 mg and 50 mg) per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 5 mg to 70 mg (e.g. between 5 mg and 70 mg) per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 5 mg to 60 mg (e.g. between 5 mg and 60 mg) per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine of approximately 10 mg per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine of approximately 15 mg per day.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine of approximately 20 mg per day.
  • (+)"3-dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine of approximately 30 mg per day.
  • (+)-3-dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine of approximately 40 mg per day.
  • the quantity of (+)-3-dihydrotetrabenazine specified may be administered once per day or in several (e.g. two) doses per day.
  • the quantity of (+)-3-dihydrotetrabenazine specified is administered once daily.
  • (+)-3-dihydrotetrabenazine typically forms part of a chronic treatment regime.
  • the (+)-3-dihydrotetrabenazine may therefore be administered to a patient for a treatment period of at least a week, more usually at least two weeks, or at least a month, and typically longer than a month. Where a patient is shown to respond well to treatment, the period of treatment can be longer than six months and may extend over a period of years.
  • the chronic treatment regime may involve the administration of the (+)- ⁇ - dihydrotetrabenazine every day, or the treatment regime may include days when no (+)"3-dihydrotetrabenazine is administered.
  • the dosage administered to the subject may vary during the treatment period.
  • the initial dosage may be increased or decreased depending on the subject's response to the treatment.
  • a subject may, for example, be given an initial low dose to test the subject's tolerance towards the (+)-3-dihydrotetrabenazine, and the dosage thereafter increased as necessary up to the maximum daily intake of 80 mg (or other daily intakes as described above).
  • an initial daily dosage administered to the patient may be selected so as to give an estimated desired degree of VMAT2 blockage, following which a lower maintenance dose may be given for the remainder of the treatment period, with the option of increasing the dosage should the subject's response to the treatment indicate that an increase is necessary.
  • the quantity of (+)-3-dihydrotetrabenazine required to achieve the desired therapeutic effect may be dependent on the weight of the subject to be treated.
  • the quantities of (+)-3-dihydrotetrabenazine administered to the subject can be defined in terms of the weight in milligrams of (+)-3-dihydrotetrabenazine administered to the subject per kilogram of the subject's body weight, which can be abbreviated to mg/kg.
  • the appropriate dosage amount can therefore be calculated by multiplying the mg/kg amount by the weight of the subject to be treated.
  • the invention also provides:
  • a method of treatment of a movement disorder in a subject in need thereof e.g. a mammalian subject such as a human
  • which treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine from 0.01 mg/kg to 2.0 mg/kg (e.g. between 0.01 mg/kg and 2.0 mg/kg) per day, provided that the total amount of (+)-3-dihydrotetrabenazine administered per day is in the range from 1 mg to 80 mg (or such other range as defined above).
  • a method of treatment of a movement disorder in a subject in need thereof e.g. a mammalian subject such as a human
  • which treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine from 0.01 mg/kg to 2.0 mg/kg (e.g. between 0.01 mg/kg and 2.0 mg/kg) per day, provided that the total amount of (+)-3-dihydrotetrabenazin
  • (+)-3-dihydrotetrabenazine for the manufacture of a medicament for the treatment of a movement disorder, which treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine from 0.01 mg/kg to 2.0 mg/kg (e.g. between 0.01 mg/kg and 2.0 mg/kg) per day, provided that the total amount of (+)-3-dihydrotetrabenazine administered per day is in the range from 1 mg to 80 mg (or such other range as defined above).
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject from 0.25 mg/kg to 1.5 mg/kg (e.g. between 0.25 mg / kg and 1.5 mg / kg) of (+)- ⁇ - dihydrotetrabenazine, provided that the total amount of (+)- ⁇ - dihydrotetrabenazine administered per day is in the range from 1 mg to 80 mg (or such other range as defined above).
  • (+)"3-dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject from 0.01 mg/kg to 1.25 mg/kg (e.g. between 0.01 mg / kg and 1 .25 mg / kg) of (+)- ⁇ - dihydrotetrabenazine per day, provided that the total amount of (+)- ⁇ - dihydrotetrabenazine administered per day is in the range from 1 mg to 60 mg (or such other range as defined above).
  • (+) ⁇ -dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject from 0.1 mg/kg to 1.25 mg/kg (e.g. between 0.1 mg / kg and 1 .25 mg / kg) of (+)- ⁇ - dihydrotetrabenazine, provided that the total amount of (+)- ⁇ - dihydrotetrabenazine administered per day is in the range from 1 mg to 60 mg (or such other range as defined above).
  • (+) ⁇ -dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject from 0.25 mg/kg to 1.25 mg/kg (e.g. between 0.25 mg / kg and 1 .25 mg / kg) of (+)- ⁇ - dihydrotetrabenazine, provided that the total amount of (+)- ⁇ - dihydrotetrabenazine administered per day is in the range from 1 mg to 60 mg (or such other range as defined above).
  • (+) ⁇ -dihydrotetrabenazine can be administered as the free base or as a pharmaceutically acceptable salt.
  • references herein to (+)- ⁇ - dihydrotetrabenazine also include pharmaceutically acceptable salts thereof.
  • the (+)-3-dihydrotetrabenazine is administered as a pharmaceutically acceptable salt.
  • the (+)-3-dihydrotetrabenazine is administered as a free base.
  • quantities or ranges of quantities of (+)-3-dihydrotetrabenazine are stated herein, these are calculated as the amounts of the free base, or when the (+)- ⁇ - dihydrotetrabenazine is in the form of a pharmaceutically acceptable salt, the amount of (+)-3-dihydrotetrabenazine free base present in the pharmaceutically acceptable salt.
  • Complete blocking of the VMAT2 proteins is considered undesirable as this can lead to unwanted side effects such as Parkinsonism.
  • the present invention provides plasma levels of (+)-3-dihydrotetrabenazine that are sufficient to give effective treatment of movement disorders but do not block the VMAT2 proteins to an extent that causes Parkinsonism and similar side effects.
  • the levels of VMAT2 blocking can be determined by competitive binding studies using Positron
  • Emission Tomography PET
  • a radioactive ligand By co-administering a radioactive ligand with the compound of interest at various concentrations, the proportion of binding sites occupied can be determined (see for example, Matthews et al., "Positron emission tomography molecular imaging for drug development", Br. J. Clin. Pharmacol., 73:2, 175-186). Accordingly, the invention also provides:
  • a method of treatment of a movement disorder in a subject in need thereof comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 90% of the VMAT2 proteins in the subject.
  • (+)-3-dihydrotetrabenazine for the manufacture of a medicament for the treatment of a movement disorder, which treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 90% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 85% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 80% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 75% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 70% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 20% to 90% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 25% to 85% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of from 30% to 80% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 35% to 75% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 35% to 70% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 40% to 75% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of from 45% to 75% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of from 35% to 80% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 50% to 80% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 55% to 80% of the VMAT2 proteins in the subject.
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 30% to 70% (e.g. between 30% and 70%).
  • (+)"3-dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a blocking level of VMAT2 proteins in the subject of from 30% to 65% (e.g. between 30% and 65%).
  • (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a blocking level of VMAT2 proteins in the subject of from 30% to 60% (e.g. between 30% and 60%).
  • (+)"3-dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level blocking of VMAT2 proteins in the subject of from 40% to 80% (e.g. between 40% and 80%).
  • (+)-3-dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 75% (e.g. between 40% and 75%).
  • (+)"3-dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 70% (e.g. between 40% and 70%).
  • (+)"3-dihydrotetrabenazine for use a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 65% (e.g. between 40% and 65%).
  • the movement disorder can be a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia, myoclonus and Tourette's syndrome.
  • the movement disorder is Tourette's syndrome
  • the (+)-3-dihydrotetrabenazine is accompanied by no more than 20% by weight, relative to the (+)- ⁇ - dihydrotetrabenazine, of any other isomer of dihydrotetrabenazine.
  • (+)-3-dihydrotetrabenazine is accompanied by no more than 10% by weight, relative to the (+)-3-dihydrotetrabenazine, of any other isomer of dihydrotetrabenazine; preferably no more than 5% by weight, relative to the (+)- ⁇ - dihydrotetrabenazine, of any other isomer of dihydrotetrabenazine; and more preferably no more than 2% by weight, relative to the (+)-3-dihydrotetrabenazine, of any other isomer of dihydrotetrabenazine.
  • (+)- ⁇ - dihydrotetrabenazine is accompanied by less than 1 % (e.g. less than 0.5% or less than 0.1 %) relative to the (+)-3-dihydrotetrabenazine, of any other isomer of dihydrotetrabenazine.
  • the (+)-3-dihydrotetrabenazine typically has an isomeric purity of at least 80%.
  • isomeric purity in the present context refers to the amount (+)- ⁇ - dihydrotetrabenazine present relative to the total amount or concentration of dihydrotetrabenazines of all isomeric forms. For example, if 90% of the total dihydrotetrabenazine present in the composition is (+)-3-dihydrotetrabenazine, then the isomeric purity is 90%.
  • the (+)"3-dihydrotetrabenazine of the invention may have an isomeric purity of greater than 82%, greater than 85%, greater than 87%, greater than 90%, greater than 91 %, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or greater than 99.9%.
  • (+)- ⁇ -dihydrotetrabenazine or pharmaceutically acceptable salts thereof typically, the (+)"3-dihydrotetrabenazine, or pharmaceutically acceptable salt thereof, are not administered with a therapeutically effective amount of amantadine. More particularly, the (+)-3-dihydrotetrabenazine, or pharmaceutically acceptable salt thereof, are not administered with any amount of amantadine.
  • the unit dosage form does not comprise a therapeutically effective amount of amantadine and, more particularly, the pharmaceutical unit dosage form does not comprise any amount of amantadine.
  • the pharmaceutical unit dosage form may be other than an extended release or delayed release dosage form.
  • the (+)-3-dihydrotetrabenazine, or pharmaceutically acceptable salt thereof may be administered as an immediate release unit dosage form.
  • (I) will be useful in the prophylaxis or treatment of inter alia the disease states and conditions for which tetrabenazine is currently used or proposed.
  • these combinations of dihydrotetrabenazine isomers may be used for the treatment of hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and, in particular, Tourette's syndrome.
  • the invention provides a pharmaceutical combination comprising:
  • the invention provides a pharmaceutical combination comprising:
  • the invention provides a pharmaceutical combination comprising:
  • the invention provides a pharmaceutical combination comprising:
  • dihydrotetrabenazine may be referred to herein collectively as "the
  • dihydrotetrabenazine or “the dihydrotetrabenazines”, unless the context indicates otherwise.
  • active compounds When describing types of pharmaceutical formulation, they may also be referred to collectively as the "active compounds”.
  • the pharmaceutical combination may be substantially free of (-)- ⁇ - dihydrotetrabenazine. Accordingly, the invention also provides a pharmaceutical combination as described herein, wherein the unit dosage form is substantially free of (-)"3-dihydrotetrabenazine.
  • substantially free of (-)-3-dihydrotetrabenazine is meant that the % weight of (-)"3-dihydrotetrabenazine present compared to the total weight of all isomers of dihydrotetrabenazine is less than 5%, preferably less than 3%, more preferably less than 2% and most preferably less than 1 %.
  • the unit dosage forms may comprise from 35 to 75 parts by weight of (+)-3-dihydrotetrabenazine and from 25 to 55 parts by weight of an odihydrotetrabenazine (which may be either (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine or a mixture thereof).
  • a pharmaceutical combination of the invention comprises:
  • the pharmaceutical combination may comprise:
  • the pharmaceutical combination comprises (+)- ⁇ - dihydrotetrabenazine and (+)-odihydrotetrabenazine in approximately equimolar amounts.
  • a pharmaceutical combination of the invention comprises: (a) 45-65 parts by weight of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
  • (+)-odihydrotetrabenazine or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical combination of the invention comprises:
  • a pharmaceutical combination of the invention comprises: (a) 45-65 parts by weight of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
  • a pharmaceutical combination of the invention comprises:
  • dihydrotetrabenazines (a) and (b) and/or (c) in a form that is suitable for administration to a subject, typically a human or other animal subject.
  • the term therefore excludes crude reaction mixtures, partially purified reaction products, whole blood samples or blood fraction samples such as plasma or other biological samples such as urine samples containing the combinations. It also excludes simple solutions of the combinations in non-pharmaceutically acceptable solvents (e.g. chloroform, dichloromethane) that are not normally used in pharmacy.
  • the pharmaceutical combinations may be in the form of mixtures of the pure compounds or the combinations may comprise one or more pharmaceutically acceptable excipients.
  • the pharmaceutical combinations comprise a pharmaceutically acceptable excipient and are formulated as unit dosage forms containing defined amounts of the dihydrotetrabenazines (a), (b) and/or (c).
  • one or more of the three dihydrotetrabenazines (a), (b) and (c) may be formulated separately but used in combination. More typically, however, the three dihydrotetrabenazines (a), (b) and (c) are formulated together in a pharmaceutical composition, and in particular a unit dosage form.
  • the sum of the amounts of the three isomers (+)-3-dihydrotetrabenazine, (-)-a- dihydrotetrabenazine and (+)-odihydrotetrabenazine may be selected so that it does not exceed 100mg.
  • the pharmaceutical unit dosage form does not comprise an effective amount of amantadine.
  • the pharmaceutical unit dosage form is one that does not comprise amantadine.
  • the pharmaceutical unit dosage form may be an immediate release unit dosage form.
  • the unit dosage form can be one which is administered orally, for example a capsule or tablet.
  • the unit dosage form can be one which is administered orally, for example a capsule or tablet.
  • hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome. More particularly, the pharmaceutical combinations (and unit dosage forms) described above are for use in the treatment of a hyperkinetic movement disorder selected from tic disorders, Huntington's disease, tardive dyskinesia and Tourette's syndrome.
  • the pharmaceutical combinations (and unit dosage forms) described above are for use in the treatment of tardive dyskinesia.
  • the pharmaceutical combinations (and unit dosage forms) described above are for use in the treatment of Tourette's syndrome.
  • the invention provides:
  • a pharmaceutical combination as defined herein for use in the treatment of a hyperkinetic movement disorder is provided.
  • a method of treatment of a hyperkinetic movement disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a pharmaceutical combination as defined herein.
  • (+)-3-dihydrotetrabenazine, (-)-a- dihydrotetrabenazine; and optionally (+)-odihydrotetrabenazine is typically administered once per day.
  • Complete blocking of VMAT2 is considered undesirable as this can lead to unwanted side effects, such as Parkinsonism.
  • the present invention provides plasma levels of dihydrotetrabenazines that are sufficient to give effective treatment of movement disorders but do not block VMAT2 to an extent that causes Parkinsonism and similar side effects.
  • the levels of VMAT2 blocking can be determined by competitive binding studies using Positron Emission Tomography (PET).
  • the proportion of binding sites occupied can be determined (see for example, Matthews et al., "Positron emission tomography molecular imaging for drug development", Br. J. Clin. Pharmacol., 73:2, 175-186).
  • the invention also provides:
  • the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of greater than 20% of
  • VMAT2 proteins in the subject are VMAT2 proteins in the subject.
  • the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of greater than 30% of
  • VMAT2 proteins in the subject are VMAT2 proteins in the subject.
  • the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of greater than 40% of
  • VMAT2 proteins in the subject are VMAT2 proteins in the subject.
  • the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of less than 80% of VMAT2 proteins in the subject.
  • the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of less than 75% of VMAT2 proteins in the subject.
  • the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of less than 70% of VMAT2 proteins in the subject.
  • the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 20% to 90% (e.g. between 20% and 90%).
  • the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 30% to 80% (e.g. between 30% and 80%).
  • the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 30% to 75% (e.g. between 30% and 75%).
  • the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 65% (e.g. between 40% and 65%).
  • the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 60% (e.g. between 40% and 60%).
  • the combinations are not administered with a therapeutically effective amount of amantadine. More particularly, the combinations, are not administered with any amount of amantadine.
  • the unit dosage form does not comprise a therapeutically effective amount of amantadine and, more particularly, the pharmaceutical unit dosage form does not comprise any amount of amantadine.
  • the pharmaceutical unit dosage form may be other than an extended release or delayed release dosage form.
  • the combinations of dihydrotetrabenazines (a) and (b) and/or (c) may be administered as an immediate release unit dosage form.
  • the salts can be synthesized from the parent compound by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties,
  • salts can be prepared by reacting the free base form of the compound with the acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, acetone, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g.
  • salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1 -19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into
  • the isomers of dihydrotetrabenazine may contain one or more isotopic
  • references to a particular element includes within its scope all isotopes of the element.
  • a reference to hydrogen includes within its scope 1 H, 2 H (D), and 3 H (T).
  • references to carbon and oxygen include within their scope respectively 11 C, 12 C, 13 C and 14 C and 16 0 and 18 0.
  • the isomers of dihydrotetrabenazine of the invention does not contain isotopes (such as 11 C or 3 H) in amounts higher than their natural abundance.
  • the percentage of the total hydrogen atoms in the (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine that are deuterium atoms is less than 2%, more typically less than 1 %, more usually less than 0.1 %, preferably less than 0.05% and most preferably no more than 0.02%.
  • the isotopes may be radioactive or non-radioactive.
  • the isomers of dihydrotetrabenazine contain no radioactive isotopes. Such compounds are preferred for therapeutic use.
  • the one or more of the isomers of dihydrotetrabenazine may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.
  • references to the isomers of dihydrotetrabenazine include any solvates formed by the compounds.
  • solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent).
  • solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulphoxide.
  • Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • X-ray crystallography X-ray crystallography
  • the solvates can be stoichiometric or non-stoichiometric solvates.
  • solvates are hydrates such as hemihydrates, monohydrates and dihydrates.
  • solvates and the methods used to make and characterise them see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.
  • the compound of the invention may be anhydrous. Therefore, in another embodiment, one or more of the isomers of dihydrotetrabenazine are in an anhydrous form.
  • (+)-a-Dihydrotetrabenazine and (-)-odihydrotetrabenazine can be prepared from tetrabenazine according to the synthetic route shown in Scheme 1.
  • Racemic tetrabenazine (3-isobutyl-9,10-dimethyoxy-1 ,3,4,6,7,1 1 b-hexahydro-2/-/- pyrido[2,1 ,a]isoquinolin-2-one) containing the RR and SS isomers of tetrabenazine is reduced with sodium borohydride to afford a mixture of four
  • dihydrotetrabenazine (RRR and SSS isomers) constitutes the major product and a racemic mixture of the ⁇ -dihydrotetrabenazines (the SRR and RSS isomers) constitutes a minor product.
  • the ⁇ -dihydrotetrabenazines can be removed during an initial purification procedure, for example by chromatography or recrystallization and then the racemic odihydrotetrabenazines resolved by well known methods such as chiral chromatography or the formation of diastereoisomeric salts by reaction with chiral acids followed by separation by recrystallisation.
  • (+)-o dihydrotetrabenazine isomer (I) ((2R, 3R, 77ibR)-3-isobutyl-9,10-dimethoxy- 1 ,3,4,6,7,1 1 b-hexahydro-2/-/-pyrido[2,1 ,a]isoquinolin-2-ol) can be obtained.
  • (+)-a-Dihydrotetrabenazine and (-)-odihydrotetrabenazine can also be prepared according to Yao et al., "Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors", Eur. J. Med. Chem., (201 1 ), 46, pp. 1841 - 1848.
  • (+)-P"Dihydrotetrabenazine (compound of formula (III)) can be prepared from tetrabenazine according to the synthetic route shown in Scheme 2.
  • Racemic tetrabenazine (S-isobutyl-g O-dimethyoxy-I ⁇ J I b-hexahydro ⁇ H- pyrido[2,1 ,a]isoquinolin-2-one) containing the RR and SS isomers of tetrabenazine is reduced with sodium borohydride to afford a mixture of four
  • dihydrotetrabenazine isomers of which a racemic mixture of the ⁇ - dihydrotetrabenazines ⁇ SRR and RSS isomers) constitutes the major product and a racemic mixture of the odihydrotetrabenazines (the RRR and SSS isomers) constitutes a minor product.
  • the odihydrotetrabenazines can be removed during an initial purification procedure, for example by chromatography or recrystallization and then the racemic ⁇ -dihydrotetrabenazines resolved (e.g.
  • the stereochemical configuration of (+)-3-dihydrotetrabenazine can be
  • (+)-a-Dihydrotetrabenazine, (-)-odihydrotetrabenazine and (+)- ⁇ - dihydrotetrabenazine can also be prepared according to Yao et al., "Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors", Eur. J. Med. Chem., (201 1 ), 46, pp. 1841 - 1848.
  • (+)-3-dihydrotetrabenazine, (-)-a- dihydrotetrabenazine and, where present the (+)-a-dihydrotetrabenazine, or their respective salts, can be mixed in the required proportions.
  • compositions of the invention can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, ophthalmic, otic, rectal, intra- vaginal, or transdermal administration.
  • compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.
  • Pharmaceutical unit dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, sprays, powders, granules, elixirs and suspensions, sublingual tablets, sprays, wafers or patches and buccal patches.
  • compositions containing the combinations of the invention are capsules and tablets.
  • Pharmaceutical unit dosage forms containing the combinations of the invention can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
  • tablet compositions can contain a unit dosage of the combination of active compounds together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g.; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, talc, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch.
  • Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g.
  • swellable crosslinked polymers such as crosslinked carboxymethylcellulose
  • lubricating agents e.g. stearates
  • preservatives e.g. parabens
  • antioxidants e.g. BHT
  • buffering agents for example phosphate or citrate buffers
  • effervescent agents such as
  • citrate/bicarbonate mixtures Such excipients are well known and do not need to be discussed in detail here.
  • Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form.
  • Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.
  • the solid dosage forms e.g.: tablets, capsules etc.
  • the solid dosage forms can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating.
  • the coating e.g. a EudragitTM type polymer
  • the coating can be designed to release the active component at a desired location within the gastro-intestinal tract.
  • the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum or duodenum.
  • the isomers of dihydrotetrabenazine, or pharmaceutically acceptable salts thereof making up the combinations of the invention can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
  • a release controlling agent for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
  • the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract.
  • compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.
  • compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.
  • formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped mouldable or waxy material containing the active compound.
  • compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known.
  • powder inhaler devices or aerosol dispensing devices are well known.
  • aerosol dispensing devices are well known.
  • formulations typically comprise the combination of dihydrotetrabenazine isomers, or pharmaceutically acceptable salts thereof together with an inert solid powdered diluent such as lactose.
  • the isomers of dihydrotetrabenazine, and their respective salts can be formulated separately and used in combination, or they can be formulated together. When formulated together, they can be provided as a mixture to which one or more pharmaceutical excipients is (are) added before processing (e.g. compressing to form a tablet or filling into a capsule) to form a pharmaceutical composition such as a unit dosage form. Alternatively, they can be added separately to an excipient or mixture of excipients and processed together.
  • the dihydrotetrabenazine isomers can be formulated separately in different granules, pellets, microbeads or mini-tablets and then brought together and processed to give a pharmaceutical composition (e.g. by filling into a capsule or compressing to form a tablet).
  • the different isomers of the dihydrotetrabenazine isomers can be contained within different layers in a multi- layered tablet.
  • Particular pharmaceutical compositions of the invention are compositions selected from:
  • Pellets and tablets formulated to provide release kinetics of the types defined above can be prepared according to methods well known the skilled person; for example as described in Remington's Pharmaceutical Sciences (idem) and "Remington - The Science and Practice of Pharmacy, 21 st edition, 2006, ISBN 0- 7817-4673-6.
  • the combinations of the invention will generally be presented in pharmaceutical unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity, as described above.
  • the combinations of the invention will be administered to a subject (patient) in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect, as described above.
  • Figure 1 shows the average total distance travelled by rats when treated with vehicle (with or without amphetamine induction) and (-)-odihydrotetrabenazine at a dose of 2.5 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 1 below.
  • Figure 2 shows the average total stereotypic behaviour by rats when treated with vehicle (with or without amphetamine induction) and (-)-odihydrotetrabenazine at a dose of 2.5 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 1 below.
  • Figure 3 shows the average total distance travelled by rats when treated with vehicle (with or without amphetamine induction) and (+)-odihydrotetrabenazine at doses of 0.1 mg/kg and 0.25 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 2 below.
  • Figure 4 shows the average total stereotypic behaviour by rats when treated with vehicle (with or without amphetamine induction) and (+)-odihydrotetrabenazine at doses of 0.1 mg/kg and 0.25 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 2 below.
  • Figure 5 shows the average total distance travelled by rats when treated with vehicle (with or without amphetamine induction) and (-)-odihydrotetrabenazine at a dose of 2 mg/kg, a combination of (+)-odihydrotetrabenazine at a dose of 2 mg/kg and (-)-odihydrotetrabenazine at a dose of 2 mg/kg, and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 3 below.
  • Figure 6 shows the average total stereotypic behaviour by rats when treated with vehicle (with or without amphetamine induction) and (-)-odihydrotetrabenazine at a dose of 2 mg/kg, a combination of (+)-odihydrotetrabenazine at a dose of 2 mg/kg and (-)-odihydrotetrabenazine at a dose of 2 mg/kg, and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 3 below.
  • Figure 7 shows the average total distance travelled by rats when treated with vehicle (with or without amphetamine induction) and combinations of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine in varying ratios, and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 4 below.
  • Figure 8 shows the average total stereotypic behaviour by rats when treated with vehicle (with or without amphetamine induction) and combinations of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine in varying ratios, and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 4 below.
  • Figure 9 shows the average total distance travelled by rats when treated with vehicle (with or without amphetamine induction), (+)-3-dihydrotetrabenazine and combinations of (+)-odihydrotetrabenazine and (+)-3-dihydrotetrabenazine in amphetamine-induced rats, as described in Example 2, Study 5 below.
  • Figure 10 shows the average total stereotypic behaviour by rats when treated with vehicle (with or without amphetamine induction), (+)-3-dihydrotetrabenazine and combinations of (+)-odihydrotetrabenazine and (+)-3-dihydrotetrabenazine in amphetamine-induced rats, as described in Example 2, Study 5 below.
  • Figure 1 1 shows the average total distance travelled by rats when treated with vehicle (with or without amphetamine induction), (+)-odihydrotetrabenazine alone, (+)-odihydrotetrabenazine in combination with (-)-3-dihydrotetrabenazine, (+)- ⁇ - dihydrotetrabenazine in combination with (-)-odihydrotetrabenazine, (+)- ⁇ - dihydrotetrabenazine in combination with (-)-3-dihydrotetrabenazine, and (+)-o dihydrotetrabenazine in combination with (+)-3-dihydrotetrabenazine in
  • Figure 12 shows the stereotypic behaviour (distance over time) by rats when treated with vehicle (with or without amphetamine induction), (+)-o
  • EXAMPLE 1 An investigation into the nature of the dihydrotetrabenazine metabolites formed after administration of tetrabenazine to human subjects A pharmacokinetic study was carried out in healthy adult male volunteers under fasting conditions at a dose of single and multiple oral administration of 25mg tablets once a day to ascertain the plasma levels of +/-a and +/- ⁇ dihydro- tetrabenazine. The data are summarised below.
  • (+)-odihydrotetrabenazine is not primarily responsible for the therapeutic properties of tetrabenazine.
  • (+)-o dihydrotetrabenazine may be responsible for a relatively small contribution to the therapeutic properties of tetrabenazine.
  • Locomotor activity of the rats was tested in open field arena.
  • the open field test was performed during the rat light cycle and under a normal lighting evenly distributed to the test chambers.
  • the paths of the rats were recorded by activity monitor (Med. Associates Inc.).
  • Tubes were then immediately put on wet ice and centrifuged (Heraeus Fresco 17) within 10-15 minutes of collecting (9.6 x1000 G/ 10 x 1000 RPM, +4°C for 2 min), and 200 ⁇ of plasma was collected in 96-tube plates (Matrix Technologies ScreenMates 0.75 ml Alphanumeric Round-Bottom Storage tubes, PP) on dry ice according to sample map.
  • Rats dosed with either vehicle, (-)-a-DHTBZ 2.5 mg/kg or risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting locomotor activity was evaluated in 3 min bins and as a total over the testing period. The normalised total distance travelled over the testing time is presented in Figure 1 .
  • Rats dosed with either vehicle, (-)-a-DHTBZ 2.5 mg/kg or risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting stereotypic activity was evaluated in 3 min bins and as a total over the testing period. The normalised total stereotypic behaviour over the testing time is presented in Figure 2.
  • (-)-a-DHTBZ at dose 2.5 mg/kg did not lead to lower locomotor activity or reduced stereotypic behaviour when compared to the vehicle-amphetamine group.
  • the rats dosed with (-)-a-DHTBZ at dose 2.5 mg/kg were less focused on what was going on around.
  • the rats dosed with (-)-a -DHTBZ were equally active when compared to the vehicle-amphetamine dosed animals suggesting that (-)-a -DHTBZ does not have a sedative effect similar to risperidone.
  • Rats dosed with either vehicle, (+)-a-DHTBZ 0.1 mg/kg, (+)-a-DHTBZ 0.25 mg/kg, or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting locomotor activity was evaluated in 3 min bins and as a total over the testing period. The normalised total distance travelled over the testing time is presented in Figure 3.
  • (+)-a-DHTBZ 0.25 mg/kg and risperidone 1 mg/kg were significantly different.
  • Rats dosed with either vehicle, (+)-a-DHTBZ 0.1 mg/kg, (+)-a-DHTBZ 0.25 mg/kg, or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting stereotypic activity was evaluated in 3 min bins and as a total over the testing period. The normalised total stereotypic behaviour over the testing time is presented in Figure 4.
  • (+)-a-DHTBZ 0.1 mg/kg, (+)-a-DHTBZ 0.25 mg/kg and risperidone 1 mg/kg were significantly different.
  • DHTBZ 2 mg/kg and (+)-a-DHTBZ 2 mg/kg or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or
  • the vehicle-amphetamine When compared to the vehicle-vehicle group the vehicle-amphetamine was significantly different. When compared to vehicle-amphetamine group the vehicle- vehicle, (+)-a-DHTBZ 2 mg/kg, the combination of (-)-a-DHTBZ 2 mg/kg and (+)-a- DHTBZ 2 mg/kg and risperidone 1 mg/kg were significantly different.
  • DHTBZ 2 mg/kg and (+)-a-DHTBZ 2 mg/kg or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or
  • (+)-a-DHTBZ 2 mg/kg When compared to vehicle-amphetamine group the vehicle-vehicle, (+)-a-DHTBZ 2 mg/kg, the combination of (-)-a-DHTBZ 2 mg/kg and (+)-a-DHTBZ 2 mg/kg and risperidone 1 mg/kg were significantly different.
  • (+)-a-DHTBZ at the tested dose the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at doses 2 mg/kg and risperidone 1 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group.
  • (+)-a-DHTBZ at the tested dose the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at doses 2 mg/kg and risperidone 1 mg/kg led to reduced stereotypic behaviour when compared to the vehicle- amphetamine group.
  • Amphetamine induced locomotor activity was less in rats treated with the combination of (+)-a-DHTBZ and (-)-a-DHTBZ than in rats treated with (+)-a-
  • (+)-a-DHTBZ When compared to vehicle-amphetamine group the vehicle-vehicle, (+)-a-DHTBZ, the combination of (+)-a-DHTBZ 0.5 mg/kg and (-)-a-DHTBZ 0.5 mg/kg, the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a-DHTBZ 0.5 mg/kg, the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a-DHTBZ 1 mg/kg and the combination of (+)-a- DHTBZ 1 .5 mg/kg and (-)-a-DHTBZ 1 mg/kg were significantly different.
  • the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a-DHTBZ 0.5 mg/kg was significantly different.
  • the combination of (+)-a-DHTBZ 0.5 mg/kg and (-)-a-DHTBZ 0.5 mg/kg, the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a-DHTBZ 0.5 mg/kg, the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a- DHTBZ 1 mg/kg and the combination of (+)-a-DHTBZ 1 .5 mg/kg and (-)-a-DHTBZ 1 mg/kg were significantly different.
  • (+)-a-DHTBZ and (-)-a-DHTBZ at all the tested combinations and risperidone 1 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group.
  • the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at all the tested doses and risperidone 1 mg/kg led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group.
  • (+)-a-DHTBZ and (-)-a- DHTBZ affecting the ability of (+)-a-DHTBZ to block the amphetamine induced hyperactivity.
  • Rats dosed with either vehicle, (+)- ⁇ - ⁇ 2.5 mg/kg, (+)- ⁇ - ⁇ 5 mg/kg or (+)- ⁇ - ⁇ 2.5 mg/kg and (+)-a-DHTBZ 2.5 mg/kg were subjected to LMA testing first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Resulting locomotor activity was evaluated in 3 minute bins and as a total over the testing period. The normalised total distance travelled over the testing time is presented in Figure 9.
  • (+)- ⁇ - DHTBZ 2.5 mg/kg and (+)- ⁇ - ⁇ 5 mg/kg.
  • (+)- ⁇ - ⁇ 2.5 mg/kg and (+)-a-DHTBZ 2.5 mg/kg, (+)- ⁇ - ⁇ 2.5 mg/kg and (+)- ⁇ - ⁇ 5 mg/kg, were significantly different.
  • Rats dosed with either vehicle, (+)- ⁇ - ⁇ 2.5 mg/kg, (+)- ⁇ - ⁇ 5 mg/kg or (+)- ⁇ - ⁇ 2.5 mg/kg and (+)-a-DHTBZ 2.5 mg/kg were subjected to LMA testing first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Resulting stereotypic activity was evaluated in 3 minute bins and as a total over the testing period. The normalised total stereotypic behaviour over the testing time is presented in Figure 10.
  • (+)- ⁇ - DHTBZ 2.5 mg/kg and (+)- ⁇ - ⁇ 5 mg/kg were significantly different.
  • the combination of (+)-3-DHTBZ 2.5 mg/kg and (+)-a-DHTBZ 2.5 mg/kg, (+)- ⁇ - ⁇ 2.5 mg/kg and (+)- ⁇ - ⁇ 5 mg/kg were significantly different.
  • Rats dosed with either vehicle or dihydrotetrabenazine were subjected to LMA testing first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Resulting locomotor activity was evaluated in 3 minute bins and as a total over the testing period. The unnormalised total distance travelled over the testing time is presented in Figure 1 1 .
  • the vehicle-amphetamine, (+)- ⁇ - DHTBZ 1 mg/kg plus (-)-a-DHTBZ 1 mg/kg and (+)- ⁇ - ⁇ 1 mg/kg plus (-)- ⁇ - DHTBZ 1 mg/kg groups were significantly different.
  • the vehicle-vehicle, all of groups 1 and 3 to 9 were significantly different.
  • Rats dosed with either vehicle or dihydroterabenazine were subjected to LMA testing first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Resulting stereotypic activity was evaluated in 3 minute bins and as a total over the testing period. The unnormalised total stereotypic behaviour over the testing time is presented in Figure 12.
  • Study 1 evaluated the effect of (-)-a-DHTBZ at a dose of 2.5 mg/kg and risperidone at a dose of 1 mg/kg on amphetamine induced locomotor activity in male CD rats.
  • (-)-a-DHTBZ at a dose of 2.5 mg/kg did not lead to lower locomotor activity or reduced stereotypic behaviour when compared to the vehicle-amphetamine group.
  • the rats dosed with (-)-a-DHTBZ at a dose of 2.5 mg/kg were less focused on what was going on around them.
  • the rats dosed with (-)-a -DHTBZ were equally active when compared to the vehicle-amphetamine dosed animals suggesting that (-)-a -DHTBZ does not have an effect on movement similar to risperidone.
  • Study 2 evaluated the effect of (+)-a-DHTBZ at doses 0.1 mg/kg and 0.25 mg/kg and risperidone at dose 1 mg/kg on amphetamine induced locomotor activity in male CD rats.
  • Study 3 evaluated the effect of (+)-a-DHTBZ at a dose of 2 mg/kg, the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at dose 2 mg/kg and risperidone at dose 1 mg/kg on amphetamine induced locomotor activity in male CD rats.
  • (+)-a-DHTBZ at all the tested dose the combination of (+)-a-DHTBZ and (-)-a- DHTBZ at doses of 2 mg/kg and risperidone at 1 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group.
  • (+)-a-DHTBZ at all the tested dose the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at doses of 2 mg/kg and risperidone 1 mg/kg led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group.
  • Amphetamine induced locomotor activity was less in rats treated with the combination of (+)-a-DHTBZ and (-)-a-DHTBZ than in rats treated with (+)-o DHTBZ only, despite it being shown that the (-)-oisomer provides very little, if any, reduction in induced locomotor activity.
  • Study 4 evaluated the effect of the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at doses 0.5 mg/kg + 0.5 mg/kg, 1 mg/kg + 0.5 mg/kg, 1 mg/kg + 1 mg/kg and 1 .5 mg/kg + 1 mg/kg on amphetamine induced locomotor activity in male CD rats.
  • (+)-a-DHTBZ and (-)-a-DHTBZ at all the tested combinations and risperidone 1 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group.
  • the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at all the tested doses and risperidone 1 mg/kg led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group.
  • Study 5 evaluated the effect of (+)- ⁇ -DHTBZ at doses 2.5 mg/kg and 5 mg/kg and the combination of (+)-a-DHTBZ at dose 2.5 mg/kg and (+)- ⁇ - ⁇ at dose 2.5 mg/kg on amphetamine induced locomotor activity in male CD rats.
  • (+)- ⁇ -DHTBZ 2.5 mg/kg, (+)- ⁇ - DHTBZ 5 mg/kg and the combination of (+)-a-DHTBZ 2.5 mg/kg and (+)- ⁇ - ⁇ 2.5 mg/kg also led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group.
  • the rats dosed with (+)- ⁇ - ⁇ at dose 5 mg/kg were less focused on what was going on around them and the rats that received the (+)- ⁇ - ⁇ 5 mg/kg were observed to have tensed limbs and were partially missing their righting reflex at the end of the test.
  • the vehicle, risperidone and all of the dihydrotetrabenazine-containing led to lower locomotor activity and led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group.

Abstract

This invention relates to the use of (+)-β-dihydrotetrabenazine and combinations of (+)-α-dihydrotetrabenazine, (-)-α-dihydrotetrabenazine and/or (+)-β- dihydrotetrabenazine, for the treatment of movement disorders, such as Tourette's syndrome. The invention also provides dosage forms containing said dihydrotetrabenazine isomers.

Description

PHARMACEUTICAL COMPOSITIONS
This invention relates to the use of (+)-3-dihydrotetrabenazine and combinations of (+)-odihydrotetrabenazine, (-)-odihydrotetrabenazine and/or (+)-β- dihydrotetrabenazine, for the treatment of movement disorders, such as Tourette's syndrome.
Background of the Invention
Movement disorders can generally be classified into two categories: hyperkinetic movement disorders and hypokinetic movement disorders. Hyperkinetic movement disorders are caused by an increase in muscular activity and can cause abnormal and/or excessive movements, including tremors, dystonia, chorea, tics, myoclonus and stereotypies.
Hyperkinetic movement disorders often are often psychological in nature and arise through improper regulation of amine neurotransmitters in the basal ganglia.
A particular hyperkinetic movement disorder is Tourette's syndrome, which is an inherited neurological condition characterised by multiple physical and vocal tics. The tics are usually repetitive, but random, physical movements or vocal noises. The vocal tics can be of various forms and include repeating one's own words, the words of others or other sounds. Onset usually occurs in children and continues through to adolescence and adulthood. While the tics associated with Tourette's syndrome are temporarily suppressible, those affected can usually only suppress their tics for limited time periods. There is yet to be an effective treatment to cover all types of tics in all patients, but certain medicaments for tic suppression have been developed.
It is known that dopamine receptor antagonists display an ability to supress tics in Tourette's syndrome patients and a number dopamine receptor antagonists are currently used in the suppression of Tourette's tics, such as fluphenazine, haloperidol and pimozide.
Type 2 vesicular monoamine transporter (VMAT2) is a membrane protein responsible for the transportation of monoamine neurotransmitters, such as dopamine, serotonin and histamine, from cellular cytosol into synaptic vesicles. Inhibition of this protein hinders presynaptic neurons from releasing dopamine, resulting in a depletion of dopamine levels in the brain.
VMAT2 inhibitors can be used to treat the symptoms of Tourette's syndrome.
Tetrabenazine (Chemical name: 1 ,3,4,6,7,1 1 b-hexahydro-9,10-dimethoxy-3-(2- methylpropyl)-2H-benzo(a)quinolizin-2-one) has been in use as a pharmaceutical drug since the late 1950s. Initially used as an anti-psychotic, tetrabenazine is currently used for treating hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic, tardive dyskinesia and Tourette's syndrome, see for example Jankovic et al., Am. J. Psychiatry. (1999) Aug;
156(8):1279-81 and Jankovic et al., Neurology (1997) Feb; 48(2):358-62.
The primary pharmacological action of tetrabenazine is to reduce the supply of monoamines (e.g. dopamine, serotonin, and norepinephrine) in the central nervous system by inhibiting the human vesicular monoamine transporter isoform 2 (hVMAT2). The drug also blocks post-synaptic dopamine receptors. The central effects of tetrabenazine closely resemble those of reserpine, but it differs from reserpine in that it lacks activity at the VMAT1 transporter. The lack of activity at the VMAT1 transporter means that tetrabenazine has less peripheral activity than reserpine and consequently does not produce VMAT1 -related side effects such as hypotension. Tetrabenazine is an effective and safe drug for the treatment of a variety of hyperkinetic movement disorders and, in contrast to typical neuroleptics, has not been demonstrated to cause tardive dyskinesia. Nevertheless, tetrabenazine does exhibit a number of dose-related side effects including causing depression, parkinsonism, drowsiness, nervousness or anxiety, insomnia and, in rare cases, neuroleptic malignant syndrome, see for example the introductory section of WO2016/127133 (Neurocrine Biosciences).
The chemical structure of tetrabenazine is as shown below.
Structure of tetrabenazine
The compound has chiral centres at the 3 and 1 1 b carbon atoms and hence can, theoretically, exist in a total of four isomeric forms, as shown below.
Possible tetrabenazine isomers
The stereochemistry of each isomer is defined using the "R and S" nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-1 14. In this patent application, the designations "R" or "S" are given in the order of the position numbers of the carbon atoms. Thus, for example, RS is a shorthand notation for 3R,1 1 bS. Similarly, when three chiral centres are present, as in the
dihydrotetrabenazines described below, the designations "R" or "S" are listed in the order of the carbon atoms 2, 3 and 1 1 b. Thus, the 2R,3S, 11 bS isomer is referred to in short hand form as RSS and so on.
Commercially available tetrabenazine is a racemic mixture of the RR and SS isomers and it would appear that the RR and SS isomers are the most
thermodynamically stable isomers. Tetrabenazine has somewhat poor and variable bioavailability. It is extensively metabolised by first-pass metabolism, and little or no unchanged tetrabenazine is typically detected in the urine. It is known that at least some of the metabolites of tetrabenazine are dihydrotetrabenazines formed by reduction of the 2-keto group in tetrabenazine.
Dihydrotetrabenazine (Chemical name: 2-hydroxy-3-(2-methylpropyl)- 1 ,3,4,6,7,1 1 b-hexahydro-9,10-dimethoxy-benzo(a)quinolizine) has three chiral centres and can therefore exist in any of the following eight optical isomeric forms:
RSR SRS Dihydrotetrabenazine isomers The synthesis and characterisation of all eight dihydrotetrabenazine isomers is described by Sun et al. {Eur. J. Med. Chem. (201 1 ), 1841 -1848).
Of the eight dihydrotetrabenazine isomers, four isomers are derived from the RR and SS isomers of the parent tetrabenazine, namely the RRR, SSS, SRR and RSS isomers.
The RRR and SSS isomers are commonly referred to as "alpha (a)"
dihydrotetrabenazines and can be referred to individually as (+)-o
dihydrotetrabenazine and (-)-odihydrotetrabenazine respectively. The alpha isomers are characterised by a trans relative orientation of the hydroxyl and 2- methylpropyl substituents at the 2- and 3-positions - see for example, Kilbourn et al., Chirality, 9:59-62 (1997) and Brossi et al., Helv. Chim. Acta., vol. XLI, No. 193, pp1793-1806 (1958.
The SRR and RSS isomers are commonly referred to as "beta (β)" isomers and can be referred to individually as (+)-3-dihydrotetrabenazine and (-)-β- dihydrotetrabenazine respectively. The beta isomers are characterised by a c/'s relative orientation of the hydroxyl and 2-methylpropyl substituents at the 2- and 3- positions.
Although dihydrotetrabenazine is believed to be primarily responsible for the activity of the drug, there have been no studies published to date that contain evidence demonstrating which of the various stereoisomers of
dihydrotetrabenazine is responsible for its biological activity. More specifically, there have been no published studies demonstrating which of the stereoisomers is responsible for the ability of tetrabenazine to treat movement disorders such as Tourette's syndrome. Schwartz et al. (Biochem. Pharmacol. (1966), 15: 645-655) describes metabolic studies of tetrabenazine carried out in rabbits, dogs and humans. Schwartz et al. identified nine metabolites, five of which were unconjugated and the other four of which were conjugated with glucuronic acid. The five unconjugated metabolites were the alpha- and beta-dihydrotetrabenazines, their two oxidised analogues in which a hydroxyl group has been introduced into the 2-methylpropyl side chain, and oxidised tetrabenazine in which a hydroxyl group has been introduced into the 2-methylpropyl side chain. The four conjugated metabolites were all compounds in which the 9-methoxy group had been demethylated to give a 9-hydroxy compound. The chirality of the various metabolites was not studied and, in particular, there was no disclosure of the chirality of the individual a- and β-isomers.
Scherman et al., (Mol. Pharmacol. (1987), 33, 72-77 describes the stereospecificity of VMAT2 binding between racemic a- and β- dihydrotetrabenazine. They reported that odihydrotetrabenazine had a 3- to 4-fold higher affinity for the Chromaffin Granule Monoamine Transporter than the β-isomer, when studied in vitro.
However, Scherman et al. does not disclose the resolution or testing of the individual enantiomers of the a- and β-dihydrotetrabenazines.
Mehvar et al. {J. Pharm. Sci. (1987), 76(6), 461 -465) reported a study of the concentrations of tetrabenazine and dihydrotetrabenazine in the brains of rats following administration of either tetrabenazine or dihydrotetrabenazine. The study showed that despite its greater polarity, dihydrotetrabenazine was able to cross the blood-brain barrier. However, the stereochemistry of the dihydrotetrabenazine was not disclosed. Mehvar et al. {Drug Metabolism and Disposition (1987), 15:2, 250-255) describes studies of the pharmacokinetics of tetrabenazine and dihydrotetrabenazine following administration of tetrabenazine to four patients affected by tardive dyskinesia. Oral administration of tetrabenazine resulted in low plasma
concentrations of tetrabenazine but relatively high concentrations of
dihydrotetrabenazine. However, the stereochemistry of the dihydrotetrabenazine formed in vivo was not reported.
Roberts et al. {Eur. J. Clin. Pharmacol. (1986), 29: 703-708) describes the pharmacokinetics of tetrabenazine and its hydroxy-metabolite in patients treated for involuntary movement disorders. Roberts et al. reported that tetrabenazine was extensively metabolised after oral administration resulting in very low plasma concentrations of tetrabenazine but much higher concentrations of a
hydroxymetabolite. Although they did not describe the identity of the
hydroxymetabolites, they suggested that the high plasma concentrations of the hydroxymetabolites may be therapeutically important (since the metabolites were known to be pharmacologically active) and that, in view of the disclosure in
Schwartz et al. {idem), the combination of c/'s and trans isomers (i.e. alpha and beta isomers) could be more therapeutically important than the parent drug. Michael Kilbourn and collaborators at the University of Michigan Medical School have published a number of studies relating to the various isomers of
dihydrotetrabenazines. In Med. Chem. Res. (1994), 5:1 13-126, Kilbourn et al. describe the use (+/-)-a-[1 1 C]-dihydrotetrabenazine as in vivo imaging agents for VMAT2 binding studies.
In Eur. J. Pharmacol (1995) 278, 249-252, Kilbourn et al. reported competition binding studies using [3H]-tetrabenazine to study the in vitro binding affinity of (+)-, (-)-, and (+/-)-a-DHTBZ. The binding assays gave a Ki value of 0.97 nM for (+)-a- dihydrotetrabenazine and 2.2 μΜ for (-)-odihydrotetrabenazine, thereby showing that the (+) alpha isomer has much greater binding affinity for the VMAT2 receptor than the (-) alpha isomer. However, no studies were reported, or conclusions drawn, as to the usefulness of either isomer in the treatment of movement disorders such as Tourette's syndrome.
In Chirality (1997) 9:59-62, Kilbourn et al. described studies aimed at identifying the absolute configuration of (+)-odihydrotetrabenazine from which they concluded that it has the 2R, 3R, \ '\ bR configuration shown above. They also referred to the Schwartz et al. and Mehvar et al. articles discussed above as indicating that the a- and β-dihydrotetrabenazines are likely to be the
pharmacologically active agents in the human brain but they drew no explicit conclusions as to the precise stereochemical identities of the active metabolites of tetrabenazine.
In Synapse (2002), 43:188-194, Kilbourn et al. described the use of (+)-a-[1 1 C]- dihydrotetrabenazine as an agent used to measure specific in vivo binding of the VMAT receptor, in "infusion to equilibrium methods". They found that (-)-o[1 1 C]- dihydrotetrabenazine produced a uniform brain distribution, consistent with the earlier observations that this enantiomer has a low VMAT affinity.
Sun et al. (idem) investigated the VMAT2 binding affinities of all eight
dihydrotetrabenazine isomers. They found that all of the dextrorotatory
enantiomers exhibited dramatically more potent VMAT2 binding activity than their corresponding laevorotatory enantiomers with the most active (+)-oisomer being found to be the most active. However, Sun et al. did not carry out any
investigations into the relative efficacies of the individual isomers in treating movement disorders such as Tourette's syndrome. WO 201 1/153157 (Auspex Pharmaceutical, Inc.) describes deuterated forms of dihydrotetrabenazine. Many deuterated forms of dihydrotetrabenazine are depicted but the application only provides sufficient information to allow a small number of the depicted compounds to be synthesised. Although racemic mixtures of d6-a-dihydrotetrabenazine and d6-3-dihydrotetrabenazine as disclosed, these mixtures were not resolved and the properties of the individual (+) and (-) isomers are not studied. Similarly, WO 2014/047167 (Auspex Pharmaceutical, Inc.) describes number of deuterated forms of tetrabenazine and its derivatives. Again, the individual (+) and (-) isomers of deuterated forms of a- and β- dihydrotetrabenazine were not separated or studied.
It is evident that, up to the present, it has been unclear as to precisely which dihydrotetrabenazine isomers are responsible for the therapeutic properties resulting from the administration of tetrabenazine. It has previously been assumed that (+)-odihydrotetrabenazine is the metabolite of tetrabenazine that is primarily responsible for its therapeutic effects (see WO 2015/171802 Neurocrine
Biosciences, Inc.), but this has not been demonstrated experimentally.
Summary of the Invention
As discussed above, the studies carried out by Schwartz et al. (referred to above) demonstrated that both alpha and beta isomers of tetrabenazine are formed as metabolites of tetrabenazine. However, the precise stereochemical configurations of the alpha and beta isomers were not investigated.
Studies in human subjects carried out by the present applicants and described in Example 1 below have confirmed the findings of Schwartz et al. that major metabolites of tetrabenazine are indeed alpha and beta dihydrotetrabenazines. However, contrary to what has previously been suggested, the main metabolites produced upon administration of tetrabenazine are the (-)-odihydrotetrabenazine isomer, which is essentially active as a VMAT2 binding agent, and the (+)-β- dihydrotetrabenazine isomer, which is significantly less active than the (+)-o dihydrotetrabenazine isomer. Thus, in a single dose study involving the administration of tetrabenazine to adult male humans, the Cmax figures for (+)-3-dihydrotetrabenazine and (-)-a- dihydrotetrabenazine respectively were 103 and 72.94 ng/ml whereas the Cmax figures for (-)-3-dihydrotetrabenazine and (+)-odihydrotetrabenazine respectively were 5.28 and 2.61 ng/ml. The area under the curve (AUC) figures for each of the (+)-3-dihydrotetrabenazine, (-)-odihydrotetrabenazine, (-)-3-dihydrotetrabenazine and (+)-odihydrotetrabenazine metabolites respectively were 375.78, 305.84, 16.28 and 7.98. A similar distribution of metabolites was found when multiple doses of tetrabenazine were administered.
The data suggest that (+)-odihydrotetrabenazine is not primarily responsible for the therapeutic properties of tetrabenazine. On the contrary, it appears that (+)-o dihydrotetrabenazine may be responsible for a relatively small contribution to the therapeutic properties of tetrabenazine. The importance of preparing enantiopure compositions for treatment of the human and animal body is known. It is well known that enantiomers may have different biological properties, for example wherein one enantiomer is useful for the treatment of a specific disease or condition and wherein the other enantiomer is toxic or produces unwanted side effects. An example of this is the drug thalidomide, which was marketed as a sedative and also prescribed to pregnant women to treat morning sickness, but it was later found that one enantiomer caused birth defects in children of the women who had been administered thalidomide during their pregnancy.
Guidance from the FDA regarding enantiomers states that applications for drug substances and drug products should include a stereochemically specific identity test and/or a stereochemically selective assay method.
Even in cases where one of the enantiomers is medically useful and the other is inactive and shows no side effects, it may still be advantageous to remove the inactive enantiomer in order to reduce the size of the dosage form administered to patients.
Combinations of (+)-a-dihydrotetrabenazine and (-)-a-dihydrotetrabenazine
It has now surprisingly been found that combinations of (+)- and (-)-a- dihydrotetrabenazine are more effective in the reduction of locomotor activity in amphetamine induced rats than (+)-odihydrotetrabenazine alone, despite the fact that it has been previously reported that the (-)-odihydrotetrabenazine is a poor VMAT2 inhibitor. It has also been shown that both racemic and scalemic (i.e. non-racemic) combinations exhibit enhanced efficacy
Studies confirmed the inactivity of (-)-odihydrotetrabenazine in treating movement disorders when administered alone (see Example 2, Study 1 ). However, it was unexpectedly found that when (-)-odihydrotetrabenazine was administered in combination with (+)-odihydrotetrabenazine, an improved effect was seen when compared to the administration of the (+)-isomer alone (see Example 2, Studies 3 and 4). It is thought that this improved effect may be due to the binding of (-)-a- dihydrotetrabenazine to proteins other than VMAT2, which may play a role in mediating hyperkinetic movement disorders.
On the basis of the studies carried out to date, it is envisaged that combinations of (+)- and (-)-odihydrotetrabenazine will be useful in the prophylaxis or treatment of the disease states and conditions for which tetrabenazine is currently used or proposed. Thus, by way of example, and without limitation, the
dihydrotetrabenazine compounds of the invention may be used for the treatment of movement disorders and in particular hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
Accordingly, in a first aspect, the invention provides a pharmaceutical unit dosage form comprising (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.
Typically, the combination of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, is not administered with a therapeutic effective amount of amantadine. In one embodiment, the combination of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, is not administered with any amount of amantadine.
The (+)-odihydrotetrabenazine and/or (-)-odihydrotetrabenazine, or
pharmaceutically acceptable salts thereof, may be administered as an immediate release unit dosage form. In another aspect, the invention provides a combination of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for use in medicine.
(+)-a-Dihydrotetrabenazine is believed to have the chemical structure (I) shown below:
(-)-a-Dihydrotetrabenazine is believed to have the chemical structure (II) shown below:
In another aspect, the invention provides a combination of (+)-o
dihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for use in medicine.
In a further aspect, the invention provides a combination of (+)-o
dihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof (pharmaceutical unit dosage form as hereinbefore defined), for use in the treatment of a movement disorder.
In further embodiments, the invention provides:
• A method of treatment of a movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject a combination of (+)-odihydrotetrabenazine and (-)-a-dihydrotetrabenazine, or pharmaceutically acceptable salts thereof.
The use of a combination of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of a movement disorder.
The inventors have also found that low doses (i.e. of 20 mg or less per day) of (+)- odihydrotetrabenazine may be useful in the treatment of movement disorders and it is therefore envisaged that such low doses of (+)-odihydrotetrabenazine, in combination with (-)-odihydrotetrabenazine, will also be useful in treating movement disorders.
Accordingly, in another embodiment, the invention provides a combination of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for use in a method of treatment of a movement disorder, wherein the method comprises administering to a subject (.e.g. a human subject) in need thereof an effective therapeutic amount of the combination sufficient to provide a dosage of from 1 mg to 20 mg of (+)-odihydrotetrabenazine per day.
In further aspects, the invention provides:
• A method of treatment of movement disorders, wherein the method
comprises administering to a subject (.e.g. a human subject) in need thereof an effective therapeutic amount of a combination of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, sufficient to provide a dosage of from 1 mg to 20 mg of (+)-odihydrotetrabenazine per day.
The use of a combination of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of a movement disorder, wherein the method comprises administering to a subject (.e.g. a human subject) in need thereof an effective therapeutic amount of the combination sufficient to provide a dosage of from 1 mg to 20 mg of (+)-o
dihydrotetrabenazine per day. • The use of a (-)-a-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for administration in combination with (+)-odihydrotetrabenazine or a pharmaceutically acceptable salt thereof for a method of treatment of a movement disorder, wherein the method comprises administering to a subject (.e.g. a human subject) in need thereof an effective therapeutic amount of the combination sufficient to provide a dosage of from 1 mg to 20 mg of (+)-o
dihydrotetrabenazine per day.
In each of the foregoing embodiments (i.e. a combination for use, a method, or a use) employing a low dose of (+)-odihydrotetrabenazine or a pharmaceutically acceptable salt thereof, the daily dose of (+)-odihydrotetrabenazine is from 1 mg to 20 mg.
In particular embodiments, there is provided
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-o dihydrotetrabenazine from 1 .5 mg to 20 mg (e.g. between 1 .5 mg and 20 mg) per day.
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-o dihydrotetrabenazine from 2 mg to 20 mg (e.g. between 2 mg and 20 mg) per day.
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-o dihydrotetrabenazine from 3 mg to 20 mg (e.g. between 3 mg and 20 mg) per day.
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-o dihydrotetrabenazine from 2 mg to 15 mg (e.g. between 2 mg and 15 mg) per day.
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-o dihydrotetrabenazine from 3 mg to 15 mg (e.g. between 3 mg and 15 mg) per day.
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-o dihydrotetrabenazine from 5 mg to 15 mg (e.g. between 5 mg and 15 mg) per day.
The administration of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine typically forms part of a chronic treatment regime. The (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine may therefore be administered to a patient for a treatment period of at least a week, more usually at least two weeks, or at least a month, and typically longer than a month. Where a patient is shown to respond well to treatment, the period of treatment can be longer than six months and may extend over a period of years.
The chronic treatment regime may involve the administration of the (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine every day, or the treatment regime may include days when no (+)-odihydrotetrabenazine or (-)-a- dihydrotetrabenazine is administered.
The dosage administered to the subject may vary during the treatment period. For example, the initial dosage may be increased or decreased depending on the subject's response to the treatment. A subject may, for example, be given an initial low dose to test the subject's tolerance towards the (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine, and the dosage thereafter increased as necessary up to the maximum daily intake of 20 mg. Alternatively, an initial daily dosage administered to the patient may be selected so as to give an estimated desired degree of VMAT2 blockage, following which a lower maintenance dose may be given for the remainder of the treatment period, with the option of increasing the dosage should the subject's response to the treatment indicate that an increase is necessary.
It is envisaged that the quantity of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine required to achieve the desired therapeutic effect will be dependent on the weight of the subject to be treated. The quantities of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine administered to the subject can be expressed in a number of mg/kg, where in the kg relates the weight of the subject to be treated. The appropriate dosage amount can therefore be calculated by multiplying the mg/kg amount by the weight of the subject to be treated.
Accordingly, in another aspect, the invention provides a combination of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine or pharmaceutically acceptable salts thereof, for use in a method for the treatment of a movement disorder, wherein the treatment comprises administering to a subject an amount of the combination of from 0.01 mg/kg to 0.3 mg/kg (e.g. between 0.01 mg/kg and 0.3 mg/kg) per day provided that the total amount of (+)-odihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg. In further aspects, the invention provides:
• A method of treatment of a movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject a combination of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, in an amount from 0.01 mg/kg to 0.3 mg/kg (e.g. between 0.01 mg/kg and 0.3 mg/kg) per day, provided that the total amount of (+)-o dihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg.
• The use of a combination of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of a movement disorder, which treatment comprises administering to the subject the combination in an amount from 0.01 mg/kg to 0.3 mg/kg (e.g. between 0.01 mg/kg and 0.3 mg/kg), provided that the total amount of (+)-odihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg.
In each of the foregoing embodiments (i.e. a combination for use, a method, or a use) wherein a combination of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, is administered in an amount from 0.01 mg/kg to 0.3 mg/kg (e.g. between 0.01 mg/kg and 0.3 mg/kg) per day, the daily dose of (+)-odihydrotetrabenazine is from 1 mg to 20 mg.
In particular embodiments, there is provided: • A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination of from 0.02 mg/kg to 0.3 mg/kg (e.g. between 0.02 mg / kg and 0.3 mg/kg) per day, provided that the total amount of (+)-o
dihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg.
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination of from 0.03 mg/kg to 0.3 mg/kg (e.g. between 0.03 mg/kg and 0.3 mg/kg) per day, provided that the total amount of (+)-o
dihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg.
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination from 0.04 mg/kg to 0.3 mg/kg (e.g. between 0.04 mg/kg and 0.3 mg/kg) per day, provided that the total amount of (+)-o
dihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg.
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination from 0.05 mg/kg to 0.3 mg/kg (e.g. between 0.05 mg/kg and 0.3 mg/kg) of (+)-odihydrotetrabenazine, provided that the total amount of (+)-odihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg.
The combinations of the invention (and dosage forms containing the combinations) are useful in the treatment of movement disorders, and in particular hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
More particularly, the combinations of the invention (and dosage forms containing the combinations) are for use in the treatment of a hyperkinetic movement disorder selected from tic disorders, Huntington's disease, tardive dyskinesia and Tourette's syndrome. In one particular embodiment, the combinations of the invention (and dosage forms containing the combinations) are for use in the treatment of tardive dyskinesia.
In another particular embodiment, the combinations of the invention (and dosage forms containing the combinations) are for use in the treatment of Tourette's syndrome.
The usefulness of the combinations of the invention in the treatment of movement disorders arises in part from the ability of (+)-odihydrotetrabenazine to bind to the vesicular monoamine transporter 2 (VMAT2).
Complete blocking of the VMAT2 proteins is considered undesirable as this can lead to unwanted side effects, such as Parkinsonism. The present invention provides plasma levels of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine that are sufficient to give effective treatment of movement disorders but do not block the VMAT2 proteins to an extent that causes
Parkinsonism and similar side effects. The levels of VMAT2 blocking can be determined by competitive binding studies using Positron Emission Tomography (PET). By co-administering a radioactive ligand with the compound of interest at various concentrations, the proportion of binding sites occupied can be determined (see for example, Matthews et al., "Positron emission tomography molecular imaging for drug development", Br. J. Clin. Pharmacol., 73:2, 175-186). Accordingly, in a further aspect, the invention provides a combination of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for use in a method for the treatment of a movement disorder, wherein the treatment comprises administering to a subject an amount of the combination sufficient to cause a level of blocking of from 20% to 90% of VMAT2 proteins in the subject.
In further aspects, the invention provides:
• A method of treatment of a movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject a combination of (+)-odihydrotetrabenazine and (-)-a-dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, sufficient to cause a level of blocking of from 20% to 90% of the VMAT2 proteins in the subject. • The use of a combination of (+)-a-dihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of a movement disorder in a subject (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 20% to 90% of VMAT2 proteins in the subject.
• The use of (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in combination with (-)-odihydrotetrabenazine or a pharmaceutically acceptable salt thereof for the treatment of a movement disorder in a subject (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 20% to 90% of VMAT2 proteins in the subject.
In further embodiments, there are provided:
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 25% to 85% of the VMAT2 proteins in the subject.
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 30% to 85% of the VMAT2 proteins in the subject.
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 35% to 85% of the VMAT2 proteins in the subject.
• A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 40% to 85% of the VMAT2 proteins in the subject. A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 45% to 85% of the VMAT2 proteins in the subject.
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 50% to 85% of the VMAT2 proteins in the subject.
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 30% to 80% of the VMAT2 proteins in the subject.
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 35% to 75% of the VMAT2 proteins in the subject.
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 35% to 70% of the VMAT2 proteins in the subject.
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 40% to 75% of the VMAT2 proteins in the subject.
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of the combination sufficient to cause a level of blocking of from 45% to 75% of the VMAT2 proteins in the subject.
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of the combination sufficient to cause a level of blocking of from 35% to 80% of the VMAT2 proteins in the subject.
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of the combination sufficient to cause a level of blocking of from 40% to 80% of the VMAT2 proteins in the subject.
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 45% to 80% of the VMAT2 proteins in the subject.
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 50% to 80% of the VMAT2 proteins in the subject.
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of from 55% to 80% of the VMAT2 proteins in the subject.
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 30% to 70% (e.g. between 30% and 70%).
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of the combination sufficient to cause a blocking level of VMAT2 proteins in the subject of from 30% to 65% (e.g. between 30% and 65%).
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of the combination sufficient to cause a blocking level of VMAT2 proteins in the subject of from 30% to 60% (e.g. between 30% and 60%).
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of the combination sufficient to cause a level blocking of VMAT2 proteins in the subject of from 40% to 80% (e.g. between 40% and 80%).
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of the combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 75% (e.g. between 40% and 75%).
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of the combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 70% (e.g. between 40% and 70%).
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of the combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 65% (e.g. between 40% and 65%).
A combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of the combination sufficient to cause a level blocking of VMAT2 proteins in the subject of from 40% to 60% (e.g. between 40% and 60%).
In each of the foregoing aspects and embodiments of the invention, the combinations of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine may be racemic. Alternatively, in each of the foregoing aspects and embodiments of the invention, the combinations of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine may be scalemic (i.e. non-racemic).
In each of the combinations of the invention, the uses thereof and pharmaceutical dosage forms containing the combinations, as defined above, the ratio of (+)-o dihydrotetrabenazine to (-)-odihydrotetrabenazine in the combination can be, for example, from 0.5:1 to 20:1. In particular embodiments, the ratio of (+)-o dihydrotetrabenazine to (-)-odihydrotetrabenazine in the combination can be a ratio in a range selected from:
(i) 1:1 to 20:1
(ϋ) 1:1 to 15:1
(iii) 1:1 to 12:1
(iv) 1:1 to 10:1
(v) 1:1 to 5:1
(vi) 1:1 to 4:1
(νϋ) 1:1 to 3:1
(viii) 1:1 to 2:1
(ix) 1.1:1 to 20:1
(x) 1.1:1 to 15:1
(xi) 1.1:1 to 12:1
(xii) 1.1:1 to 10:1
(xiii) 1.1:1 to 5:1
(xiv) 1.1:1 to4:1
(XV) 1.1:1 to 3:1
(xvi) 1.1:1 to 2:1
(xvii) 1.2:1 to 20:1
(xviii) 1.2:1 to 15:1
(xix) 1.2:1 to 12:1
(XX) 1.2:1 to 10:1
(xxi) 1.2:1 to 5:1
(xxii) 1.2:1 to 4:1
(xxiii) 1.2:1 to 3:1
(xxiv) 1.2:1 to 2:1 In each of the foregoing aspects and embodiments of the invention, the
combinations of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine are typically unaccompanied by other dihydrotetrabenazine isomers.
In some embodiments, minor amounts of other tetrabenazine isomers may be present but these generally are present in amounts corresponding to no more than 20% by weight (i.e. 0.2:1 ), compared to the total weight of the combination. More usually, other dihydrotetrabenazine isomers are present in amounts corresponding to no more than 10% or 5%, or 2%, or 1 % by weight (i.e. 0.2:1 ), compared to the total weight of the combination. More preferably, other dihydrotetrabenazine isomers are either completely absent, or are present in amounts of less than 1 % by weight, for example less than 0.5% by weight.
In each of the foregoing aspects and embodiments, the (+)-odihydrotetrabenazine and/or (-)-odihydrotetrabenazine can be administered as the free base or as a pharmaceutically acceptable salt. In one embodiment, one or both of the (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine are administered as pharmaceutically acceptable salts. In another embodiment, both the (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine are administered as free bases. Unless stated otherwise, or unless the context indicates otherwise, the quantities of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine are calculated as the amounts of the free base, or when the (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine is in the form of a pharmaceutically acceptable salt, the amount of (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine per se present in the pharmaceutically acceptable salt.
In each of the foregoing aspects and embodiments of the invention relating to combinations of (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine or pharmaceutically acceptable salts thereof, typically, the (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine or pharmaceutically acceptable salt thereof, are not administered with a therapeutically effective amount of amantadine. More particularly, the (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine, or pharmaceutically acceptable salt thereof, are not administered with any amount of amantadine.
For example, with reference to pharmaceutical unit dosage forms, typically the unit dosage form does not comprise a therapeutically effective amount of amantadine and, more particularly, the pharmaceutical unit dosage form does not comprise any amount of amantadine.
Furthermore, in each of the foregoing aspects and embodiments of the invention relating to (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine or
pharmaceutically acceptable salts thereof, the pharmaceutical unit dosage form may be other than an extended release or delayed release dosage form.
Thus, for example, the (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine, or pharmaceutically acceptable salt thereof, may be administered as an immediate release unit dosage form. (+)-B-dihydrotetrabenazine
As discussed above, the present inventors have found that (+)-o
dihydrotetrabenazine does not appear to be primarily responsible for the therapeutic properties of tetrabenazine. On the contrary, it appears that (+)-o dihydrotetrabenazine may be responsible for a relatively small contribution to the therapeutic properties of tetrabenazine.
Therefore, despite the earlier findings that the (+)-oisomer was 3- to 4-times more active than the (+)-3-isomer, the fact that the (+)-3-isomer is present in the body following administration of tetrabenazine in an amount over 50 times greater suggests that (+)-3-dihydrotetrabenazine may make a major contribution to the activity of tetrabenazine.
Investigations made by the present inventors indicate that (+)-β- dihydrotetrabenazine per se having the chemical name, (S,R,R,)-3-isobutyl-9,10- dimethyloxy-1 ,3,4,5,7,1 1 b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-ol, and having the formula (III) shown below
(III) is effective in the treatment of movement disorders, despite previous findings that it has a lower VMAT2 activity than (+)-odihydrotetrabenazine.
Accordingly, in a first aspect, the invention provides a unit dosage form comprising (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In another aspect, the invention provides (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in medicine.
There is also provided a unit dosage form comprising (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, which is substantially free of other dihydrotetrabenazine isomers.
The unit dosage form can be one which is administered orally, for example a capsule or tablet. Alternatively, the (+)-3-dihydrotetrabenazine or a
pharmaceutically acceptable salt thereof can be administered in a non-solid dosage form such as a solution, syrup, suspension or gel. In particular embodiments of the invention, there is provided:
• A unit dosage form comprising from 1 mg to 200 mg (e.g. between 1 mg and 200 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• A unit dosage form comprising from 1 mg to 150 mg (e.g. between 1 mg and 150 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• A unit dosage form comprising from 1 mg to 100 mg (e.g. between 1 mg and 100 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• A unit dosage form comprising from 1 mg to 80 mg (e.g. between 1 mg and 80 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A unit dosage form comprising from 3 mg to 200 mg (e.g. between 3 mg and 200 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A unit dosage form comprising from 3 mg to 150 mg (e.g. between 3 mg and 150 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A unit dosage form comprising from 3 mg to 100 mg (e.g. between 3 mg and 100 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A unit dosage form comprising from 3 mg to 80 mg (e.g. between 3 mg and 80 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A unit dosage form comprising from 5 mg to 200 mg (e.g. between 5 mg and 200 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A unit dosage form comprising from 5 mg to 150 mg (e.g. between 5 mg and 150 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A unit dosage form comprising from 5 mg to 100 mg (e.g. between 5 mg and 100 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A unit dosage form comprising from 5 mg to 80 mg (e.g. between 5 mg and 80 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A unit dosage form comprising from 3 mg to 60 mg (e.g. between 3 mg and 60 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A unit dosage form comprising from 5 mg to 60 mg (e.g. between 5 mg and 60 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. • A unit dosage form comprising from 10 mg to 60 mg (e.g. between 10 mg and 60 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• A unit dosage form comprising from 15 mg to 60 mg (e.g. between 15 mg and 60 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• A unit dosage form comprising approximately 20 mg of (+)-β- dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. · A unit dosage form comprising approximately 30 mg of (+)-β- dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• A unit dosage form comprising approximately 40 mg of (+)-β- dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• A unit dosage form comprising approximately 50mg of (+)-β- dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• A unit dosage form comprising approximately 60 mg of (+)-β- dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
The unit dosage forms defined and described above are typically for use in the treatment of a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
More particularly, the unit dosage forms described above are for use in the treatment of a hyperkinetic movement disorder selected from tic disorders, Huntington's disease, tardive dyskinesia and Tourette's syndrome.
In one particular embodiment, the unit dosage forms described above are for use in the treatment of tardive dyskinesia. In another particular embodiment, the unit dosage forms described above are for use in the treatment of Tourette's syndrome.
The present inventors have found that (+)-3-dihydrotetrabenazine is useful in the blocking of the VMAT2 receptor in the treatment of movement disorders.
Accordingly, the invention provides a pharmaceutical composition comprising (+)- β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
The invention also provides (+)-3-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for use as a VMAT2 inhibitor. In further embodiments of the Invention, there are provided:
• (+)"3-Dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for use in the treatment of a hyperkinetic movement disorder.
• (+)"3-Dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for use in the treatment of Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia or Tourette's syndrome.
• A method of treatment of a hyperkinetic movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human), which method comprises administering to the subject a therapeutically effective amount of (+)"3-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof. · A method of treatment of Huntington's disease, hemiballismus, senile
chorea, tic disorders, tardive dyskinesia, dystonia or Tourette's syndrome in a subject in need thereof (e.g. a mammalian subject such as a human), which method comprises administering to the subject a therapeutically effective amount of (+)-3-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.
• The use of (+)-3-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a hyperkinetic movement disorder.
• The use of (+)-3-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a of Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia or Tourette's syndrome.
• (+)"3-dihydrotetrabenazine for use in a method for the treatment of a
movement disorder, wherein the treatment comprises administering to a subject an amount of (+)-3-dihydrotetrabenzine from 1 mg to 200 mg (e.g. between 1 mg and 200 mg) per day.
• A method of treatment of a movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine from 1 mg to 200 mg (e.g. between 1 mg and 200 mg) per day.
• The use of (+)-3-dihydrotetrabenazine for the manufacture of a medicament for the treatment of a movement disorder, which treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine from 1 mg to 200 mg (e.g. between 1 mg and 200 mg) per day.
• Typically, the (+)-3-dihydrotetrabenazine, or pharmaceutically acceptable salt thereof, is not administered with an effective amount of amantadine. In one embodiment, the (+)-3-dihydrotetrabenazine, or pharmaceutically acceptable salt thereof, is not administered with amantadine.
The (+)"3-dihydrotetrabenazine, or pharmaceutically acceptable salt thereof, may be administered as an immediate release unit dosage form.
In further embodiments, there are provided:
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 1 mg to 150 mg (e.g. between 1 mg and 150) mg per day.
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 1 mg to 100 mg (e.g. between 1 mg and 100) mg per day. (+)-3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 1 mg to 80 mg (e.g. between 1 mg and 80) mg per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 3 mg to 200 mg (e.g. between 3 mg and 200) mg per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 3 mg to 150 mg (e.g. between 3 mg and 150) mg per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 3 mg to 100 mg (e.g. between 3 mg and 100) mg per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 5 mg to 200 mg (e.g. between 5 mg and 200) mg per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 5 mg to 150 mg (e.g. between 5 mg and 150) mg per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 5 mg to 100 mg (e.g. between 5 mg and 100) mg per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine from 1 mg to 70 mg (e.g. between 1 mg and 70) mg per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 1 mg to 60 mg (e.g. between 1 mg and 60 mg) per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 1 mg to 50 mg (e.g. between 1 mg and 50 mg) per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 5 mg to 70 mg (e.g. between 5 mg and 70 mg) per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine from 5 mg to 60 mg (e.g. between 5 mg and 60 mg) per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine of approximately 10 mg per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine of approximately 15 mg per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine of approximately 20 mg per day.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine of approximately 30 mg per day. • (+)-3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine of approximately 40 mg per day.
In each case, the quantity of (+)-3-dihydrotetrabenazine specified may be administered once per day or in several (e.g. two) doses per day.
In some embodiments, the quantity of (+)-3-dihydrotetrabenazine specified is administered once daily.
The administration of (+)-3-dihydrotetrabenazine typically forms part of a chronic treatment regime. The (+)-3-dihydrotetrabenazine may therefore be administered to a patient for a treatment period of at least a week, more usually at least two weeks, or at least a month, and typically longer than a month. Where a patient is shown to respond well to treatment, the period of treatment can be longer than six months and may extend over a period of years.
The chronic treatment regime may involve the administration of the (+)-β- dihydrotetrabenazine every day, or the treatment regime may include days when no (+)"3-dihydrotetrabenazine is administered.
The dosage administered to the subject may vary during the treatment period. For example, the initial dosage may be increased or decreased depending on the subject's response to the treatment. A subject may, for example, be given an initial low dose to test the subject's tolerance towards the (+)-3-dihydrotetrabenazine, and the dosage thereafter increased as necessary up to the maximum daily intake of 80 mg (or other daily intakes as described above). Alternatively, an initial daily dosage administered to the patient may be selected so as to give an estimated desired degree of VMAT2 blockage, following which a lower maintenance dose may be given for the remainder of the treatment period, with the option of increasing the dosage should the subject's response to the treatment indicate that an increase is necessary.
The quantity of (+)-3-dihydrotetrabenazine required to achieve the desired therapeutic effect may be dependent on the weight of the subject to be treated. The quantities of (+)-3-dihydrotetrabenazine administered to the subject can be defined in terms of the weight in milligrams of (+)-3-dihydrotetrabenazine administered to the subject per kilogram of the subject's body weight, which can be abbreviated to mg/kg. The appropriate dosage amount can therefore be calculated by multiplying the mg/kg amount by the weight of the subject to be treated.
Accordingly, the invention also provides:
• (+)"3-dihydrotetrabenazine for use in a method for the treatment of a
movement disorder, wherein the treatment comprises administering to a subject an amount of (+)-3-dihydrotetrabenazine from 0.01 mg/kg to 2.0 mg/kg (e.g. between 0.01 mg/kg and 2.0 mg/kg) per day provided that the total amount of (+)-3-dihydrotetrabenazine administered per day is in the range from 1 mg to 80 mg (or such other range as defined above). · A method of treatment of a movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine from 0.01 mg/kg to 2.0 mg/kg (e.g. between 0.01 mg/kg and 2.0 mg/kg) per day, provided that the total amount of (+)-3-dihydrotetrabenazine administered per day is in the range from 1 mg to 80 mg (or such other range as defined above).
• The use of (+)-3-dihydrotetrabenazine for the manufacture of a medicament for the treatment of a movement disorder, which treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine from 0.01 mg/kg to 2.0 mg/kg (e.g. between 0.01 mg/kg and 2.0 mg/kg) per day, provided that the total amount of (+)-3-dihydrotetrabenazine administered per day is in the range from 1 mg to 80 mg (or such other range as defined above).
In further embodiments, there is provided: · (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject from 0.01 mg/kg to 1.5 mg/kg (e.g. between 0.01 mg/kg and 1 .5 mg/kg) of (+)-β- dihydrotetrabenazine per day, provided that the total amount of (+)-β- dihydrotetrabenazine administered per day is in the range from 1 mg to 80 mg (or such other range as defined above).
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject from 0.1 mg/kg to 1.5 mg/kg (e.g. between 0.1 mg / kg and 1 .5 mg / kg) of (+)-β- dihydrotetrabenazine, provided that the total amount of (+)-β- dihydrotetrabenazine administered per day is in the range from 1 mg to 80 mg (or such other range as defined above). · (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject from 0.25 mg/kg to 1.5 mg/kg (e.g. between 0.25 mg / kg and 1.5 mg / kg) of (+)-β- dihydrotetrabenazine, provided that the total amount of (+)-β- dihydrotetrabenazine administered per day is in the range from 1 mg to 80 mg (or such other range as defined above).
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject from 0.01 mg/kg to 1.25 mg/kg (e.g. between 0.01 mg / kg and 1 .25 mg / kg) of (+)-β- dihydrotetrabenazine per day, provided that the total amount of (+)-β- dihydrotetrabenazine administered per day is in the range from 1 mg to 60 mg (or such other range as defined above).
• (+)^-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject from 0.1 mg/kg to 1.25 mg/kg (e.g. between 0.1 mg / kg and 1 .25 mg / kg) of (+)-β- dihydrotetrabenazine, provided that the total amount of (+)-β- dihydrotetrabenazine administered per day is in the range from 1 mg to 60 mg (or such other range as defined above).
• (+)^-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject from 0.25 mg/kg to 1.25 mg/kg (e.g. between 0.25 mg / kg and 1 .25 mg / kg) of (+)-β- dihydrotetrabenazine, provided that the total amount of (+)-β- dihydrotetrabenazine administered per day is in the range from 1 mg to 60 mg (or such other range as defined above).
In each of the foregoing aspects and embodiments, the (+)^-dihydrotetrabenazine can be administered as the free base or as a pharmaceutically acceptable salt. Unless the context indicates otherwise, references herein to (+)-β- dihydrotetrabenazine also include pharmaceutically acceptable salts thereof. In one general embodiment, the (+)-3-dihydrotetrabenazine is administered as a pharmaceutically acceptable salt.
In another general embodiment, the (+)-3-dihydrotetrabenazine is administered as a free base. Where quantities or ranges of quantities of (+)-3-dihydrotetrabenazine are stated herein, these are calculated as the amounts of the free base, or when the (+)-β- dihydrotetrabenazine is in the form of a pharmaceutically acceptable salt, the amount of (+)-3-dihydrotetrabenazine free base present in the pharmaceutically acceptable salt. Complete blocking of the VMAT2 proteins is considered undesirable as this can lead to unwanted side effects such as Parkinsonism. The present invention provides plasma levels of (+)-3-dihydrotetrabenazine that are sufficient to give effective treatment of movement disorders but do not block the VMAT2 proteins to an extent that causes Parkinsonism and similar side effects. The levels of VMAT2 blocking can be determined by competitive binding studies using Positron
Emission Tomography (PET). By co-administering a radioactive ligand with the compound of interest at various concentrations, the proportion of binding sites occupied can be determined (see for example, Matthews et al., "Positron emission tomography molecular imaging for drug development", Br. J. Clin. Pharmacol., 73:2, 175-186). Accordingly, the invention also provides:
• (+)"3-dihydrotetrabenazine for use in a method for the treatment of a
movement disorder, wherein the treatment comprises administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 90% of the VMAT2 proteins in the subject. · A method of treatment of a movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 90% of the VMAT2 proteins in the subject. · The use of (+)-3-dihydrotetrabenazine for the manufacture of a medicament for the treatment of a movement disorder, which treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 90% of the VMAT2 proteins in the subject.
In further embodiments, there is provided:
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 85% of the VMAT2 proteins in the subject.
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 80% of the VMAT2 proteins in the subject.
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 75% of the VMAT2 proteins in the subject.
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of up to 70% of the VMAT2 proteins in the subject.
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 20% to 90% of the VMAT2 proteins in the subject.
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 25% to 85% of the VMAT2 proteins in the subject.
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of from 30% to 80% of the VMAT2 proteins in the subject.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 35% to 75% of the VMAT2 proteins in the subject.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 35% to 70% of the VMAT2 proteins in the subject.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 40% to 75% of the VMAT2 proteins in the subject.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of from 45% to 75% of the VMAT2 proteins in the subject.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of from 35% to 80% of the VMAT2 proteins in the subject.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of from 40% to 80% of the VMAT2 proteins in the subject. (+)-3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of from 45% to 80% of the VMAT2 proteins in the subject.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 50% to 80% of the VMAT2 proteins in the subject.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of from 55% to 80% of the VMAT2 proteins in the subject.
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)"3-dihydrotetrabenazine sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 30% to 70% (e.g. between 30% and 70%).
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a blocking level of VMAT2 proteins in the subject of from 30% to 65% (e.g. between 30% and 65%).
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a blocking level of VMAT2 proteins in the subject of from 30% to 60% (e.g. between 30% and 60%).
(+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level blocking of VMAT2 proteins in the subject of from 40% to 80% (e.g. between 40% and 80%). • (+)-3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 75% (e.g. between 40% and 75%).
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 70% (e.g. between 40% and 70%).
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 65% (e.g. between 40% and 65%).
• (+)"3-dihydrotetrabenazine for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level blocking of VMAT2 proteins in the subject of from 40% to 60% (e.g. between 40% and 60%). The movement disorder can be a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia, myoclonus and Tourette's syndrome. In one Embodiment, the movement disorder is Tourette's syndrome
In each of the foregoing embodiments, the (+)-3-dihydrotetrabenazine is accompanied by no more than 20% by weight, relative to the (+)-β- dihydrotetrabenazine, of any other isomer of dihydrotetrabenazine. More usually the (+)-3-dihydrotetrabenazine is accompanied by no more than 10% by weight, relative to the (+)-3-dihydrotetrabenazine, of any other isomer of dihydrotetrabenazine; preferably no more than 5% by weight, relative to the (+)-β- dihydrotetrabenazine, of any other isomer of dihydrotetrabenazine; and more preferably no more than 2% by weight, relative to the (+)-3-dihydrotetrabenazine, of any other isomer of dihydrotetrabenazine. Most preferably the (+)-β- dihydrotetrabenazine is accompanied by less than 1 % (e.g. less than 0.5% or less than 0.1 %) relative to the (+)-3-dihydrotetrabenazine, of any other isomer of dihydrotetrabenazine. Thus, the (+)-3-dihydrotetrabenazine typically has an isomeric purity of at least 80%.
The term "isomeric purity" in the present context refers to the amount (+)-β- dihydrotetrabenazine present relative to the total amount or concentration of dihydrotetrabenazines of all isomeric forms. For example, if 90% of the total dihydrotetrabenazine present in the composition is (+)-3-dihydrotetrabenazine, then the isomeric purity is 90%.
The (+)"3-dihydrotetrabenazine of the invention may have an isomeric purity of greater than 82%, greater than 85%, greater than 87%, greater than 90%, greater than 91 %, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or greater than 99.9%.
In each of the foregoing aspects and embodiments of the invention relating to (+)- β-dihydrotetrabenazine or pharmaceutically acceptable salts thereof, typically, the (+)"3-dihydrotetrabenazine, or pharmaceutically acceptable salt thereof, are not administered with a therapeutically effective amount of amantadine. More particularly, the (+)-3-dihydrotetrabenazine, or pharmaceutically acceptable salt thereof, are not administered with any amount of amantadine.
For example, with reference to pharmaceutical unit dosage forms, typically the unit dosage form does not comprise a therapeutically effective amount of amantadine and, more particularly, the pharmaceutical unit dosage form does not comprise any amount of amantadine. Furthermore, in each of the foregoing aspects and embodiments of the invention relating to (+)-3-dihydrotetrabenazine or pharmaceutically acceptable salts thereof, the pharmaceutical unit dosage form may be other than an extended release or delayed release dosage form. Thus, for example, the (+)-3-dihydrotetrabenazine, or pharmaceutically acceptable salt thereof, may be administered as an immediate release unit dosage form.
Combinations of (+)-B-dihydrotetrabenazine with (-)-g-dihydrotetrabenazine and/or (+)-g-dihydrotetrabenazine
In a further aspect, it is envisaged that combinations of (+)-3-dihydrotetrabenazine, having the formula (III),
and
(-)-odihydrotetrabenazine, having the formula (II),
(II) and/or (+)-odihydrotetrabenazine, having the formula (I),
(I) will be useful in the prophylaxis or treatment of inter alia the disease states and conditions for which tetrabenazine is currently used or proposed. Thus, by way of example, and without limitation, it is envisaged that these combinations of dihydrotetrabenazine isomers may be used for the treatment of hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and, in particular, Tourette's syndrome.
Accordingly, in a first aspect, the invention provides a pharmaceutical combination comprising:
(a) (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and one or both of:
(b) (-)-a-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and
(c) (+)-a-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
In one embodiment, the invention provides a pharmaceutical combination comprising:
(a) (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and
(b) (-)-a-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
In another embodiment, the invention provides a pharmaceutical combination comprising:
(a) (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and
(c) (+)-a-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof. In another embodiment, the invention provides a pharmaceutical combination comprising:
(a) (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
(b) (-)-a-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and
(c) (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
The (+)"3-dihydrotetrabenazine, (-)-odihydrotetrabenazine and (+)-o
dihydrotetrabenazine may be referred to herein collectively as "the
dihydrotetrabenazine isomers of the invention" or "isomers of
dihydrotetrabenazine" or "the dihydrotetrabenazines", unless the context indicates otherwise. When describing types of pharmaceutical formulation, they may also be referred to collectively as the "active compounds".
The pharmaceutical combination may be substantially free of (-)-β- dihydrotetrabenazine. Accordingly, the invention also provides a pharmaceutical combination as described herein, wherein the unit dosage form is substantially free of (-)"3-dihydrotetrabenazine.
By "substantially free of (-)-3-dihydrotetrabenazine" is meant that the % weight of (-)"3-dihydrotetrabenazine present compared to the total weight of all isomers of dihydrotetrabenazine is less than 5%, preferably less than 3%, more preferably less than 2% and most preferably less than 1 %.
The relative proportions of the (+)-3-dihydrotetrabenazine, (-)-a- dihydrotetrabenazine and (+)-odihydrotetrabenazine may be expressed in terms of parts by weight of the individual isomers. Thus, for example, the unit dosage forms may comprise from 35 to 75 parts by weight of (+)-3-dihydrotetrabenazine and from 25 to 55 parts by weight of an odihydrotetrabenazine (which may be either (+)-odihydrotetrabenazine or (-)-odihydrotetrabenazine or a mixture thereof). It will be appreciated that the proportions expressed above as parts by weight could instead be expressed in terms of molar ratios (as all of the isomers have the same molecular weight), in which case the relative proportions of the isomers could be expressed as a molar ratio of (+)-3-dihydrotetrabenazine : o dihydrotetrabenazine (which may be either (+)-odihydrotetrabenazine or (-)-a- dihydrotetrabenazine or a mixture thereof) of 35-70 : 25-55. In one embodiment, a pharmaceutical combination of the invention comprises:
(a) 40-65 parts by weight of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and
(c) 40-65 parts by weight of (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
For example, the pharmaceutical combination may comprise:
(a) 45-55 parts by weight of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and
(c) 45-55 parts by weight of (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
In one particular embodiment, the pharmaceutical combination comprises (+)-β- dihydrotetrabenazine and (+)-odihydrotetrabenazine in approximately equimolar amounts.
In another embodiment, a pharmaceutical combination of the invention comprises: (a) 45-65 parts by weight of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
(b) 30-50 parts by weight of (-)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and optionally
(c) 0.1 -5 parts by weight of (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
In another embodiment, a pharmaceutical combination of the invention comprises:
(a) 45-65 parts by weight of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
(b) 30-50 parts by weight of (-)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and optionally
(c) 0.1 -3 parts by weight of (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
In another embodiment, a pharmaceutical combination of the invention comprises: (a) 45-65 parts by weight of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
(b) 30-50 parts by weight of (-)-a-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and optionally
(c) 0.1 -2 parts by weight of (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
In a further embodiment, a pharmaceutical combination of the invention comprises:
(a) 45-65 parts by weight of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
(b) 30-50 parts by weight of (-)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and optionally
(c) 0.1 -1 .5 parts by weight of (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
By pharmaceutical combination is meant a combination of the three
dihydrotetrabenazines (a) and (b) and/or (c) in a form that is suitable for administration to a subject, typically a human or other animal subject. The term therefore excludes crude reaction mixtures, partially purified reaction products, whole blood samples or blood fraction samples such as plasma or other biological samples such as urine samples containing the combinations. It also excludes simple solutions of the combinations in non-pharmaceutically acceptable solvents (e.g. chloroform, dichloromethane) that are not normally used in pharmacy.
The pharmaceutical combinations may be in the form of mixtures of the pure compounds or the combinations may comprise one or more pharmaceutically acceptable excipients. Typically, the pharmaceutical combinations comprise a pharmaceutically acceptable excipient and are formulated as unit dosage forms containing defined amounts of the dihydrotetrabenazines (a), (b) and/or (c).
In the pharmaceutical combinations of the invention, one or more of the three dihydrotetrabenazines (a), (b) and (c) may be formulated separately but used in combination. More typically, however, the three dihydrotetrabenazines (a), (b) and (c) are formulated together in a pharmaceutical composition, and in particular a unit dosage form.
In a unit dosage form of the invention containing a combination as defined herein, the sum of the amounts of the three isomers (+)-3-dihydrotetrabenazine, (-)-a- dihydrotetrabenazine and (+)-odihydrotetrabenazine (the "total amount") may be selected so that it does not exceed 100mg.
Typically, the pharmaceutical unit dosage form does not comprise an effective amount of amantadine. In one embodiment the pharmaceutical unit dosage form is one that does not comprise amantadine. The pharmaceutical unit dosage form may be an immediate release unit dosage form.
In particular embodiments:
• the total amount of the three isomers does not exceed 75mg; or
• the total amount of the three isomers does not exceed 50mg; or
· the total amount of the three isomers does not exceed 40mg; or
• the total amount of the three isomers does not exceed 30mg; or
• the total amount of the three isomers does not exceed 20mg.
The unit dosage form can be one which is administered orally, for example a capsule or tablet. The unit dosage form can be one which is administered orally, for example a capsule or tablet.
The pharmaceutical combinations as defined herein are provided for use in medicine.
More particularly, the pharmaceutical combinations (and unit dosage forms) defined and described above are provided for use in the treatment of a
hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome. More particularly, the pharmaceutical combinations (and unit dosage forms) described above are for use in the treatment of a hyperkinetic movement disorder selected from tic disorders, Huntington's disease, tardive dyskinesia and Tourette's syndrome.
In one particular embodiment, the pharmaceutical combinations (and unit dosage forms) described above are for use in the treatment of tardive dyskinesia.
In another particular embodiment, the pharmaceutical combinations (and unit dosage forms) described above are for use in the treatment of Tourette's syndrome.
In further aspects, the invention provides:
A pharmaceutical combination as defined herein for use in the treatment of a hyperkinetic movement disorder.
A method of treatment of a hyperkinetic movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human), which method comprises administering to the subject a therapeutically effective amount of a pharmaceutical combination as defined herein.
The use of a pharmaceutical combination as defined herein for the manufacture of a medicament for the treatment of a hyperkinetic movement disorder.
A unit dosage form for use, a pharmaceutical combination for use, a method or a use as described herein wherein the hyperkinetic movement disorder is selected from Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
A unit dosage form for use, a pharmaceutical combination for use, a method or a use as described herein wherein the hyperkinetic movement disorder is Tourette's syndrome.
In each case, the combination of (+)-3-dihydrotetrabenazine, (-)-a- dihydrotetrabenazine; and optionally (+)-odihydrotetrabenazine is typically administered once per day. Complete blocking of VMAT2 is considered undesirable as this can lead to unwanted side effects, such as Parkinsonism. The present invention provides plasma levels of dihydrotetrabenazines that are sufficient to give effective treatment of movement disorders but do not block VMAT2 to an extent that causes Parkinsonism and similar side effects. The levels of VMAT2 blocking can be determined by competitive binding studies using Positron Emission Tomography (PET). By co-administering a radioactive ligand with the compound of interest at various concentrations, the proportion of binding sites occupied can be determined (see for example, Matthews et al., "Positron emission tomography molecular imaging for drug development", Br. J. Clin. Pharmacol., 73:2, 175-186).
Accordingly, the invention also provides:
• A unit dosage form for use, a pharmaceutical combination for use, a
method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of greater than 20% of
VMAT2 proteins in the subject.
• A unit dosage form for use, a pharmaceutical combination for use, a
method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of greater than 30% of
VMAT2 proteins in the subject.
• A unit dosage form for use, a pharmaceutical combination for use, a
method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of greater than 40% of
VMAT2 proteins in the subject.
• A unit dosage form for use, a pharmaceutical combination for use, a
method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of less than 90% of VMAT2 proteins in the subject. • A unit dosage form for use, a pharmaceutical combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of less than 85% of VMAT2 proteins in the subject.
• A unit dosage form for use, a pharmaceutical combination for use, a
method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of less than 80% of VMAT2 proteins in the subject.
• A unit dosage form for use, a pharmaceutical combination for use, a
method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of less than 75% of VMAT2 proteins in the subject.
• A unit dosage form for use, a pharmaceutical combination for use, a
method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a blocking level of less than 70% of VMAT2 proteins in the subject.
• A unit dosage form for use, a pharmaceutical combination for use, a
method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 20% to 90% (e.g. between 20% and 90%).
• A unit dosage form for use, a pharmaceutical combination for use, a
method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 30% to 80% (e.g. between 30% and 80%).
• A unit dosage form for use, a pharmaceutical combination for use, a
method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 30% to 75% (e.g. between 30% and 75%).
A unit dosage form for use, a pharmaceutical combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 30% to 70% (e.g. between 30% and 70%).
A unit dosage form for use, a pharmaceutical combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 30% to 65% (e.g. between 30% and 65%).
A unit dosage form for use, a pharmaceutical combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 30% to 60% (e.g. between 30% and 60%).
A unit dosage form for use, a pharmaceutical combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 80% (e.g. between 40% and 80%).
A unit dosage form for use, a pharmaceutical combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 75% (e.g. between 40% and 75%). A unit dosage form for use, a pharmaceutical combination for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 70% (e.g. between 40% and 70%).
• A unit dosage form for use, a pharmaceutical combination for use, a
method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 65% (e.g. between 40% and 65%).
• A unit dosage form for use, a pharmaceutical combination for use, a
method or a use as described herein, wherein the treatment comprises administering to the subject an amount of the unit dosage form or combination sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 40% to 60% (e.g. between 40% and 60%).
In each of the foregoing aspects and embodiments of the invention relating to combinations of dihydrotetrabenazines (a) and (b) and/or (c), typically the combinations are not administered with a therapeutically effective amount of amantadine. More particularly, the combinations, are not administered with any amount of amantadine.
For example, with reference to pharmaceutical unit dosage forms, typically the unit dosage form does not comprise a therapeutically effective amount of amantadine and, more particularly, the pharmaceutical unit dosage form does not comprise any amount of amantadine.
Furthermore, in each of the foregoing aspects and embodiments of the invention relating to combinations of dihydrotetrabenazines (a) and (b) and/or (c), the pharmaceutical unit dosage form may be other than an extended release or delayed release dosage form.
Thus, for example, the combinations of dihydrotetrabenazines (a) and (b) and/or (c) may be administered as an immediate release unit dosage form.
Free bases and salts
In each of the foregoing aspects and embodiments of the invention, all references herein to the individual isomers of dihydrotetrabenazine refer to both the free bases and salts thereof, unless the context indicates otherwise. The salts are typically acid addition salts.
The salts can be synthesized from the parent compound by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties,
Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free base form of the compound with the acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, acetone, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
Acid addition salts may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulphonic, (+)-(1 S)-camphor-10-sulphonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric, ethane-1 ,2- disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), ooxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, (+)-L-lactic, (±)-DL-lactic, lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulphonic, naphthalene-2- sulphonic, naphthalene-1 ,5-disulphonic, 1 -hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulphuric, tannic, (+)-L- tartaric, thiocyanic, p-toluenesulphonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.
The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1 -19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into
pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.
The isomers of dihydrotetrabenazine may contain one or more isotopic
substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope 1H, 2H (D), and 3H (T). Similarly, references to carbon and oxygen include within their scope respectively 11C, 12C, 13C and 14C and 160 and 180.
Typically, the isomers of dihydrotetrabenazine of the invention does not contain isotopes (such as 11C or 3H) in amounts higher than their natural abundance. In one embodiment, the percentage of the total hydrogen atoms in the (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine that are deuterium atoms is less than 2%, more typically less than 1 %, more usually less than 0.1 %, preferably less than 0.05% and most preferably no more than 0.02%.
In an analogous manner, a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise.
The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the isomers of dihydrotetrabenazine contain no radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the one or more of the isomers of dihydrotetrabenazine may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.
References to the isomers of dihydrotetrabenazine include any solvates formed by the compounds.
Examples of solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulphoxide. Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography.
The solvates can be stoichiometric or non-stoichiometric solvates.
Particular examples of solvates are hydrates such as hemihydrates, monohydrates and dihydrates. For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.
Alternatively, rather than existing as a hydrate, the compound of the invention may be anhydrous. Therefore, in another embodiment, one or more of the isomers of dihydrotetrabenazine are in an anhydrous form.
Methods for the Preparation of the Dihydrotetrabenazine Isomers
(+)-a-Dihydrotetrabenazine and (-)-odihydrotetrabenazine can be prepared from tetrabenazine according to the synthetic route shown in Scheme 1.
(I) (II)
Scheme 1
Racemic tetrabenazine (3-isobutyl-9,10-dimethyoxy-1 ,3,4,6,7,1 1 b-hexahydro-2/-/- pyrido[2,1 ,a]isoquinolin-2-one) containing the RR and SS isomers of tetrabenazine is reduced with sodium borohydride to afford a mixture of four
dihydrotetrabenazine isomers of which a racemic mixture of the o
dihydrotetrabenazine (RRR and SSS isomers) constitutes the major product and a racemic mixture of the β-dihydrotetrabenazines (the SRR and RSS isomers) constitutes a minor product. The β-dihydrotetrabenazines can be removed during an initial purification procedure, for example by chromatography or recrystallization and then the racemic odihydrotetrabenazines resolved by well known methods such as chiral chromatography or the formation of diastereoisomeric salts by reaction with chiral acids followed by separation by recrystallisation.
For example, by recrystallisation of the racemic mixture with di-p-toluoyl-L-tartaric acid or (R)-(-)-camphorsulfonic acid or by chiral chromatography, the (+)-o dihydrotetrabenazine isomer (I) ((2R, 3R, 77ibR)-3-isobutyl-9,10-dimethoxy- 1 ,3,4,6,7,1 1 b-hexahydro-2/-/-pyrido[2,1 ,a]isoquinolin-2-ol) can be obtained.
By recrystallisation of the racemic mixture with di-p-toluoyl-R-tartaric acid or (L)- (+)-camphorsulfonic acid or by chiral chromatography, the (-)-a- dihydrotetrabenazine isomer (I) ((2S, 3S, 77bS)-3-isobutyl-9,10-dimethoxy- 1 ,3,4,6,7,1 1 b-hexahydro-2/-/-pyrido[2,1 ,a]isoquinolin-2-ol) can be obtained.
(+)-a-Dihydrotetrabenazine and (-)-odihydrotetrabenazine can also be prepared according to Yao et al., "Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors", Eur. J. Med. Chem., (201 1 ), 46, pp. 1841 - 1848.
(+)-P"Dihydrotetrabenazine (compound of formula (III)) can be prepared from tetrabenazine according to the synthetic route shown in Scheme 2.
(III)
Scheme 2
Racemic tetrabenazine (S-isobutyl-g O-dimethyoxy-I ^^^J I b-hexahydro^H- pyrido[2,1 ,a]isoquinolin-2-one) containing the RR and SS isomers of tetrabenazine is reduced with sodium borohydride to afford a mixture of four
dihydrotetrabenazine isomers of which a racemic mixture of the β- dihydrotetrabenazines {SRR and RSS isomers) constitutes the major product and a racemic mixture of the odihydrotetrabenazines (the RRR and SSS isomers) constitutes a minor product. The odihydrotetrabenazines can be removed during an initial purification procedure, for example by chromatography or recrystallization and then the racemic β-dihydrotetrabenazines resolved (e.g. by recrystallisation with di-p-toluoyl-L-tartaric acid or (R)-(-)-camphorsulfonic acid or by chiral chromatography), to afford (+)-3-dihydrotetrabenazine (III) {{2S, 3R, 11bR)-3- isobutyl-9,10-dimethoxy-1 ,3,4,6,7,1 1 b-hexahydro-2/-/-pyrido[2,1 ,a]isoquinolin-2-ol). The stereochemical configuration of (+)-3-dihydrotetrabenazine can be
determined, so example by forming a salt such as the mesylate salt in crystalline form and the structure identified by X-ray crystallography.
(+)-a-Dihydrotetrabenazine, (-)-odihydrotetrabenazine and (+)-β- dihydrotetrabenazine can also be prepared according to Yao et al., "Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors", Eur. J. Med. Chem., (201 1 ), 46, pp. 1841 - 1848.
Once prepared and purified, the (+)-3-dihydrotetrabenazine, (-)-a- dihydrotetrabenazine and, where present the (+)-a-dihydrotetrabenazine, or their respective salts, can be mixed in the required proportions. Pharmaceutical Formulations and Methods of Treatment
The pharmaceutical unit dosage forms of the invention can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, ophthalmic, otic, rectal, intra- vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.
Pharmaceutical unit dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, sprays, powders, granules, elixirs and suspensions, sublingual tablets, sprays, wafers or patches and buccal patches.
Particular examples of pharmaceutical unit dosage forms containing the combinations of the invention are capsules and tablets. Pharmaceutical unit dosage forms containing the combinations of the invention can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
Thus, tablet compositions can contain a unit dosage of the combination of active compounds together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g.; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, talc, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as
citrate/bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.
Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof. The solid dosage forms (e.g.: tablets, capsules etc.) can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating. The coating (e.g. a Eudragit™ type polymer) can be designed to release the active component at a desired location within the gastro-intestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum or duodenum.
Instead of, or in addition to, a coating, the isomers of dihydrotetrabenazine, or pharmaceutically acceptable salts thereof making up the combinations of the invention can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract.
Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.
Compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.
Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped mouldable or waxy material containing the active compound.
Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered
formulations typically comprise the combination of dihydrotetrabenazine isomers, or pharmaceutically acceptable salts thereof together with an inert solid powdered diluent such as lactose.
The isomers of dihydrotetrabenazine, and their respective salts can be formulated separately and used in combination, or they can be formulated together. When formulated together, they can be provided as a mixture to which one or more pharmaceutical excipients is (are) added before processing (e.g. compressing to form a tablet or filling into a capsule) to form a pharmaceutical composition such as a unit dosage form. Alternatively, they can be added separately to an excipient or mixture of excipients and processed together. In a further alternative, at least some of the dihydrotetrabenazine isomers can be formulated separately in different granules, pellets, microbeads or mini-tablets and then brought together and processed to give a pharmaceutical composition (e.g. by filling into a capsule or compressing to form a tablet). As another alternative, the different isomers of the dihydrotetrabenazine isomers can be contained within different layers in a multi- layered tablet. Particular pharmaceutical compositions of the invention are compositions selected from:
• Sublingual compositions;
• Intranasal; · Pellets or tablets formulated to provide release kinetics corresponding to zero order release of the active compound;
• Pellets or tablets formulated to provide first fast release followed by
constant rate release (zero order) of the active compound;
• Pellets or tablets formulated to provide a mixture of first order and zero order release of the active compound; and
• Pellets or tablets formulated to provide a combination of zero order and first order release of the active compound; and optionally a further order of release of the active compound selected from second, third and fourth orders of release and combinations thereof. Pellets and tablets formulated to provide release kinetics of the types defined above can be prepared according to methods well known the skilled person; for example as described in Remington's Pharmaceutical Sciences (idem) and "Remington - The Science and Practice of Pharmacy, 21 st edition, 2006, ISBN 0- 7817-4673-6. The combinations of the invention will generally be presented in pharmaceutical unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity, as described above.
The combinations of the invention will be administered to a subject (patient) in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect, as described above.
Brief Description of the Drawings
Figure 1 shows the average total distance travelled by rats when treated with vehicle (with or without amphetamine induction) and (-)-odihydrotetrabenazine at a dose of 2.5 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 1 below. Figure 2 shows the average total stereotypic behaviour by rats when treated with vehicle (with or without amphetamine induction) and (-)-odihydrotetrabenazine at a dose of 2.5 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 1 below. Figure 3 shows the average total distance travelled by rats when treated with vehicle (with or without amphetamine induction) and (+)-odihydrotetrabenazine at doses of 0.1 mg/kg and 0.25 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 2 below.
Figure 4 shows the average total stereotypic behaviour by rats when treated with vehicle (with or without amphetamine induction) and (+)-odihydrotetrabenazine at doses of 0.1 mg/kg and 0.25 mg/kg and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 2 below.
Figure 5 shows the average total distance travelled by rats when treated with vehicle (with or without amphetamine induction) and (-)-odihydrotetrabenazine at a dose of 2 mg/kg, a combination of (+)-odihydrotetrabenazine at a dose of 2 mg/kg and (-)-odihydrotetrabenazine at a dose of 2 mg/kg, and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 3 below.
Figure 6 shows the average total stereotypic behaviour by rats when treated with vehicle (with or without amphetamine induction) and (-)-odihydrotetrabenazine at a dose of 2 mg/kg, a combination of (+)-odihydrotetrabenazine at a dose of 2 mg/kg and (-)-odihydrotetrabenazine at a dose of 2 mg/kg, and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 3 below. Figure 7 shows the average total distance travelled by rats when treated with vehicle (with or without amphetamine induction) and combinations of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine in varying ratios, and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 4 below.
Figure 8 shows the average total stereotypic behaviour by rats when treated with vehicle (with or without amphetamine induction) and combinations of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine in varying ratios, and risperidone at a dose of 1 mg/kg in amphetamine-induced rats, as described in Example 2, Study 4 below.
Figure 9 shows the average total distance travelled by rats when treated with vehicle (with or without amphetamine induction), (+)-3-dihydrotetrabenazine and combinations of (+)-odihydrotetrabenazine and (+)-3-dihydrotetrabenazine in amphetamine-induced rats, as described in Example 2, Study 5 below.
Figure 10 shows the average total stereotypic behaviour by rats when treated with vehicle (with or without amphetamine induction), (+)-3-dihydrotetrabenazine and combinations of (+)-odihydrotetrabenazine and (+)-3-dihydrotetrabenazine in amphetamine-induced rats, as described in Example 2, Study 5 below.
Figure 1 1 shows the average total distance travelled by rats when treated with vehicle (with or without amphetamine induction), (+)-odihydrotetrabenazine alone, (+)-odihydrotetrabenazine in combination with (-)-3-dihydrotetrabenazine, (+)-β- dihydrotetrabenazine in combination with (-)-odihydrotetrabenazine, (+)-β- dihydrotetrabenazine in combination with (-)-3-dihydrotetrabenazine, and (+)-o dihydrotetrabenazine in combination with (+)-3-dihydrotetrabenazine in
amphetamine-induced rats, as described in Example 2, Study 6 below.
Figure 12 shows the stereotypic behaviour (distance over time) by rats when treated with vehicle (with or without amphetamine induction), (+)-o
dihydrotetrabenazine alone, (+)-odihydrotetrabenazine in combination with (-)-β- dihydrotetrabenazine, (+)-3-dihydrotetrabenazine in combination with (-)-a- dihydrotetrabenazine, (+)-3-dihydrotetrabenazine in combination with (-)-β- dihydrotetrabenazine, and (+)-odihydrotetrabenazine in combination with (+)-β- dihydrotetrabenazine in amphetamine-induced rats, as described in Example 2, Study 6 below.
EXAMPLES
The following non-limiting examples illustrate the synthesis and properties of the compositions of the invention.
EXAMPLE 1 An investigation into the nature of the dihydrotetrabenazine metabolites formed after administration of tetrabenazine to human subjects A pharmacokinetic study was carried out in healthy adult male volunteers under fasting conditions at a dose of single and multiple oral administration of 25mg tablets once a day to ascertain the plasma levels of +/-a and +/-β dihydro- tetrabenazine. The data are summarised below.
Table 1 summarises the pharmacokinetic data obtained following single-dose oral administration of tetrabenazine at a dose level of 25 mg (fasting, N = 08).
Table 1
Table 2 summarises the pharmacokinetic data obtained following multiple-dose oral administration of tetrabenazine at a dose level of 25mg (fasting, N = 07).
Table 2
Analyte Tmaxss Cminss
Mean Cmaxss AUC(O-t) Ctss Cavg
(h) (ng/mL) (ng/mL) (ng.h/mL) (ng/mL) (ng.h/mL)
Tetrabenazine 96.89 0.73 0.01 2.79 0.10 0.12
(+) a-DHTBZ 97.18 3.31 0.00 13.74 0.44 0.57
(-) a-DHTBZ 96.96 98.34 5.61 474.17 6.10 19.76
(+) β-DHTBZ 97.1 1 144.76 5.45 598.76 5.54 24.95
(-) β-DHTBZ 97.1 1 7.78 0.16 25.17 0.57 1 .05 The data presented in Tables 1 and 2 demonstrate that, in humans, the major metabolites are the (-)-a-dihydrotetrabenazine isomer, which is essentially active as a VMAT2 binding agent, and the (+)-3-dihydrotetrabenazine isomer, which is significantly less active than the (+)-odihydrotetrabenazine isomer, (-)-β- Dihydrotetrabenazine and (+)-odihydrotetrabenazine were shown to be minor metabolites
The data suggest that (+)-odihydrotetrabenazine is not primarily responsible for the therapeutic properties of tetrabenazine. On the contrary, it appears that (+)-o dihydrotetrabenazine may be responsible for a relatively small contribution to the therapeutic properties of tetrabenazine.
EXAMPLE 2
Investigation of the effect of combinations of (+)-a-dihvdrotetrabenazine and (-)-a- dihvdrotetrabenazine on locomotor activity and stereotypies in rats
The effects of combinations of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine on locomotor activity and stereotypies in rats were investigated and compared to the effects of the individual (+)-o
dihydrotetrabenazine and (-)-odihydrotetrabenazine isomers.
MATERIALS AND METHODS
Equipment
Open field arena, Med Associates Inc.
Plastic syringes 1 ml, Terumo. Ref: SS-01 T1
Animal feeding needle 15 G, Instech Solomon, Cat: 72-4446
Sartorius Mechatronics Scale A22101 , Sartorius Weighting Technology, Germany
Needle 27 G Terumo Myjector, 0,5 ml, Ref: 8300010463
Plastic syringes 3 ml, Soft-Ject, Ref: 8300005761
BD Microtainer K2EDTA tubes Ref: 365975
Matrix 0,75 ml, Alphanum Tubes, Thermo Scientific, Ref: 4274
Microplate Devices, Uniplate 24 wells, 10 ml, Ref: 734-1217
Thermo Electron Corp. Heraeus Fresco 17, refrigerated centrifuge
Test Animals All animal experiments were carried out according to the National Institute of Health (NIH) guidelines for the care and use of laboratory animals, and approved by the National Animal Experiment Board, Finland. Male CD (Charles River Laboratories, Germany) at weight range of 200-250 g (165-200 g upon arrival) were used for the experiments. Animals were housed at a standard temperature (22 ± 1 °C) and in a light-controlled environment (lights on from 7 am to 8 pm) with ad libitum access to food and water.
Methods
Locomotor activity of the rats was tested in open field arena. The open field test was performed during the rat light cycle and under a normal lighting evenly distributed to the test chambers. The paths of the rats were recorded by activity monitor (Med. Associates Inc.).
Dosing the vehicle, amphetamine, (+)-a-DHTBZ, (-)-a-DHTBZ,(+)-3-DHTBZ, (-)-β- DHTBZ or risperidone was done prior to LMA test. The rats were placed in the center of the arena, and the path was recorded for 30 minutes. After 30 minutes of testing vehicle or amphetamine was dosed and the rat was placed in the center of the arena, and the path was recorded for 60 minutes, the total testing time being 90 minutes.
Endpoint, Blood Samples and Tissue Processing
Within 10 minutes from the end of the test animals were euthanized by an overdose of C02. The terminal blood sample was collected with cardiac puncture from all compound treated rats from each group excluding vehicle rats. 0.5 ml of blood was collected with syringe attached to 18 G needle and moved into precooled K2-EDTA microtubes. The EDTA microtube was inverted several times to mix up the EDTA and blood. Tubes were then immediately put on wet ice and centrifuged (Heraeus Fresco 17) within 10-15 minutes of collecting (9.6 x1000 G/ 10 x 1000 RPM, +4°C for 2 min), and 200 μΙ of plasma was collected in 96-tube plates (Matrix Technologies ScreenMates 0.75 ml Alphanumeric Round-Bottom Storage tubes, PP) on dry ice according to sample map.
After collection of blood the neck was dislocated at the base of the skull. Brain was collected and weighed. Brain weights were recorded and the brain was frozen on dry ice on the 24 well plate.
The plasma and brain samples were stored at -80°C on dry ice until sent for analysis. STUDY 1
Animals were grouped as follows:
Group 1 10 rats treated with Vehicle (t= 0 min) and Vehicle (t= 30 min) Group 2 10 rats treated with Vehicle (t= 0 min) and Amphetamine (t= 30 min)
• Group 3: 10 rats treated with (-)-a-DHTBZ 2.5 mg/kg (t=0 min) and
Amphetamine (t= 30 min)
• Group 4: 10 rats treated with risperidone 1 mg/kg (t=0 min) and
Amphetamine (t= 30 min)
Results
1 . Distance Travelled
Rats dosed with either vehicle, (-)-a-DHTBZ 2.5 mg/kg or risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting locomotor activity was evaluated in 3 min bins and as a total over the testing period. The normalised total distance travelled over the testing time is presented in Figure 1 .
When compared to the vehicle-vehicle group the vehicle-amphetamine and (-)-a- DHTBZ 2.5 mg/kg were significantly different. When compared to vehicle- amphetamine group the vehicle-vehicle and risperidone 1 mg/kg were significantly different.
2. Stereotypic Behaviour
Rats dosed with either vehicle, (-)-a-DHTBZ 2.5 mg/kg or risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting stereotypic activity was evaluated in 3 min bins and as a total over the testing period. The normalised total stereotypic behaviour over the testing time is presented in Figure 2.
When compared to the vehicle-vehicle group the vehicle-amphetamine and (-)-a- DHTBZ 2.5 mg/kg were significantly different. When compared to vehicle- amphetamine group the vehicle-vehicle and risperidone 1 mg/kg were significantly different.
Conclusions This study evaluated the effect of (-)-a-DHTBZ at dose 2.5 mg/kg and risperidone at dose 1 mg/kg on amphetamine induced locomotor activity in male CD rats.
(-)-a-DHTBZ at dose 2.5 mg/kg did not lead to lower locomotor activity or reduced stereotypic behaviour when compared to the vehicle-amphetamine group. The rats dosed with (-)-a-DHTBZ at dose 2.5 mg/kg were less focused on what was going on around. The rats dosed with (-)-a -DHTBZ were equally active when compared to the vehicle-amphetamine dosed animals suggesting that (-)-a -DHTBZ does not have a sedative effect similar to risperidone.
STUDY 2
The effects on stereotypic behaviour and the distance travelled in rats following administration of (+)-odihydrotetrabenazine dosed at 0.1 mg/kg to 0.25 mg/kg, as well as risperidone at 1 mg/kg, were studied.
Animals were grouped as follows:
• Group 1 : 10 rats treated with Vehicle (t= 0 min) and Vehicle (t= 30 min) · Group 2: 10 rats treated with Vehicle (t= 0 min) and Amphetamine (t= 30 min)
• Group 3: 10 rats treated with (+)-a-DHTBZ 0.1 mg/kg (t=0 min) and
Amphetamine (t=30 min)
• Group 4: 10 rats treated with (+)-a-DHTBZ 0.25 mg/kg (t=0 min) and
Amphetamine (t=30 min)
• Group 5: 10 rats treated with risperidone 1 mg/kg (t=0 min) and
Amphetamine (t= 30 min)
Results
1 Distance Travelled
Rats dosed with either vehicle, (+)-a-DHTBZ 0.1 mg/kg, (+)-a-DHTBZ 0.25 mg/kg, or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting locomotor activity was evaluated in 3 min bins and as a total over the testing period. The normalised total distance travelled over the testing time is presented in Figure 3.
When compared to vehicle-amphetamine group the vehicle-vehicle, (+)-a-DHTBZ 0.25 mg/kg and risperidone 1 mg/kg were significantly different. 2 Stereotypic Behaviour
Rats dosed with either vehicle, (+)-a-DHTBZ 0.1 mg/kg, (+)-a-DHTBZ 0.25 mg/kg, or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting stereotypic activity was evaluated in 3 min bins and as a total over the testing period. The normalised total stereotypic behaviour over the testing time is presented in Figure 4.
When compared to vehicle-amphetamine group the vehicle-vehicle, (+)-a-DHTBZ 0.1 mg/kg, (+)-a-DHTBZ 0.25 mg/kg and risperidone 1 mg/kg were significantly different.
Conclusions
This study evaluated the effect of (+)-a-DHTBZ at doses 0.1 mg/kg and 0.25 mg/kg and risperidone at dose 1 mg/kg on amphetamine induced locomotor activity in male CD rats.
(+)-a-DHTBZ at 0.25 mg/kg and risperidone 1 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group. (+)-a-DHTBZ at both the tested doses and risperidone 1 mg/kg led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group.
STUDY 3
Animals were grouped as follows:
Group 1 : 10 rats treated with Vehicle (t= 0 min) and Vehicle (t= 30 min)
Group 2: 10 rats treated with Vehicle (t= 0 min) and Amphetamine (t= 30 min)
Group 3: 10 rats treated with (+)-a-DHTBZ 2 mg/kg (t=0 min) and Amphetamine (t= 30 min)
Group 4: 10 rats treated with (+)-a-DHTBZ 2mg/kg with (-)-a-DHTBZ 2mg/kg (t=0 min) and Amphetamine (t=30 min)
Group 5: 10 rats treated with risperidone 1 mg/kg (t=0 min) and Amphetamine (t= 30 min)
Results
1 Distance Travelled
Rats dosed with either vehicle, (+)-a-DHTBZ 2 mg/kg, the combination of (-)-a-
DHTBZ 2 mg/kg and (+)-a-DHTBZ 2 mg/kg or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or
amphetamine challenge. Resulting locomotor activity was evaluated in 3 min bins and as a total over the testing period. The normalised total distance travelled over the testing time is presented in Figure 5.
When compared to the vehicle-vehicle group the vehicle-amphetamine was significantly different. When compared to vehicle-amphetamine group the vehicle- vehicle, (+)-a-DHTBZ 2 mg/kg, the combination of (-)-a-DHTBZ 2 mg/kg and (+)-a- DHTBZ 2 mg/kg and risperidone 1 mg/kg were significantly different.
2 Stereotypic Behaviour
Rats dosed with either vehicle, (+)-a-DHTBZ 2 mg/kg, the combination of (-)-a-
DHTBZ 2 mg/kg and (+)-a-DHTBZ 2 mg/kg or Risperidone 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or
amphetamine challenge. Resulting stereotypic activity was evaluated in 3 min bins and as a total over the testing period. The normalised total stereotypic behaviour over the testing time is presented in Figure 6.
When compared to vehicle-amphetamine group the vehicle-vehicle, (+)-a-DHTBZ 2 mg/kg, the combination of (-)-a-DHTBZ 2 mg/kg and (+)-a-DHTBZ 2 mg/kg and risperidone 1 mg/kg were significantly different.
Conclusions
This study evaluated the effect of compounds (+)-a-DHTBZ at a dose of 2 mg/kg, the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at dose 2 mg/kg and risperidone at dose 1 mg/kg on amphetamine induced locomotor activity in male CD rats.
(+)-a-DHTBZ at the tested dose, the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at doses 2 mg/kg and risperidone 1 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group. (+)-a-DHTBZ at the tested dose, the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at doses 2 mg/kg and risperidone 1 mg/kg led to reduced stereotypic behaviour when compared to the vehicle- amphetamine group.
Amphetamine induced locomotor activity was less in rats treated with the combination of (+)-a-DHTBZ and (-)-a-DHTBZ than in rats treated with (+)-a-
DHTBZ only, despite it being shown that the (-)-oisomer provides very little, if any, reduction induced locomotor activity.
STUDY 4 Animals were grouped as follows:
• Group 1 : 10 rats treated with Vehicle (t= 0 min) and Vehicle (t= 30 min)
• Group 2: 10 rats treated with Vehicle (t= 0 min) and Amphetamine (t= 30 min)
· Group 3: 10 rats treated with (+)-a-DHTBZ 0.5 mg/kg (t=0 min) and (-)-a-
DHTBZ 0.5 mg/kg and Amphetamine (t=30 min)
• Group 4: 10 rats treated with (+)-a-DHTBZ 1.0 mg/kg (t=0 min) and (-)-a- DHTBZ 0.5 mg/kg and Amphetamine (t=30 min)
• Group 5: 10 rats treated with (+)-a-DHTBZ 1.0 mg/kg (t=0 min) and (-)-a- DHTBZ 1.0 mg/kg and Amphetamine (t=30 min)
• Group 6: 10 rats treated with (+)-a-DHTBZ 1.5 mg/kg (t=0 min) and (-)-a- DHTBZ 1.0 mg/kg and Amphetamine (t=30 min)
Results
1 Distance Travelled
Rats dosed with either vehicle, the combination of (+)-a-DHTBZ 0.5 mg/kg and (-)- a-DHTBZ 0.5 mg/kg, the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a-DHTBZ 0.5 mg/kg, the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a-DHTBZ 1 mg/kg or the combination of (+)-a-DHTBZ 1.5 mg/kg and (-)-a-DHTBZ 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting locomotor activity was evaluated in 3 min bins and as a total over the testing period. The normalised total distance travelled over the testing time is presented in Figure 7.
When compared to vehicle-amphetamine group the vehicle-vehicle, (+)-a-DHTBZ, the combination of (+)-a-DHTBZ 0.5 mg/kg and (-)-a-DHTBZ 0.5 mg/kg, the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a-DHTBZ 0.5 mg/kg, the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a-DHTBZ 1 mg/kg and the combination of (+)-a- DHTBZ 1 .5 mg/kg and (-)-a-DHTBZ 1 mg/kg were significantly different.
2 Stereotypic Behaviour
Rats dosed with either vehicle, the combination of (+)-a-DHTBZ 0.5 mg/kg and (-)- a-DHTBZ 0.5 mg/kg, the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a-DHTBZ 0.5 mg/kg, the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a-DHTBZ 1 mg/kg or the combination of (+)-a-DHTBZ 1.5 mg/kg and (-)-a-DHTBZ 1 mg/kg were subjected to LMA testing first for 30 min and then for 60 minutes after vehicle or amphetamine challenge. Resulting stereotypic activity was evaluated in 3 min bins and as a total over the testing period. The normalised total stereotypic behaviour over the testing time is presented in Figure 8.
When compared to the vehicle-vehicle group the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a-DHTBZ 0.5 mg/kg was significantly different. When compared to vehicle-amphetamine group the vehicle-vehicle, the combination of (+)-a-DHTBZ 0.5 mg/kg and (-)-a-DHTBZ 0.5 mg/kg, the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a-DHTBZ 0.5 mg/kg, the combination of (+)-a-DHTBZ 1 mg/kg and (-)-a- DHTBZ 1 mg/kg and the combination of (+)-a-DHTBZ 1 .5 mg/kg and (-)-a-DHTBZ 1 mg/kg were significantly different.
Conclusions
This study evaluated the effect of the combination of (+)-a-DHTBZ and (-)-a- DHTBZ at doses of 0.5 mg/kg + 0.5 mg/kg, 1 mg/kg + 0.5 mg/kg, 1 mg/kg + 1 mg/kg and 1.5 mg/kg + 1 mg/kg on amphetamine induced locomotor activity in male CD rats.
The combination of (+)-a-DHTBZ and (-)-a-DHTBZ at all the tested combinations and risperidone 1 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group. The combination of (+)-a-DHTBZ and (-)-a-DHTBZ at all the tested doses and risperidone 1 mg/kg led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group.
It would appear that there are interactions between the (+)-a-DHTBZ and (-)-a- DHTBZ affecting the ability of (+)-a-DHTBZ to block the amphetamine induced hyperactivity.
Comparing the data for rats dosed with a combination of (+)-a-DHTBZ at a dose of 1 mg/kg and (-)-a-DHTBZ at a dose of 0.5 mg/kg and rats dosed with a combination of (+)-a-DHTBZ at a dose of 1 mg/kg and (-)-a-DHTBZ at a dose of 1 mg/kg, given the demonstrated lack of efficiency of the (-)-oisomer in isolation, it would not be expected that increases in the amount of (-)-oisomer in the combination treatment would lead to a reduction in the locomotor activity in the tested rats.
STUDY 5
Animals were grouped as follows:
• Group 1 : 10 rats treated with Vehicle (t= 0 min) and Vehicle (t= 30 min) • Group 2: 10 rats treated with Vehicle (t= 0 min) and Amphetamine (t= 30 min)
• Group 3: 10 rats treated with (+)-β-ϋΗΤΒΖ 2.5 mg/kg (t=0 min) and
Amphetamine (t=30 min)
· Group 4: 10 rats treated with (+)-β-ϋΗΤΒΖ 5 mg/kg (t=0 min) and
Amphetamine (t=30 min)
• Group 5: 10 rats treated with and (+)-β-ϋΗΤΒΖ 2.5 mg/kg and (+)-a-DHTBZ 2.5 mg/kg (t=0 min) and Amphetamine (t=30 min)
Results
1 Distance Travelled
Rats dosed with either vehicle, (+)-β-ϋΗΤΒΖ 2.5 mg/kg, (+)-β-ϋΗΤΒΖ 5 mg/kg or (+)-β-ϋΗΤΒΖ 2.5 mg/kg and (+)-a-DHTBZ 2.5 mg/kg were subjected to LMA testing first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Resulting locomotor activity was evaluated in 3 minute bins and as a total over the testing period. The normalised total distance travelled over the testing time is presented in Figure 9.
When compared to the vehicle-vehicle group the vehicle-amphetamine, (+)-β- DHTBZ 2.5 mg/kg and (+)-β-ϋΗΤΒΖ 5 mg/kg. When compared to vehicle- amphetamine group the vehicle-vehicle, the combination of (+)-β-ϋΗΤΒΖ 2.5 mg/kg and (+)-a-DHTBZ 2.5 mg/kg, (+)-β-ϋΗΤΒΖ 2.5 mg/kg and (+)-β-ϋΗΤΒΖ 5 mg/kg, were significantly different.
2 Stereotypic Behaviour
Rats dosed with either vehicle, (+)-β-ϋΗΤΒΖ 2.5 mg/kg, (+)-β-ϋΗΤΒΖ 5 mg/kg or (+)-β-ϋΗΤΒΖ 2.5 mg/kg and (+)-a-DHTBZ 2.5 mg/kg were subjected to LMA testing first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Resulting stereotypic activity was evaluated in 3 minute bins and as a total over the testing period. The normalised total stereotypic behaviour over the testing time is presented in Figure 10.
When compared to the vehicle-vehicle group the vehicle-amphetamine, (+)-β- DHTBZ 2.5 mg/kg and (+)-β-ϋΗΤΒΖ 5 mg/kg were significantly different. When compared to vehicle-amphetamine group the vehicle-vehicle, the combination of (+)-3-DHTBZ 2.5 mg/kg and (+)-a-DHTBZ 2.5 mg/kg, (+)-β-ϋΗΤΒΖ 2.5 mg/kg and (+)-β-ϋΗΤΒΖ 5 mg/kg were significantly different.
STUDY 6
Animals were grouped as follows:
Group 1 : 10 rats treated with Vehicle (t= 0 min) and Vehicle (t= 30 min)
Group 2: 10 rats treated with Vehicle (t= 0 min) and Amphetamine (t= 30 min)
Group 3: 10 rats treated with (+)-a-DHTBZ 1 mg/kg (t=0 min) and amphetamine (t =30 min)
· Group 4: 10 rats treated with (+)-a-DHTBZ 1 mg/kg plus (-)-a-DHTBZ 1 mg/kg (t=0 min); and amphetamine (t=30 min)
Group 5: 10 rats treated with (+)-a-DHTBZ 1 mg/kg plus (-)-β-ϋΗΤΒΖ 1 mg/kg (t=0 min) and t=30 min) amphetamine
Group 6: 10 rats treated with (+)-β-ϋΗΤΒΖ 1 mg/kg plus (-)-a-DHTBZ 1 nig/kg (t=0 min) and amphetamine (t=30 min)
Group 7: 10 rats treated with (+)-β-ϋΗΤΒΖ 1 mg/kg plus (-)-β-ϋΗΤΒΖ 1 mg/kg (t=0 min); and amphetamine (t=30 min)
Group 8: 10 rats treated with (+)-a-DHTBZ 1 mg/kg plus (+)-β-ϋΗΤΒΖ 1 mg/kg (t=0 min); and amphetamine (t=30 min)
· Group 9: 10 rats treated with risperidone 1 mg/kg (t=0 min); and
amphetamine (t=30 min)
Results
1 Distance Travelled
Rats dosed with either vehicle or dihydrotetrabenazine were subjected to LMA testing first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Resulting locomotor activity was evaluated in 3 minute bins and as a total over the testing period. The unnormalised total distance travelled over the testing time is presented in Figure 1 1 .
When compared to the vehicle-vehicle group, the vehicle-amphetamine, (+)-β- DHTBZ 1 mg/kg plus (-)-a-DHTBZ 1 mg/kg and (+)-β-ϋΗΤΒΖ 1 mg/kg plus (-)-β- DHTBZ 1 mg/kg groups were significantly different. When compared to the vehicle- amphetamine group, the vehicle-vehicle, all of groups 1 and 3 to 9 were significantly different.
2 Stereotypic Behaviour
Rats dosed with either vehicle or dihydroterabenazine were subjected to LMA testing first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Resulting stereotypic activity was evaluated in 3 minute bins and as a total over the testing period. The unnormalised total stereotypic behaviour over the testing time is presented in Figure 12.
When compared to the vehicle-vehicle group, the vehicle-amphetamine, (+)-β- DHTBZ 1 mg/kg plus (-)-a-DHTBZ 1 mg/kg and (+)-β-ϋΗΤΒΖ 1 mg/kg plus (-)-β- DHTBZ 1 mg/kg groups were significantly different. When compared to the vehicle- amphetamine group, the vehicle-vehicle, all of groups 1 and 3 to 9 were significantly different. Comments
Study 1 evaluated the effect of (-)-a-DHTBZ at a dose of 2.5 mg/kg and risperidone at a dose of 1 mg/kg on amphetamine induced locomotor activity in male CD rats.
(-)-a-DHTBZ at a dose of 2.5 mg/kg did not lead to lower locomotor activity or reduced stereotypic behaviour when compared to the vehicle-amphetamine group. The rats dosed with (-)-a-DHTBZ at a dose of 2.5 mg/kg were less focused on what was going on around them. The rats dosed with (-)-a -DHTBZ were equally active when compared to the vehicle-amphetamine dosed animals suggesting that (-)-a -DHTBZ does not have an effect on movement similar to risperidone.
Study 2 evaluated the effect of (+)-a-DHTBZ at doses 0.1 mg/kg and 0.25 mg/kg and risperidone at dose 1 mg/kg on amphetamine induced locomotor activity in male CD rats.
(+)-a-DHTBZ at 0.25 mg/kg and risperidone 1 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group. (+)-a-DHTBZ at both the tested doses and risperidone 1 mg/kg led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group. Study 3 evaluated the effect of (+)-a-DHTBZ at a dose of 2 mg/kg, the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at dose 2 mg/kg and risperidone at dose 1 mg/kg on amphetamine induced locomotor activity in male CD rats.
(+)-a-DHTBZ at all the tested dose, the combination of (+)-a-DHTBZ and (-)-a- DHTBZ at doses of 2 mg/kg and risperidone at 1 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group. (+)-a-DHTBZ at all the tested dose, the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at doses of 2 mg/kg and risperidone 1 mg/kg led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group.
Amphetamine induced locomotor activity was less in rats treated with the combination of (+)-a-DHTBZ and (-)-a-DHTBZ than in rats treated with (+)-o DHTBZ only, despite it being shown that the (-)-oisomer provides very little, if any, reduction in induced locomotor activity.
Study 4 evaluated the effect of the combination of (+)-a-DHTBZ and (-)-a-DHTBZ at doses 0.5 mg/kg + 0.5 mg/kg, 1 mg/kg + 0.5 mg/kg, 1 mg/kg + 1 mg/kg and 1 .5 mg/kg + 1 mg/kg on amphetamine induced locomotor activity in male CD rats.
The combination of (+)-a-DHTBZ and (-)-a-DHTBZ at all the tested combinations and risperidone 1 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group. The combination of (+)-a-DHTBZ and (-)-a-DHTBZ at all the tested doses and risperidone 1 mg/kg led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group.
Comparing the data for rats dosed with a combination of (+)-a-DHTBZ at a dose of 1 mg/kg and (-)-a-DHTBZ at a dose of 0.5 mg/kg and rats dosed with a combination of (+)-a-DHTBZ at a dose of 1 mg/kg and (-)-a-DHTBZ at a dose of 1 mg/kg, given the demonstrated lack of efficiency of the (-)-oisomer in isolation, it was surprising that increasing the amount of (-)-oisomer in the combination treatment led to a reduction in the locomotor activity in the tested rats.
Study 5 evaluated the effect of (+)-β -DHTBZ at doses 2.5 mg/kg and 5 mg/kg and the combination of (+)-a-DHTBZ at dose 2.5 mg/kg and (+)-β-ϋΗΤΒΖ at dose 2.5 mg/kg on amphetamine induced locomotor activity in male CD rats.
(+)-β -DHTBZ 2.5 mg/kg, (+)-β -DHTBZ 5 mg/kg, and the combination of (+)-a- DHTBZ 2.5 mg/kg and (+)-β-ϋΗΤΒΖ 2.5 mg/kg led to lower locomotor activity when compared to the vehicle-amphetamine group. (+)-β -DHTBZ 2.5 mg/kg, (+)-β - DHTBZ 5 mg/kg and the combination of (+)-a-DHTBZ 2.5 mg/kg and (+)-β-ϋΗΤΒΖ 2.5 mg/kg also led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group. The rats dosed with (+)-β-ϋΗΤΒΖ at dose 5 mg/kg were less focused on what was going on around them and the rats that received the (+)-β-ϋΗΤΒΖ 5 mg/kg were observed to have tensed limbs and were partially missing their righting reflex at the end of the test.
Study 6 evaluated the effect of (+)-a-DHTBZ at a dose of 1 mg/kg, a combination of (+)-a-DHTBZ at a dose of 1 mg/kg plus (-)-a-DHTBZ at a dose of 1 mg/kg, a combination of (+)-a-DHTBZ at a dose of 1 mg/kg plus (-)-β-ϋΗΤΒΖ at a dose of 1 mg/kg, a combination of (+)-β-ϋΗΤΒΖ at a dose of 1 mg/kg plus (-)-a-DHTBZ at a dose of 1 mg/kg, a combination of (+)-β-ϋΗΤΒΖ at a dose of 1 mg/kg plus (-)-β- DHTBZ at a dose of 1 mg/kg, a combination of (+)-a-DHTBZ at a dose of 1 mg/kg plus (+)-β-ϋΗΤΒΖ at a dose of 1 mg/kg, and risperidone at a dose of 1 mg/kg (t=0 min) on amphetamine induced locomotor activity in male CD rats.
The vehicle, risperidone and all of the dihydrotetrabenazine-containing led to lower locomotor activity and led to reduced stereotypic behaviour when compared to the vehicle-amphetamine group.
The results obtained from the six studies indicate that combinations of (+)-β- dihydrotetrabenazine, (-)-odihydrotetrabenazine and (+)-odihydrotetrabenazine will be useful in the treatment of movement disorders. Equivalents
It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.

Claims

1 . A pharmaceutical combination comprising:
(a) (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and one or both of:
(b) (-)-a-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and
(c) (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical combination according to claim 1 comprising:
(a) (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and
(b) (-)-a-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
3. A pharmaceutical combination according to claim 1 comprising:
(a) (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and
(c) (+)-a-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical combination according to claim 1 comprising:
(a) (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
(b) (-)-a-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and
(c) (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical combination according to any one of claims 1 to 4 which comprises from 35 to 75 parts by weight of (+)-3-dihydrotetrabenazine and from 25 to 55 parts by weight of an a-dihydrotetrabenazine consisting of either (+)-o dihydrotetrabenazine or (-)-odihydrotetrabenazine or a mixture thereof.
6. A pharmaceutical combination according to claim 5 comprising:
(a) 40-65 parts by weight of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and (c) 40-65 parts by weight of (+)-a-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical combination according to claim 6 comprising:
(a) 45-55 parts by weight of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and
(c) 45-55 parts by weight of (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical combination according to claim 6 which comprises:
(a) 45-65 parts by weight of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
(b) 30-50 parts by weight of (-)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof; and optionally
(c) 0.1 -5 parts by weight of (+)-odihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical combination according to any one of claims 1 to 8 for use in medicine.
10. A pharmaceutical unit dosage form comprising a pharmaceutically acceptable excipient and a pharmaceutical combination as defined in any one of claims 1 to 9.
1 1 . A pharmaceutical unit dosage form according to claim 10 wherein the sum of the amounts of (+)-3-dihydrotetrabenazine, (-)-odihydrotetrabenazine and (+)-o dihydrotetrabenazine does not exceed 100mg.
12. A pharmaceutical unit dosage form according to claim 10 or claim 1 1 which is selected from (i) solid dosage forms such as capsules and tablets and (ii) liquid dosage forms such as solutions, syrups, suspensions and gels.
13. A pharmaceutical combination according to any one of claims 1 to 9 or a pharmaceutical unit dosage form according to any one of claims 10 to 12 which is for use in the treatment of a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
A pharmaceutical combination or unit dosage form for use according to claim 13 wherein the use comprises administering to a subject an amount of the pharmaceutical combination or unit dosage form sufficient to cause a level of blocking of VMAT2 proteins in the subject of from 20% to 90%.
A pharmaceutical unit dosage form comprising a combination of (+)-o dihydrotetrabenazine and (-)-odihydrotetrabenazine, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.
A combination of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for use in medicine.
A combination of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, or a pharmaceutical unit dosage form as defined in claim 15, for use in the treatment of a movement disorder.
A combination of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for use in a method of treatment of a movement disorder, wherein the method comprises administering to a subject (e.g. a human subject) in need thereof an effective therapeutic amount of the combination sufficient to provide a dosage of from 1 mg to 20 mg of (+)-odihydrotetrabenazine per day.
A combination of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine or pharmaceutically acceptable salts thereof, for use in a method for the treatment of a movement disorder, wherein the treatment comprises administering to a subject an amount of the combination of from 0.01 mg/kg to 0.3 mg/kg (e.g. between 0.01 mg/kg and 0.3 mg/kg) per day provided that the total amount of (+)-odihydrotetrabenazine administered per day is in the range from 1 mg to 20 mg.
A combination for use according to any one of claims 17 to 19 wherein the movement disorder is a hyperkinetic movement disorder selected from Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
21 . A combination for use according to claim 20 wherein the movement disorder is Tourette's syndrome.
A combination of (+)-odihydrotetrabenazine and (-)-a- dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, for use in a method for the treatment of a movement disorder, wherein the treatment comprises administering to a subject an amount of the combination sufficient to cause a level of blocking of from 20% to 90% of VMAT2 proteins in the subject.
A pharmaceutical unit dosage form according to claim 15 or a combination for use according to any one of claims 16 to 22 wherein the combination of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine is
unaccompanied by any other isomers of dihydrotetrabenazine.
A pharmaceutical unit dosage form according to claim 15 or a combination for use according to any one of claims 16 to 23 wherein the combination of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine is a racemic mixture.
A pharmaceutical unit dosage form according to claim 15 or a combination for use according to any one of claims 16 to 23 wherein the combination of (+)-odihydrotetrabenazine and (-)-odihydrotetrabenazine is a scalemic mixture.
A unit dosage form comprising (+)-3-dihydrotetrabenazine, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the (+)-3-dihydrotetrabenazine is
accompanied by no more than 20% by weight, relative to the (+)-β- dihydrotetrabenazine, of any other dihydrotetrabenazine isomers.
A unit dosage form according to claim 26 wherein the (+)-β- dihydrotetrabenazine is accompanied by no more than 1 % of any other dihydrotetrabenazine isomers.
28. A unit dosage form according to claim 26 or claim 27 comprising from 1 mg to 200 mg (e.g. between 1 mg and 200 mg) of (+)-3-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
29. A unit dosage form according to any one of claims 26 to 28 in the form of (i) a solid dosage form such as a capsule or tablet; or (ii) a liquid dosage form such as a solution, syrup, suspension or gel.
30. A unit dosage form according to any one of claims 26 to 29 for use in the treatment of a hyperkinetic movement disorder.
31 . (+)"3-Dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for use in the treatment of a hyperkinetic movement disorder.
32. (+)"3-dihydrotetrabenazine for use in a method for the treatment of a
movement disorder, wherein the treatment comprises administering to a subject an amount of (+)-3-dihydrotetrabenzine from 1 mg to 200 mg (e.g. between 1 mg and 200 mg) per day.
33. (+)"3-dihydrotetrabenazine for use in a method for the treatment of a
movement disorder, wherein the treatment comprises administering to a subject an amount of (+)-3-dihydrotetrabenazine from 1 mg/kg to 10 mg/kg (e.g. between 1 mg/kg and 10 mg/kg) per day.
34. (+)"3-dihydrotetrabenazine for use in a method for the treatment of a
movement disorder, wherein the treatment comprises administering to a subject an amount of (+)-3-dihydrotetrabenazine sufficient to cause a level of blocking of from 20% to 90% of the VMAT2 proteins in the subject.
35. The (+)"3-dihydrotetrabenazine for use according to any one of claims 31 to 34 wherein the (+)-3-dihydrotetrabenazine typically has an isomeric purity of at least 80%.
36. A unit dosage form for use according to claim 30 or (+)-β- dihydrotetrabenazine for use according to claims 31 to 34, wherein the hyperkinetic movement disorder is selected from Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
37. (+)-3-Dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in medicine.
EP18718398.3A 2017-04-01 2018-03-29 Dihydrotetrabenazine for use in the treatment a movement disorder Pending EP3606530A2 (en)

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US201762515940P 2017-06-06 2017-06-06
US201762515935P 2017-06-06 2017-06-06
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