JP2023029975A - Dihydrotetrabenazine for use in treatment of movement disorder - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical for the treatment of movement disorders, such as Tourette's syndrome.

SOLUTION: A unit dosage form contains 5 mg-80 mg of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, where (+)-β-dihydrotetrabenazine involves any other dihydrotetrabenazine isomers of 20 wt.% or less relative to (+)-β-dihydrotetrabenazine.

SELECTED DRAWING: None

COPYRIGHT: (C)2023,JPO&INPIT

Description

The present invention provides (+)-β-dihydrotetrabenazine and (+)-α-dihydrotetrabenazine, (-)-α-dihydrotetrabenazine and/or Use of the combination 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 increased muscle activity and can lead to abnormal and/or excessive movements including tremors, dystonias, chorea, tics, myoclonus and stereotypies.

Hyperkinetic movement disorders are often psychological in nature and arise through inappropriate regulation of amine neurotransmitters in the basal ganglia.

A particular hyperkinetic movement disorder is Tourette's syndrome, an inherited neurological condition characterized by multiple physical and vocal tics. Tics are usually repetitive but random physical movements or vocal noises. Vocal tics can take various forms and include repeating one's own words, someone else's words, or other sounds. Onset usually occurs in children and lasts into adolescence and adulthood.

Although the tics associated with Tourette's syndrome can be temporarily suppressed, affected patients are usually able to suppress their tics for a limited period of time. Although no effective therapy yet exists to cover all types of tics in all patients, specific drugs are being developed for tic suppression.

Dopamine receptor antagonists are known to exhibit the ability to suppress tics in Tourette's syndrome patients, and a number of dopamine receptor antagonists are currently used to suppress Tourette tics, such as fluphenazine, haloperidol and pimozide. .

The type 2 vesicular monoamine transporter (VMAT2) is a membrane protein involved in the transport of monoamine neurotransmitters such as dopamine, serotonin and histamine from the cytosol to synaptic vesicles. Inhibition of this protein prevents presynaptic neurons from releasing dopamine, resulting in depletion of dopamine levels in the brain.

VMAT2 inhibitors can be used to treat the symptoms of Tourette's Syndrome.

Tetrabenazine (chemical name: 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo(a)quinolidin-2-one) was It has been used as a medicine since the latter half. Originally used as an antipsychotic, tetrabenazine is now used to treat hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tics, tardive dyskinesias and Tourette's syndrome. (See, e.g., Jankovic et al., Am. J. Psychiatry (1999) Aug;156(8):1279-81 and Jankovic et al., Neurology (1997) Feb;48(2):358-62. ).

The main pharmacological action of tetrabenazine is to reduce the supply of monoamines (eg, dopamine, serotonin, and norepinephrine) in the central nervous system by inhibiting the human vesicular monoamine transporter isoform 2 (hVMAT2). The drug also blocks postsynaptic dopamine receptors.

The central action of tetrabenazine is very similar to that of reserpine, but differs from reserpine in that it lacks activity at the VMAT1 transporter. Lack of activity at the VMAT1 transporter means that tetrabenazine is less peripherally active 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 various hyperkinetic movement disorders and, in contrast to typical neuroleptics, has not been proven to cause tardive dyskinesias. Nevertheless, tetrabenazine exhibits many dose-related side effects, including causing depression, parkinsonism, drowsiness, nervousness or anxiety, insomnia, and, in rare cases, neuroleptic malignant syndrome (see, e.g., WO2016/ 127133 (Neurocrine Biosciences), introductory section).

The chemical structure of tetrabenazine is shown below.

This compound has chiral centers at the 3 and 11b carbon atoms and therefore can theoretically exist in a total of 4 isomeric forms as shown below.

The stereochemistry of each isomer is defined using the "R and S" nomenclature developed by Cahn, Ingold and Prelog (Advanced Organic Chemistry by Jerry March, 4th ed., John Wiley & Sons, New York, 1992 , pages 109-114). In this patent application, the designations "R" or "S" are given in the order of the carbon atom position numbers. Thus, for example, RS is a shorthand notation for 3R,11bS. Similarly, when three chiral centers are present, as in the dihydrotetrabenazines described below, the designations "R" or "S" are listed in the order of carbon atoms 2, 3 and 11b. The 2R,3S,11bS isomers are therefore abbreviated as RSS and the like.

Commercially available tetrabenazine is a racemic mixture of RR and SS isomers, with the RR and SS isomers believed to be the most thermodynamically stable isomers.

Tetrabenazine has a somewhat weaker and more variable bioavailability. It is extensively metabolized by first-pass metabolism, and little or no unchanged tetrabenazine is typically detected in the urine. At least some of the metabolites of tetrabenazine are known to be dihydrotetrabenazines formed by reduction of the 2-keto group in tetrabenazine.

Dihydrotetrabenazine (chemical name: 2-hydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxybenzo(a)quinolidine) is a three-chiral It has a center and can therefore exist in any of the following eight optical isomeric forms:

The synthesis and characterization of all eight dihydrotetrabenazine isomers are described by Sun et al. (Eur. J. Med. Chem. (2011), 1841-1848).

Of the eight dihydrotetrabenazine isomers, four isomers, the RRR, SSS, SRR and RSS isomers, are derived from the RR and SS isomers of the parent tetrabenazine.

The RRR and SSS isomers are commonly referred to as "alpha (α)" dihydrotetrabenazine, and may be referred to as (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, respectively. The α isomer is characterized by the trans relative orientation of the hydroxyl and 2-methylpropyl substituents at the 2 and 3 positions. See, eg, Kilborn et al., Chirality, 9:59-62 (1997) and Brossi et al., Helv. Chim. Acta, vol. XLI, No. 193, pp 1793-1806 (1958).

The SRR and RSS isomers are commonly referred to as the "beta (β)" isomers and may be referred to as (+)-β-dihydrotetrabenazine and (−)-β-dihydrotetrabenazine, respectively. The β isomer is characterized by the cis relative orientation of the hydroxyl and 2-methylpropyl substituents at the 2 and 3 positions.

Although dihydrotetrabenazine is thought to be primarily responsible for the drug's activity, it contains evidence demonstrating which of the various stereoisomers of dihydrotetrabenazine is responsible for its biological activity. No studies have been published to date. More specifically, there are no published studies demonstrating which stereoisomer is responsible for tetrabenazine's ability to treat movement disorders such as Tourette's syndrome.

Schwartz et al. (Biochem. Pharmacol. (1966), 15:645-655) describe tetrabenazine metabolic studies conducted in rabbits, dogs and humans. Schwartz et al. identified nine metabolites, five of which were unbound and the other four bound to glucuronic acid. The five unconjugated metabolites were α- and β-dihydrotetrabenazine, two oxidized analogues hydroxylated at the 2-methylpropyl side chain, and hydroxylated at the 2-methylpropyl side chain. oxidized tetrabenazine. All four bound metabolites were compounds in which the 9-methoxy group was demethylated to give a 9-hydroxy compound.

The chirality of the various metabolites was not studied, in particular there was no disclosure of the chirality of the individual α- and β-isomers.

Scherman et al. (Mol. Pharmacol. (1987), 33, 72-77) describe the stereospecificity of VMAT2 binding between racemic α- and β-dihydrotetrabenazine. They reported that α-dihydrotetrabenazine has a 3-4-fold higher affinity for the chromaffin granule monoamine transporter than the β isomer when studied in vitro. However, Scherman et al. do not disclose the separation or testing of the individual enantiomers of α- and β-dihydrotetrabenazine.

Mehvar et al. (J. Pharm. Sci. (1987), 76(6), 461-465) reported concentrations of tetrabenazine and dihydrotetrabenazine in the brain of rats after administration of either tetrabenazine or dihydrotetrabenazine. reported a study on This study showed that dihydrotetrabenazine can cross the blood-brain barrier despite its greater polarity. However, the stereochemistry of dihydrotetrabenazine is not disclosed.

Mehvar et al. (1987, Drug Metabolism and Distribution, 15:2, 250-255) studied the pharmacokinetics of tetrabenazine and dihydrotetrabenazine when tetrabenazine was administered to four patients with tardive dyskinesia. is described. Oral administration of tetrabenazine resulted in low plasma concentrations of tetrabenazine, but relatively high concentrations of dihydrotetrabenazine. However, the stereochemistry of dihydrotetrabenazine formed in vivo has not been reported.

Roberts et al. (Eur. J. Clin. Pharmacol. (1986), 29:703-708) describe the pharmacokinetics of tetrabenazine and its hydroxy metabolites in patients treated for involuntary movement disorders. Roberts et al. reported that tetrabenazine is extensively metabolized after oral administration, yielding very low plasma concentrations of tetrabenazine but much higher concentrations of hydroxy metabolites. Although they did not describe the identity of the hydroxy metabolites, they noted that high plasma concentrations of the hydroxy metabolites could be of therapeutic importance (the metabolites are known to be pharmacologically active ingredients). ), and given the disclosure in Schwartz et al. suggested that

Michael Kilbourn and coworkers at the University of Michigan School of Medicine have published a number of studies on the various isomers of dihydrotetrabenazine. Med. Chem. Res. (1994), 5:113-126, Kilbourn et al. describe the use of (+/-)-α-[11C]-dihydrotetrabenazine as an in vivo contrast agent for VMAT2 binding studies.

Eur. J. In Pharmacol (1995) 278, 249-252, Kilbourn et al. reported competitive binding studies with [3H]-tetrabenazine, and (+)-, (-)-, and (+/-)-α-DHTBZ. In vitro binding affinities were tested. Binding assays gave Ki values of 0.97 nM for (+)-α-dihydrotetrabenazine and 2.2 μM for (−)-α-dihydrotetrabenazine, whereby the (+)α isomer was ( -) showed a much greater binding affinity for the VMAT2 receptor than the α isomer. However, no studies of the usefulness of either isomer in the treatment of movement disorders such as Tourette's syndrome have been reported and inconclusive.

In Chirality (1997) 9:59-62, Kilbourn et al. describe a study aimed at identifying the absolute configuration of (+)-α-dihydrotetrabenazine, from which Kilbourn et al. concluded that it has the 2R, 3R, 11bR configuration shown in They also refer to the Schwartz et al. and Mehvar et al. papers discussed above as indicating that α- and β-dihydrotetrabenazine are likely pharmacologically active agents in the human brain. However, they did not draw clear conclusions regarding the precise stereochemical identity of the active metabolite of tetrabenazine.

In Synapse (2002), 43:188-194, Kilbourn et al., in "Injection into Equilibrium Method", (+)-α as an agent used to measure specific in vivo binding of VMAT receptors. -[11C]-dihydrotetrabenazine has been described. They found that (−)-α-[11C]-dihydrotetrabenazine produced uniform brain distribution, consistent with previous observations that this enantiomer has low VMAT affinity.

Sun et al. (Id.) investigated the VMAT2 binding affinities of all eight dihydrotetrabenazine isomers. They found that all of the dextrorotatory enantiomers were dramatically more potent than their corresponding levorotatory enantiomers, with the (+)-α-isomer being the most active. It was found that the VMAT2-binding activity was high. However, Sun et al. did not study the relative efficacy of individual isomers in treating movement disorders such as Tourette's syndrome.

WO2011/153157 (Auspex Pharmaceutical, Inc.) describes deuterated forms of dihydrotetrabenazine. Although many deuterated forms of dihydrotetrabenazine are indicated, the application provides only enough information to allow synthesis of the few indicated compounds. Racemic mixtures of d ₆ -α-dihydrotetrabenazine and d ₆ -β-dihydrotetrabenazine are as disclosed, but these mixtures are not separated and the individual (+) and (−) isomers Body properties have not been studied. Similarly, WO2014/047167 (Auspex Pharmaceutical, Inc.) describes a number of deuterated forms of tetrabenazine and its derivatives. Again, the individual (+) and (-) isomers of the deuterated forms of α- and β-dihydrotetrabenazine were not separated or investigated.

To date, it has been unclear exactly which dihydrotetrabenazine isomer is responsible for the therapeutic properties resulting from administration of tetrabenazine. Although (+)-α-dihydrotetrabenazine has been previously postulated to be the metabolite of tetrabenazine that is primarily responsible for its therapeutic effects (WO2015/171802 Neurocrine Biosciences, Inc.), this has been experimentally not proven.

SUMMARY OF THE INVENTION As noted above, studies conducted by Schwartz et al. (see above) demonstrated that both the alpha and beta isomers of tetrabenazine are formed as metabolites of tetrabenazine. However, the exact stereochemical configuration of the alpha and beta isomers was not investigated.

Studies in human subjects conducted by the applicant and described in Example 1 below confirmed Schwartz et al.'s findings that the major metabolites of tetrabenazine are indeed α and β dihydrotetrabenazines. However, in contrast to previous suggestions, the major metabolite produced upon administration of tetrabenazine is the (−)-α-dihydrotetrabenazine isomer, which is intrinsically active as a VMAT2 binder. , and (+)-β-dihydrotetrabenazine isomers that are significantly less active than the (+)-α-dihydrotetrabenazine isomers.

Therefore, in a single-dose study of tetrabenazine in adult males, the C _max values for (+)-β-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine were 103 and 72.94 ng/ml, respectively. whereas the C _max values for (−)-β-dihydrotetrabenazine and (+)-α-dihydrotetrabenazine were 5.28 and 2.61 ng/ml, respectively. Area under the curve of (+)-β-dihydrotetrabenazine, (−)-α-dihydrotetrabenazine, (−)-β-dihydrotetrabenazine and (+)-α-dihydrotetrabenazine metabolites ( AUC) values were 375.78, 305.84, 16.28 and 7.98, respectively. A similar distribution of metabolites was found when multiple doses of tetrabenazine were administered.

The data suggest that (+)-α-dihydrotetrabenazine is not primarily responsible for the therapeutic properties of tetrabenazine. Conversely, (+)-α-dihydrotetrabenazine may be responsible for a relatively minor contribution to the therapeutic properties of tetrabenazine.

The importance of preparing enantiomeric compositions for the treatment of the human and animal body is well known. Enantiomers may have different biological properties, for example one enantiomer may be useful in treating a particular disease or condition and the other enantiomer may be toxic or produce undesirable side effects. is well known. An example of this is the drug thalidomide, marketed as a sedative and also prescribed to pregnant women to treat morning sickness, although one enantiomer was later found to have congenital anomalies in the children of women who received thalidomide during pregnancy. was found to cause

According to FDA guidance for enantiomers, drug substance and drug product uses should include stereochemically specific identity tests and/or stereochemically selective assays.

Even if one of the enantiomers is medically useful and the other is inactive and does not exhibit side effects, the inactive enantiomer can be removed to reduce the size of the dosage form administered to the patient. It can still be advantageous.

Combination of (+)-α-Dihydrotetrabenazine and (−)-α-Dihydrotetrabenazine The combination of (+)- and (−)-α-dihydrotetrabenazine is (−)-α-dihydrotetrabenazine More effective than (+)-α-dihydrotetrabenazine alone in reducing locomotor activity in amphetamine-induced rats, despite previously reported fact that benazine is a poor VMAT2 inhibitor This time it was surprisingly found.

It has also been shown that both racemic and scalemic (ie non-racemic) combinations exhibit enhanced potency.

Studies have confirmed the inactivity of (−)-α-dihydrotetrabenazine in treating movement disorders when administered alone (see Example 2, Study 1). However, when (−)-α-dihydrotetrabenazine was administered in combination with (+)-α-dihydrotetrabenazine, improved effects were seen compared to administration of the (+)-isomer alone. (See Example 2, Tests 3 and 4). This improved effect may be due to the binding of (−)-α-dihydrotetrabenazine to proteins other than VMAT2, which may play a role in mediating hyperkinetic movement disorder.

Based on research conducted to date, combinations of (+)- and (-)-α-dihydrotetrabenazine are useful in the prevention or treatment of disease states and conditions for which tetrabenazine is currently used or proposed. It is believed that there is. Thus, by way of example, but not limitation, the dihydrotetrabenazine compounds of the present invention may be used to treat movement disorders, particularly Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia, and Tourette's syndrome. It can be used to treat hyperkinetic movement disorder.

Accordingly, in a first aspect, the present invention provides (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable A pharmaceutical unit dosage form is provided that includes excipients.

Typically, a combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is not administered with a therapeutically effective amount of amantadine. In one embodiment, the combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is not administered with any amount of amantadine.

(+)-α-Dihydrotetrabenazine and/or (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, can be administered in an immediate release unit dosage form.

In another aspect, the present invention provides a combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in medicine offer.

(+)-α-Dihydrotetrabenazine is believed to have the chemical structure (I) shown below:

(-)-α-Dihydrotetrabenazine is believed to have the chemical structure (II) shown below:

In another aspect, the present invention provides a combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in medicine offer.

In a further aspect, the present invention provides a combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable compound thereof, for use in treating movement disorders. Provide a salt (pharmaceutical unit dosage form as defined above).

In further embodiments, the invention provides:
- A subject in need of treatment comprising administering to the subject a combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof Methods of treating movement disorders in the body (eg, mammalian subjects such as humans).

- Use of a combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of movement disorders .

The inventors have also found that low doses of (+)-α-dihydrotetrabenazine (i.e., 20 mg or less per day) can be useful in the treatment of movement disorders; (+)-α-Dihydrotetrabenazine, in combination with (−)-α-dihydrotetrabenazine, is also believed to be useful in treating movement disorders.

Accordingly, in another embodiment, the combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutical composition thereof, for use in a method of treating movement disorders, according to the present invention. and the method of treatment provides a subject (e.g., a human subject) in need thereof with a dosage of 1 mg to 20 mg of (+)-α-dihydrotetrabenazine per day. administering an effective therapeutic amount of the combination sufficient to

In further aspects, the invention provides:
- A method of treating a movement disorder, comprising administering (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine to a subject (e.g., a human subject) in need thereof, or The above method comprising administering an effective therapeutic amount of the pharmaceutically acceptable salt combination sufficient to provide a dose of (+)-α-dihydrotetrabenazine of 1 mg to 20 mg per day.

- in the use of a combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of movement disorders and the method is sufficiently therapeutically effective to provide a subject (e.g., a human subject) in need thereof with a dosage of 1 mg to 20 mg of (+)-α-dihydrotetrabenazine per day. Any of the above uses comprising administering a combination of amounts.

- (-)-α-dihydrotetra for the manufacture of a medicament for administration in combination with (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for a method of treating movement disorders Use of benazine or a pharmaceutically acceptable salt thereof, wherein the method provides a subject (eg, a human subject) in need thereof with 1 mg to 20 mg of (+)-α-dihydrotetra The use above comprising administering an effective therapeutic amount of the combination sufficient to provide a dosage of benazine.

In each of the foregoing embodiments (i.e., the combination, method, or use for use) using a low dose of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, (+) The daily dose of -α-dihydrotetrabenazine is 1 mg to 20 mg.

In certain embodiments, provided are combinations, methods or uses for the uses described herein, wherein the treatment is between 1.5 mg and 20 mg per day (e.g., 1.5 mg and 20 mg) of (+)-α-dihydrotetrabenazine to the subject.

- A combination, method or use for any of the uses described herein wherein the treatment is (+)-α-dihydrotetra in an amount of 2 mg to 20 mg (eg between 2 mg and 20 mg) per day. Any of the above combinations, methods or uses comprising administering benazine to a subject.

- A combination, method or use for any of the uses described herein wherein the treatment is (+)-α-dihydrotetra in an amount of 3 mg to 20 mg (eg between 3 mg and 20 mg) per day. Any of the above combinations, methods or uses comprising administering benazine to a subject.

- A combination, method or use for any use described herein wherein the treatment is (+)-α-dihydrotetra in an amount of 2 mg to 15 mg (eg between 2 mg and 15 mg) per day. Any of the above combinations, methods or uses comprising administering benazine to a subject.

- A combination, method or use for any of the uses described herein wherein the treatment is (+)-α-dihydrotetra in an amount of 3 mg to 15 mg (eg between 3 mg and 15 mg) per day. Any of the above combinations, methods or uses comprising administering benazine to a subject.

- A combination, method or use for any of the uses described herein wherein the treatment is (+)-α-dihydrotetra in an amount of 5 mg to 15 mg (eg between 5 mg and 15 mg) per day. Any of the above combinations, methods or uses comprising administering benazine to a subject.

Administration of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine typically form part of a chronic treatment regimen. Thus, (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine are administered for at least 1 week, more usually at least 2 weeks, or at least 1 month, typically longer than 1 month. can be administered to the patient for a period of time. The duration of treatment may be longer than 6 months and may extend over several years if the patient is shown to respond well to treatment.

A chronic treatment regimen may include daily administration of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a treatment regimen may include (+)-α-dihydrotetrabenazine or ( -)-α-dihydrotetrabenazine may include days on which it is not administered.

The dosage administered to a subject may vary during treatment. For example, the initial dosage may be increased or decreased depending on the subject's response to treatment. For example, a subject may be given an initial low dose to test the subject's tolerance to (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, followed by If necessary, the dosage is increased up to a maximum daily intake of 20 mg. Alternatively, the initial daily dosage administered to the patient may be selected to provide an estimated desired degree of VMAT2 blockade, followed by lower maintenance doses for the remainder of the treatment period, and treatment With the option of increasing the dosage if the subject's response to the drug indicates the need for an increase.

The amount of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine required to achieve the desired therapeutic effect may depend on the weight of the subject being treated. is assumed. The amount of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine administered to a subject can be expressed in terms of mg/kg, where kg is the weight of the subject being treated. Regarding weight. Accordingly, an appropriate dose can be calculated by multiplying the mg/kg amount by the weight of the subject to be treated.

Accordingly, in another aspect, the present invention provides (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine or pharmaceutical compounds thereof for use in a method for the treatment of movement disorders. Provided is an acceptable salt combination, wherein the treatment is daily, provided that the total amount of (+)-α-dihydrotetrabenazine administered per day is in the range of 1 mg to 20 mg. administering to the subject an amount of the combination of 0.01 mg/kg to 0.3 mg/kg (eg, between 0.01 mg/kg and 0.3 mg/kg) per dose.

In further aspects, the invention provides:
A combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, administered daily (+)-α-dihydrotetrabenazine in an amount of 0.01 mg/kg to 0.3 mg/kg (eg, between 0.01 mg/kg and 0.3 mg/kg) per day, provided that the total amount of benazine is in the range of 1 mg to 20 mg A method of treating a movement disorder in a subject in need thereof (eg, a mammalian subject such as a human) comprising administering to the subject.

- in the use of a combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of movement disorders 0.01 mg/kg to 0.3 mg/kg (e.g., administration of the combination to a subject in an amount between 0.01 mg/kg and 0.3 mg/kg).

The combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is 0.01 mg/kg to 0.3 mg/kg per day (for example , between 0.01 mg/kg and 0.3 mg/kg). The daily dose of dihydrotetrabenazine is 1 mg to 20 mg.

Certain embodiments provide:
- A combination, method or use for any of the uses described herein wherein the treatment is in the range of 1 mg to 20 mg total amount of (+)-α-dihydrotetrabenazine administered per day administering to the subject an amount of the combination between 0.02 mg/kg and 0.3 mg/kg (eg, between 0.02 mg/kg and 0.3 mg/kg) per day, provided that , method or use.

- A combination, method or use for any of the uses described herein wherein the treatment is in the range of 1 mg to 20 mg total amount of (+)-α-dihydrotetrabenazine administered per day administering to the subject an amount of the combination between 0.03 mg/kg and 0.3 mg/kg (eg, between 0.03 mg/kg and 0.3 mg/kg) per day, provided that , method or use.

- A combination, method or use for any of the uses described herein wherein the treatment is in the range of 1 mg to 20 mg total amount of (+)-α-dihydrotetrabenazine administered per day administering to the subject an amount of the combination between 0.04 mg/kg and 0.3 mg/kg (eg, between 0.04 mg/kg and 0.3 mg/kg) per day, provided that , method or use.

- A combination, method or use for any of the uses described herein wherein the treatment is in the range of 1 mg to 20 mg total amount of (+)-α-dihydrotetrabenazine administered per day subject to an amount of (+)-α-dihydrotetrabenazine combination of 0.05 mg/kg to 0.3 mg/kg (e.g., between 0.05 mg/kg and 0.3 mg/kg), provided that any of the above combinations, methods or uses, including administering to.

The combinations (and dosage forms containing the combinations) of the present invention are used in the treatment of movement disorders, particularly hyperkinetic movement disorders such as Huntington's disease, hemiballismus, chorea, tic disorders, tardive dyskinesias, dystonia and Tourette's syndrome. Useful.

More particularly, the combinations (and dosage forms containing the combinations) of the invention are for use in the treatment of hyperkinetic movement disorders selected from tic disorders, Huntington's disease, tardive dyskinesias and Tourette's syndrome. be.

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 specific embodiment, the combination of the invention (and dosage forms comprising the combination) are for use in treating Tourette's Syndrome.

The utility of the combinations of the invention in treating movement disorders arises in part from the ability of (+)-α-dihydrotetrabenazine to bind to vesicular monoamine transporter 2 (VMAT2).

Complete blockade of the VMAT2 protein is considered undesirable as it can lead to undesirable side effects (eg Parkinsonism). The present invention provides plasma levels of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, which are sufficient to provide effective treatment of movement disorders, but not Parkinsonism. and does not block the VMAT2 protein to the extent that it causes similar side effects. The level of VMAT2 blockade can be determined by competitive binding studies using positron emission tomography (PET). By co-administering the radioligand with the compound of interest at various concentrations, the percentage of binding sites occupied can be determined (see, e.g., Matthews et al., "Positron emission tomography molecular imaging for drug development" ("Drug Development Positron Emission Tomography for Molecular Imaging”), Br. J. Clin. Pharmacol, 73:2, 175-186).

Accordingly, in a further aspect, the present invention provides a combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutical composition thereof, for use in a method for the treatment of movement disorders. A pharmaceutically acceptable salt is provided, wherein treatment comprises administering to the subject an amount of the combination sufficient to cause a level of block of VMAT2 protein of 20% to 90% in the subject.

In further aspects, the invention provides:
- A method of treating movement disorders in a subject in need thereof (e.g., a mammalian subject such as a human) comprising (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, to the subject sufficient to cause a level of blockade of 20% to 90% of VMAT2 protein in the subject.

- a subject (e.g., a mammalian subject, such as a human) of a combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of movement disorders in humans, the treatment comprising administering the combination to a subject in an amount sufficient to cause a level of block of VMAT2 protein of 20% to 90% in the subject The above uses, including administering to.

(+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof in combination with (-)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof to a subject (e.g., for the manufacture of a medicament for use in the treatment of movement disorders in a mammalian subject such as a human, the treatment resulting in a block level of VMAT2 protein of 20% to 90% in the subject The above uses, comprising administering to the subject an amount of the combination sufficient to cause

Further embodiments provide:
- A combination, method or use for use as described herein, wherein the treatment is subject to an amount of the combination sufficient to cause a block level of 25% to 85% of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment is subject to a sufficient amount of the combination to cause a block level of 30% to 85% of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment is subject to a sufficient amount of the combination to cause a block level of 35% to 85% of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment is subject to a sufficient amount of the combination to cause a level of blockade of 40% to 85% of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment is subject to an amount of the combination sufficient to cause a level of blockade of 45% to 85% of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment is tested in an amount sufficient to cause a 50% to 85% block level of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment is subject to an amount of the combination sufficient to cause a block level of 30% to 80% of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment is subject to a sufficient amount of the combination to cause a block level of 35% to 75% of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment is subject to a sufficient amount of the combination to cause a block level of 35% to 70% of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment is subject to a sufficient amount of the combination to cause a level of blockade of 40% to 75% of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment comprises administering to a subject in need thereof, the method comprising 45% to 45% of the VMAT2 protein in the subject Any of the above combinations, methods or uses comprising administering to the subject an amount of the combination sufficient to cause a level of blockade of 75%.

- A combination, method or use for any of the uses described herein, wherein treatment comprises administering to a subject in need thereof, the method comprising administering from 35% to 80% of VMAT2 protein in the subject Any of the above combinations, methods or uses comprising administering to the subject an amount of the combination sufficient to cause a % blockade level.

- A combination, method or use for any of the uses described herein, wherein treatment comprises administering to a subject in need thereof, the method comprising administering from 40% to 80% of VMAT2 protein in the subject Any of the above combinations, methods or uses comprising administering to the subject an amount of the combination sufficient to cause a % blockade level.

- A combination, method or use for use as described herein, wherein the treatment is subject to a sufficient amount of the combination to cause a level of blockade of 45% to 80% of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment is subject to an amount of the combination sufficient to cause a 50% to 80% block level of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment is subject to a sufficient amount of the combination to cause a level of blockade of 55% to 80% of VMAT2 protein in the subject. Any of the above combinations, methods or uses comprising administering to the body.

- A combination, method or use for use as described herein, wherein the treatment reduces the level of blockade of VMAT2 protein by 30% to 70% (e.g., between 30% and 70%) in the subject Any of the above combinations, methods or uses comprising administering to the subject an amount of the combination sufficient to cause the effect.

- A combination, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method reduces the level of blockade of VMAT2 protein in the subject by 30% Any of the above combinations, methods or uses comprising administering to the subject an amount of the combination sufficient to achieve -65% (eg, between 30% and 65%).

- A combination, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method reduces the level of blockade of VMAT2 protein in the subject by 30% Any of the above combinations, methods or uses comprising administering to the subject an amount of the combination sufficient to achieve ˜60% (eg, between 30% and 60%).

- A combination, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method reduces the level of blockade of VMAT2 protein in the subject by 40% Any of the above combinations, methods or uses comprising administering to the subject an amount of the combination sufficient to achieve ˜80% (eg, between 40% and 80%).

- A combination, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method reduces the level of blockade of VMAT2 protein in the subject by 40% Any of the above combinations, methods or uses comprising administering to the subject an amount of the combination sufficient to achieve ˜75% (eg, between 40% and 75%).

- A combination, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method reduces the level of blockade of VMAT2 protein in the subject by 40% Any of the above combinations, methods or uses comprising administering to the subject an amount of the combination sufficient to achieve ˜70% (eg, between 40% and 70%).

- A combination, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method reduces the level of blockade of VMAT2 protein in the subject by 40% Any of the above combinations, methods or uses comprising administering to the subject an amount of the combination sufficient to achieve ˜65% (eg, between 40% and 65%).

- A combination, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method reduces the level of blockade of VMAT2 protein in the subject by 40% Any of the above combinations, methods or uses comprising administering to the subject an amount of the combination sufficient to achieve ˜60% (eg, between 40% and 60%).

In each of the foregoing aspects and embodiments of the invention, the combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine may be racemic.

Alternatively, in each of the foregoing aspects and embodiments of the invention, the combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine may be scalemic (i.e., non-racemic) .

In each of the combinations of the invention, the use thereof, and the pharmaceutical dosage forms containing the combination as defined above, are (+)-α-dihydrotetrabenazine versus (−)-α-dihydrotetrabenazine in the combination can be, for example, 0.5:1 to 20:1. In certain embodiments, the ratio of (+)-α-dihydrotetrabenazine to (−)-α-dihydrotetrabenazine in the combination can be in a range selected from:

(i) 1:1 to 20:1
(ii) 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
(vii) 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 to 4:1
(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 combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine is typically the other dihydrotetrabenazine isomer not associated with the body.

Minor amounts of other tetrabenazine isomers may be present in some embodiments, but these generally represent no more than 20% by weight (i.e., 0.2:1) compared to the total weight of the combination. present in quantity. More usually, the other dihydrotetrabenazine isomer will be 10% or less, 5% or less, or 2% or less, or 1% or less (i.e., 0.2% or less) relative to the total weight of the combination. : present in an amount corresponding to 1). More preferably, the other dihydrotetrabenazine isomers are completely absent or present in an amount of less than 1 wt%, such as less than 0.5 wt%.

In each of the foregoing aspects and embodiments, (+)-α-dihydrotetrabenazine and/or (−)-α-dihydrotetrabenazine are administered as a free base or as a pharmaceutically acceptable salt. obtain. In one embodiment, one or both of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine is administered as a pharmaceutically acceptable salt. In another embodiment, both (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine are administered as free bases. Unless otherwise indicated, or unless the context dictates otherwise, amounts of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine are calculated as amounts of free base, or or when (+)-α-dihydrotetrabenazine or (−)-α-dihydrotetrabenazine is in the form of a pharmaceutically acceptable salt, present in the pharmaceutically acceptable salt (+) -α-dihydrotetrabenazine or (−)-α-dihydrotetrabenazine itself.

In each of the foregoing aspects and embodiments of the invention relating to combinations of (+)-α-dihydrotetrabenazine or (−)-α-dihydrotetrabenazine or pharmaceutically acceptable salts thereof, typically , (+)-α-dihydrotetrabenazine or (−)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is not administered with a therapeutically effective amount of amantadine. More specifically, (+)-α-dihydrotetrabenazine or (−)-α-dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, are not administered with any amount of amantadine.

For example, with respect to pharmaceutical unit dosage forms, typically the unit dosage form does not contain a therapeutically effective amount of amantadine, more particularly the pharmaceutical unit dosage form does not contain any amount of amantadine.

Further, in each of the foregoing aspects and embodiments of the invention relating to (+)-α-dihydrotetrabenazine or (−)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, the pharmaceutical unit dosage form may be other than sustained or delayed release dosage forms.

Thus, for example, (+)-α-dihydrotetrabenazine or (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, can be administered as an immediate release unit dosage form.

(+)-β-Dihydrotetrabenazine As noted above, we note that (+)-α-dihydrotetrabenazine does not appear to be the major contributor to the therapeutic properties of tetrabenazine. Found it. Conversely, (+)-α-dihydrotetrabenazine appears to contribute a relatively minor contribution to the therapeutic properties of tetrabenazine.

Thus, despite previous findings that the (+)-α-isomer was 3-4 times more active than the (+)-β-isomer, the (+)-β-isomer was more than 50-fold more The fact that it is present in the body after administration of tetrabenazine in large amounts suggests that (+)-β-dihydrotetrabenazine is the major contributor to tetrabenazine's activity.

が、（＋）‐α‐ジヒドロテトラベナジンよりも低いＶＭＡＴ２活性を有するという、これまでの知見にもかかわらず、運動障害の治療に有効である。 According to our research, (+)-β-dihydrotetrabenazine itself has the chemical name (S,R,R)-3-isobutyl-9,10-dimethyloxy-1,3,4, 5,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol and having the following formula (III)

is effective in treating movement disorders, despite previous findings that it has lower VMAT2 activity than (+)-α-dihydrotetrabenazine.

Accordingly, in a first aspect, the invention provides a unit dosage form comprising (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. .

In another aspect, the invention provides (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in medicine.

A unit dosage form comprising (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient substantially free of other dihydrotetrabenazine isomers is also provided.

A unit dosage form can be orally administered, such as a capsule or tablet. Alternatively, (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof may be administered in non-solid dosage forms such as aqueous solutions, syrups, suspensions or gels.

Certain embodiments of the present invention provide:
A unit dosage form comprising 1 mg to 200 mg (eg, between 1 mg and 200 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 1 mg to 150 mg (eg, between 1 mg and 150 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 1 mg to 100 mg (eg, between 1 mg and 100 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 1 mg to 80 mg (eg, between 1 mg and 80 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 3 mg to 200 mg (eg, between 3 mg and 200 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 3 mg to 150 mg (eg, between 3 mg and 150 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 3 mg to 100 mg (eg, between 3 mg and 100 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 3 mg to 80 mg (eg, between 3 mg and 80 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 5 mg to 200 mg (eg, between 5 mg and 200 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 5 mg to 150 mg (eg, between 5 mg and 150 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 5 mg to 100 mg (eg, between 5 mg and 100 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 5 mg to 80 mg (eg, between 5 mg and 80 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 3 mg to 60 mg (eg, between 3 mg and 60 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 5 mg to 60 mg (eg, between 5 mg and 60 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 10 mg to 60 mg (eg, between 10 mg and 60 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

A unit dosage form comprising 15 mg to 60 mg (eg, between 15 mg and 60 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

• A unit dosage form containing about 20 mg of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

• A unit dosage form containing about 30 mg of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

• A unit dosage form containing about 40 mg of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

• A unit dosage form containing about 50 mg of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

• A unit dosage form containing about 60 mg of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

The unit dosage form as defined and described above is typically for use in the treatment of hyperkinetic movement disorders such as Huntington's disease, hemiballismus, chorea senile, tic disorders, tardive dyskinesias, dystonias and Tourette's syndrome. belongs to.

More particularly, the unit dosage form described above is 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 form described above is for use in the treatment of tardive dyskinesia.

In another specific embodiment, the unit dosage form described above is for use in the treatment of Tourette's Syndrome.

The inventors have found that (+)-β-dihydrotetrabenazine is useful for blocking VMAT2 receptors in the treatment of movement disorders. Accordingly, the present invention provides pharmaceutical compositions comprising (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

The present invention also provides (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for use as a VMAT2 inhibitor.

Further embodiments of the present invention provide:
• (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for use in the treatment of hyperkinetic movement disorder.

• (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in the treatment of Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesias, dystonias or Tourette's syndrome.

A subject in need thereof (e.g., a mammalian subject such as a human), comprising administering to the subject a therapeutically effective amount of (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof methods of treating hyperkinetic movement disorders in the body).

- A method of treating Huntington's disease, hemiballismus, 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), wherein the treatment is effective The above method comprising administering to the subject an amount of (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.

• Use of (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of hyperkinetic movement disorder.

(+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for the treatment of Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia or Tourette's syndrome Use for manufacturing.

- (+)-β-dihydrotetrabenazine for use in a method for the treatment of movement disorders, wherein the treatment comprises (+ (+)-β-dihydrotetrabenazine, comprising administering )-β-dihydrotetrabenazine to a subject.

- A method of treating a movement disorder in a subject in need thereof (e.g., a mammalian subject, such as a human) comprising (+ )-β-dihydrotetrabenazine to the subject.

- The use of (+)-β-dihydrotetrabenazine for the manufacture of a medicament for the treatment of movement disorders, wherein the treatment is in an amount of 1 mg to 200 mg (eg between 1 mg and 200 mg) per day The above use comprising administering (+)-β-dihydrotetrabenazine to the subject.

• Typically (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is not administered with an effective amount of amantadine. In one embodiment, (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is not administered with amantadine.

(+)-β-Dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, can be administered as an immediate release unit dosage form.

Further embodiments provide:
- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for any of the uses described herein, wherein the treatment comprises ( (+)-β-dihydrotetrabenazine, method or use above comprising administering +)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment comprises (+)-β-dihydrotetrabenazine in an amount of about 10 mg per day (+)-β-dihydrotetrabenazine, method or use as described above, comprising administering to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment comprises (+)-β-dihydrotetrabenazine in an amount of about 15 mg per day (+)-β-dihydrotetrabenazine, method or use as described above, comprising administering to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment comprises (+)-β-dihydrotetrabenazine in an amount of about 20 mg per day (+)-β-dihydrotetrabenazine, method or use as described above, comprising administering to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment comprises (+)-β-dihydrotetrabenazine in an amount of about 30 mg per day (+)-β-dihydrotetrabenazine, method or use as described above, comprising administering to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment comprises (+)-β-dihydrotetrabenazine in an amount of about 40 mg per day (+)-β-dihydrotetrabenazine, method or use as described above, comprising administering to a subject.

In each case, the amount of (+)-β-dihydrotetrabenazine specified may be administered once a day, or in several (eg, twice) doses per day.

In some embodiments, the specified amount of (+)-β-dihydrotetrabenazine is administered once daily.

Administration of (+)-β-dihydrotetrabenazine typically forms part of a chronic treatment regimen. Thus, (+)-β-dihydrotetrabenazine can be administered to the patient for a treatment period of at least 1 week, more usually at least 2 weeks, or at least 1 month, typically longer than 1 month. . The duration of treatment may be longer than 6 months and may extend over several years if the patient is shown to respond well to treatment.

A chronic treatment regimen can include daily administration of (+)-β-dihydrotetrabenazine, or a treatment regimen can include days on which (+)-β-dihydrotetrabenazine is not administered.

The dosage administered to a subject may vary during treatment. For example, the initial dosage may be increased or decreased depending on the subject's response to treatment. For example, a subject may be given an initial low dose to test the subject's tolerance to (+)-β-dihydrotetrabenazine, after which the dosage is optionally increased to 80 mg. It is increased up to the maximum daily intake (or other daily intake as above). Alternatively, the initial daily dosage administered to the patient may be selected to provide an estimated desired degree of VMAT2 blockade, followed by lower maintenance doses for the remainder of the treatment period, and treatment With the option of increasing the dosage if the subject's response to the drug indicates the need for an increase.

The amount of (+)-β-dihydrotetrabenazine required to achieve the desired therapeutic effect may depend on the weight of the subject being treated. The amount of (+)-β-dihydrotetrabenazine administered to the subject is weight in milligrams of (+)-β-dihydrotetrabenazine administered to the subject per kilogram of body weight of the subject. defined and abbreviated as mg/kg. Accordingly, an appropriate dosage can be calculated by multiplying the mg/kg amount by the weight of the subject to be treated. Accordingly, the present invention also provides:

- (+)-β-dihydrotetrabenazine for use in a method for the treatment of movement disorders, wherein the treatment is administered to a subject from 0.01 mg/kg to 2.0 mg/kg per day (e.g. , between 0.01 mg/kg and 2.0 mg/kg) of (+)-β-dihydrotetrabenazine, provided that (+)-β-dihydrotetrabenazine administered per day The total amount of tetrabenazine ranges from 1 mg to 80 mg (or other range as defined above).

- A method of treating movement disorders in a subject in need thereof (e.g., a mammalian subject, such as a human), wherein the total amount of (+)-beta-dihydrotetrabenazine administered per day is 0.01 mg/kg to 2.0 mg/kg (e.g., 0.01 mg/kg and 2.0 mg/kg) per day, provided that it is 1 mg to 80 mg (or other range as defined above). kg) of (+)-β-dihydrotetrabenazine to the subject.

- The use of (+)-β-dihydrotetrabenazine for the manufacture of a medicament for the treatment of movement disorders, wherein the total amount of (+)-β-dihydrotetrabenazine administered per day is 1 mg 0.01 mg/kg to 2.0 mg/kg (e.g., 0.01 mg/kg and 2.0 mg/kg between) amounts of (+)-β-dihydrotetrabenazine to the subject.

Further embodiments provide:
- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment is of (+)-β-dihydrotetrabenazine administered daily 0.01 mg/kg to 1.5 mg/kg per day (e.g. 0.01 mg/kg and 1.5 mg (+)-β-dihydrotetrabenazine, method or use, comprising administering (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment is of (+)-β-dihydrotetrabenazine administered daily 0.1 mg/kg to 1.5 mg/kg (for example, 0.1 mg/kg and 1.5 mg/kg (+)-β-dihydrotetrabenazine, method or use above, comprising administering (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment is of (+)-β-dihydrotetrabenazine administered daily 0.25 mg/kg to 1.5 mg/kg (for example, 0.25 mg/kg and 1.5 mg/kg (+)-β-dihydrotetrabenazine, method or use above, comprising administering (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment is of (+)-β-dihydrotetrabenazine administered daily 0.01 mg/kg to 1.25 mg/kg per day (for example, 0.01 mg/kg and 1.25 mg (+)-β-dihydrotetrabenazine, method or use, comprising administering (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment is of (+)-β-dihydrotetrabenazine administered daily 0.1 mg/kg to 1.25 mg/kg (for example, 0.1 mg/kg and 1.25 mg/kg (+)-β-dihydrotetrabenazine, method or use above, comprising administering (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment is of (+)-β-dihydrotetrabenazine administered daily 0.25 mg/kg to 1.25 mg/kg (for example, 0.25 mg/kg and 1.25 mg/kg (+)-β-dihydrotetrabenazine, method or use above, comprising administering (+)-β-dihydrotetrabenazine to a subject.

In each of the foregoing aspects and embodiments, (+)-β-dihydrotetrabenazine may be administered as a free base or as a pharmaceutically acceptable salt. Unless the context dictates otherwise, references herein to (+)-β-dihydrotetrabenazine also include pharmaceutically acceptable salts thereof.

In one general embodiment, (+)-β-dihydrotetrabenazine is administered as a pharmaceutically acceptable salt.

In another general embodiment, (+)-β-dihydrotetrabenazine is administered as the free base.

When amounts or ranges of amounts of (+)-β-dihydrotetrabenazine are described herein, these are as amounts of the free base or when (+)-β-dihydrotetrabenazine is pharmaceutically If in the form of an acceptable salt, it is calculated as the amount of (+)-β-dihydrotetrabenazine free base present in the pharmaceutically acceptable salt.

Complete blockade of the VMAT2 protein is considered undesirable as it can lead to undesirable side effects such as Parkinsonism. The present invention provides plasma levels of (+)-β-dihydrotetrabenazine that are sufficient to provide effective treatment of movement disorders, but do not block VMAT2 protein to the extent that it causes Parkinsonism and similar side effects. The level of VMAT2 blockade can be determined by competitive binding studies using positron emission tomography (PET). By co-administering the radioligand with the compound of interest at various concentrations, the percentage of binding sites occupied can be determined (see, e.g., Matthews et al., "Positron emission tomography molecular imaging for drug development" ("Drug Development Positron Emission Tomography for Molecular Imaging”), Br. J. Clin. Pharmacol, 73:2, 175-186). Accordingly, the present invention also provides:

- (+)-β-dihydrotetrabenazine for use in a method for the treatment of a movement disorder, the amount sufficient such that the treatment causes a level of blockade of VMAT2 protein of up to 90% in the subject. (+)-β-dihydrotetrabenazine, comprising administering (+)-β-dihydrotetrabenazine to a subject.

- A method of treating a movement disorder in a subject (e.g., a mammalian subject such as a human) in need thereof, comprising an amount of ( +)-β-dihydrotetrabenazine as described above, comprising administering to the subject.

- The use of (+)-β-dihydrotetrabenazine for the manufacture of a medicament for the treatment of movement disorders, wherein the treatment is sufficient to cause a level of blockade of VMAT2 protein of up to 90% in a subject amount of (+)-β-dihydrotetrabenazine to the subject.

Further embodiments provide:
- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment is sufficient to cause a level of blockade of VMAT2 protein of up to 85% in the subject The above (+)-β-dihydrotetrabenazine, method or use comprising administering an amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment is sufficient to cause a level of blockade of VMAT2 protein of up to 80% in the subject The above (+)-β-dihydrotetrabenazine, method or use comprising administering an amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment is sufficient to cause a level of blockade of VMAT2 protein of up to 75% in the subject The above (+)-β-dihydrotetrabenazine, method or use comprising administering an amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment is sufficient to cause a level of blockade of VMAT2 protein of up to 70% in the subject The above (+)-β-dihydrotetrabenazine, method or use comprising administering an amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment causes a level of blockade of VMAT2 protein of 20% to 90% in the subject (+)-β-dihydrotetrabenazine, method or use as described above comprising administering a sufficient amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment causes a level of blockade of VMAT2 protein of 25% to 85% in the subject (+)-β-dihydrotetrabenazine, method or use as described above comprising administering a sufficient amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment causes a level of blockade of VMAT2 protein of 30% to 80% in the subject (+)-β-dihydrotetrabenazine, method or use as described above comprising administering a sufficient amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment causes a level of blockade of VMAT2 protein of 35% to 75% in the subject (+)-β-dihydrotetrabenazine, method or use as described above comprising administering a sufficient amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment causes a level of blockade of VMAT2 protein of 35% to 70% in the subject (+)-β-dihydrotetrabenazine, method or use as described above comprising administering a sufficient amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment causes a level of blockade of VMAT2 protein of 40% to 75% in the subject (+)-β-dihydrotetrabenazine, method or use as described above comprising administering a sufficient amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method comprises (+)-β-dihydrotetrabenazine comprising administering to the subject an amount of (+)-β-dihydrotetrabenazine sufficient to cause a level of block of VMAT2 protein of 45% to 75%. , method or use.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method comprises said (+)-β-dihydrotetrabenazine comprising administering to the subject an amount of (+)-β-dihydrotetrabenazine sufficient to cause a level of block of VMAT2 protein of 35% to 80%. , method or use.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method comprises said (+)-β-dihydrotetrabenazine comprising administering to the subject an amount of (+)-β-dihydrotetrabenazine sufficient to cause a level of block of VMAT2 protein of 40% to 80%. , method or use.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment causes a level of blockade of VMAT2 protein of 45% to 80% in the subject (+)-β-dihydrotetrabenazine, method or use as described above comprising administering a sufficient amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment causes a level of blockade of VMAT2 protein of 50% to 80% in the subject (+)-β-dihydrotetrabenazine, method or use as described above comprising administering a sufficient amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein the treatment causes a level of blockade of VMAT2 protein of 55% to 80% in the subject (+)-β-dihydrotetrabenazine, method or use as described above comprising administering a sufficient amount of (+)-β-dihydrotetrabenazine to a subject.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein treatment is between 30% and 70% (e.g., between 30% and 70%) in subjects above (+)-β-dihydrotetrabenazine, method or use comprising administering to the subject an amount of (+)-β-dihydrotetrabenazine sufficient to cause a blocking level of the VMAT2 protein of .

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method comprises administering to the subject an amount of (+)-β-dihydrotetrabenazine sufficient to cause a block level of VMAT2 protein of 30% to 65% (e.g., between 30% and 65%); (+)-β-dihydrotetrabenazine, method or use as described above.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method comprises administering to the subject an amount of (+)-β-dihydrotetrabenazine sufficient to cause a block level of VMAT2 protein of 30% to 60% (e.g., between 30% and 60%); (+)-β-dihydrotetrabenazine, method or use as described above.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method comprises administering to the subject an amount of (+)-β-dihydrotetrabenazine sufficient to cause a block level of VMAT2 protein of 40% to 80% (e.g., between 40% and 80%); (+)-β-dihydrotetrabenazine, method or use as described above.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method comprises administering to the subject an amount of (+)-β-dihydrotetrabenazine sufficient to cause a block level of VMAT2 protein of 40% to 75% (e.g., between 40% and 75%); (+)-β-dihydrotetrabenazine, method or use as described above.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method comprises administering to the subject an amount of (+)-β-dihydrotetrabenazine sufficient to cause a block level of VMAT2 protein of 40% to 70% (e.g., between 40% and 70%); (+)-β-dihydrotetrabenazine, method or use as described above.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method comprises administering to the subject an amount of (+)-β-dihydrotetrabenazine sufficient to cause a block level of VMAT2 protein of 40% to 65% (e.g., between 40% and 65%); (+)-β-dihydrotetrabenazine, method or use as described above.

- (+)-β-dihydrotetrabenazine, method or use for use as described herein, wherein treatment comprises administering to a subject in need thereof, wherein the method comprises administering to the subject an amount of (+)-β-dihydrotetrabenazine sufficient to cause a block level of VMAT2 protein of 40% to 60% (e.g., between 40% and 60%); (+)-β-dihydrotetrabenazine, method or use as described above.

The movement disorder can be Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesias, dystonias, myoclonus, and hyperkinetic movement disorders such as Tourette's syndrome. In one embodiment, the movement disorder is Tourette's Syndrome

In each of the foregoing embodiments, (+)-β-dihydrotetrabenazine is no more than 20% by weight relative to (+)-β-dihydrotetrabenazine of any other isomer of dihydrotetrabenazine Accompanied by

More usually (+)-β-dihydrotetrabenazine is 10% or less by weight of (+)-β-dihydrotetrabenazine of any other isomer of dihydrotetrabenazine; preferably (+ )-β-dihydrotetrabenazine up to 5% by weight of any other isomer of dihydrotetrabenazine; more preferably (+)-β-dihydrotetrabenazine up to 2% by weight of dihydro With any other isomer of tetrabenazine. Most preferably, (+)-β-dihydrotetrabenazine is less than 1% (eg, less than 0.5% or less than 0.1%) of dihydrotetrabenazine relative to (+)-β-dihydrotetrabenazine. With any other isomer of benazine.

Therefore, (+)-β-dihydrotetrabenazine typically has an isomeric purity of at least 80%.

The term "isomeric purity" in the present context refers to the amount of (+)-β-dihydrotetrabenazine present relative to the total amount or concentration of all isomeric forms of dihydrotetrabenazine. For example, if 90% of the total dihydrotetrabenazine present in the composition is (+)-β-dihydrotetrabenazine, the isomeric purity is 90%.

(+)-β-Dihydrotetrabenazine of the present invention is 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 a pharmaceutically acceptable salt thereof, typically (+)-β-dihydrotetrabenazine or A pharmaceutically acceptable salt is not administered with a therapeutically effective amount of amantadine. More specifically, (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is not administered with any amount of amantadine.

For example, with respect to pharmaceutical unit dosage forms, typically the unit dosage form does not contain a therapeutically effective amount of amantadine, more particularly the pharmaceutical unit dosage form does not contain any amount of amantadine.

Further, in each of the foregoing aspects and embodiments of the invention relating to (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, the pharmaceutical unit dosage form is other than a sustained release or delayed release dosage form. There may be.

Thus, for example, (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, can be administered as an immediate release unit dosage form.

及び
式（ＩＩ）を有する（－）‐α‐ジヒドロテトラベナジン

及び／又は式（Ｉ）を有する（＋）‐α‐ジヒドロテトラベナジン

の組み合わせが、とりわけ、テトラベナジンが現在使用又は提案されている疾患状態及び症状の予防又は治療に有用であろうと考えられる。したがって、例として、限定するものではないが、ジヒドロテトラベナジン異性体のこれらの組み合わせは、ハンチントン病、ヘミバリスム、老人舞踏病、チック障害、遅発性ジスキネジア、ジストニア、及び特にトゥレット症候群などの多動性運動障害の治療に使用することができると考えられる。 Combinations of (+)-β-dihydrotetrabenazine with (−)-α-dihydrotetrabenazine and/or (+)-α-dihydrotetrabenazine In a further embodiment (+) having formula (III) -β-dihydrotetrabenazine

and (−)-α-dihydrotetrabenazine having formula (II)

and/or (+)-α-dihydrotetrabenazine having formula (I)

will be useful, inter alia, in the prevention or treatment of disease states and symptoms for which tetrabenazine is currently used or proposed. Thus, by way of example, but not by way of limitation, these combinations of dihydrotetrabenazine isomers are useful in many diseases such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesias, dystonias, and especially Tourette's syndrome. It is believed that it can be used in the treatment of dynamic movement disorders.

Accordingly, in a first aspect, the present invention provides a pharmaceutical combination comprising:
(a) (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
and either or both of the following:
(b) (-)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof;
and (c) (+)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a pharmaceutical combination comprising:
(a) (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
and (b) (-)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a pharmaceutical combination comprising:
(a) (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
and (c) (+)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a pharmaceutical composition comprising:
(a) (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof;
(b) (-)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof;
and (c) (+)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof.

(+)-β-dihydrotetrabenazine, (−)-α-dihydrotetrabenazine and (+)-α-dihydrotetrabenazine are herein collectively They may be referred to as "dihydrotetrabenazine isomers of the invention" or "isomers of dihydrotetrabenazine" or "dihydrotetrabenazine." When describing types of pharmaceutical formulations, they are sometimes collectively referred to as "active compounds."

The pharmaceutical combination may be substantially free of (-)-β-dihydrotetrabenazine. Accordingly, the present invention also provides a pharmaceutical combination as described herein, wherein the unit dosage form is substantially free of (-)-β-dihydrotetrabenazine.

"Substantially free of (-)-β-dihydrotetrabenazine" means the weight of (-)-β-dihydrotetrabenazine present relative to the total weight of all isomers of dihydrotetrabenazine. % is less than 5%, preferably less than 3%, more preferably less than 2%, most preferably less than 1%.

The relative proportions of (+)-β-dihydrotetrabenazine, (-)-α-dihydrotetrabenazine and (+)-α-dihydrotetrabenazine can be expressed in parts by weight of the individual isomers. Thus, for example, the unit dosage form contains 35 to 75 parts by weight of (+)-β-dihydrotetrabenazine and 25 to 55 parts by weight of α-dihydrotetrabenazine ((+)-α-dihydrotetrabenazine or (-)-α-dihydrotetrabenazine or mixtures thereof). The proportions expressed above as parts by weight can alternatively be expressed as molar ratios (as all isomers have the same molecular weight), where the relative proportions of the isomers are 35-70:25-55 (+)-β-dihydrotetrabenazine: α-dihydrotetrabenazine (either ((+)-α-dihydrotetrabenazine or (-)-α-dihydrotetrabenazine or mixtures thereof) may be expressed as a molar ratio.

In one embodiment, the pharmaceutical combination of the invention comprises:
(a) 40-65 parts by weight of (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof (c) 40-65 parts by weight of (+)-α-dihydrotetrabenazine or a pharmaceutical agent thereof acceptable salt.

For example, a pharmaceutical combination can include:
(a) 45-55 parts by weight of (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof (c) 45-55 parts by weight of (+)-α-dihydrotetrabenazine or a pharmaceutical agent thereof acceptable salt.

In one particular embodiment, the pharmaceutical combination comprises (+)-β-dihydrotetrabenazine and (+)-α-dihydrotetrabenazine in approximately equimolar amounts.

In another embodiment, the pharmaceutical combination of the invention comprises:
(a) 45-65 parts by weight of (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof;
(b) 30-50 parts by weight of (-)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof; and optionally (c) 0.1-5 parts by weight of (+)-α- Dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical combination of the invention comprises:
(a) 45-65 parts by weight of (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof;
(b) 30-50 parts by weight of (-)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof; and optionally (c) 0.1-3 parts by weight of (+)-α- Dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical combination of the invention comprises:
(a) 45-65 parts by weight of (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof;
(b) 30-50 parts by weight of (-)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof; and optionally (c) 0.1-2 parts by weight of (+)-α- Dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.

In a further embodiment, the pharmaceutical combination of the invention comprises:
(a) 45-65 parts by weight of (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof;
(b) 30-50 parts by weight of (-)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof; and optionally (c) 0.1-1.5 parts by weight of (+)- α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof.

A pharmaceutical combination is a combination of three dihydrotetrabenazines (a) and (b) and/or (c) in a form suitable for administration to a subject, typically a human or other animal subject. means. Thus, the term 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 combinations . It also excludes simple solutions of combinations in pharmaceutically unacceptable solvents (eg chloroform, dichloromethane) not commonly used in pharmacy.

A pharmaceutical combination may be in the form of a mixture of pure compounds, or the combination may contain one or more pharmaceutically acceptable excipients.

Typically, the pharmaceutical combination comprises a pharmaceutically acceptable excipient and is formulated as a unit dosage form containing a defined amount of dihydrotetrabenazine (a), (b) and/or (c). be.

In the pharmaceutical combination of the present invention one or more of the three dihydrotetrabenazines (a), (b) and (c) may be formulated separately but used in combination. However, more typically the three dihydrotetrabenazines (a), (b) and (c) are formulated together in a pharmaceutical composition, particularly a unit dosage form.

In the unit dosage form of the present invention containing the combinations defined herein, the three isomers (+)-β-dihydrotetrabenazine, (−)-α-dihydrotetrabenazine and (+)-α - the total amount of dihydrotetrabenazine ("total amount") may be selected not to exceed 100 mg;

Typically, pharmaceutical unit dosage forms do not contain an effective amount of amantadine. In one embodiment, the pharmaceutical unit dosage form does not contain amantadine.

The pharmaceutical unit dosage form can be an immediate release unit dosage form.

In certain embodiments:
- The total amount of the three isomers does not exceed 75 mg,
・The total amount of the three isomers does not exceed 50 mg,
- The total amount of the three isomers does not exceed 40 mg,
・The total amount of the three isomers does not exceed 30 mg,
• The total amount of the three isomers does not exceed 20 mg.

A unit dosage form can be orally administered, such as a capsule or tablet.

A unit dosage form can be orally administered, such as a capsule or tablet.

A pharmaceutical combination as defined herein is provided for use in medicine.

More particularly, the pharmaceutical combination (and unit dosage form) as defined and described above is used for hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesias, dystonias and Tourette's syndrome. for use in the treatment of

More particularly, the pharmaceutical combination (and unit dosage form) described above is 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 combination (and unit dosage form) described above is for use in the treatment of tardive dyskinesia.

In another specific embodiment, the pharmaceutical combination (and unit dosage form) described above is 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 hyperkinetic movement disorder.

- A method of treating hyperkinetic movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human) comprising a therapeutically effective amount of a pharmaceutical combination as defined herein to the subject.

- Use of a pharmaceutical combination as defined herein for the manufacture of a medicament for the treatment of hyperkinetic movement disorder.

a unit dosage form for use as described herein, wherein the hyperkinetic movement disorder is selected from Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesias, dystonia and Tourette's syndrome; A pharmaceutical combination, method or use for use.

A unit dosage form for use, a pharmaceutical combination for use, a method or use as described herein wherein the hyperkinetic movement disorder is Tourette's Syndrome.

In each case, the combination of (+)-β-dihydrotetrabenazine, (−)-α-dihydrotetrabenazine; and optionally (+)-α-dihydrotetrabenazine is typically administered for one day. administered once at

Complete blockade of VMAT2 is considered undesirable as it can lead to undesirable side effects such as Parkinsonism. The present invention provides plasma levels of dihydrotetrabenazine that are sufficient to provide effective treatment of movement disorders, but do not block VMAT2 to the extent that it causes Parkinsonism and similar side effects. The level of VMAT2 blockade can be determined by competitive binding studies using positron emission tomography (PET). By co-administering the radioligand with the compound of interest at various concentrations, the percentage of binding sites occupied can be determined (see, e.g., Matthews et al., "Positron emission tomography molecular imaging for drug development" ("Drug Development Positron Emission Tomography for Molecular Imaging”), Br. J. Clin. Pharmacol, 73:2, 175-186). Accordingly, the present invention also provides:

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein the treatment causes a level of blockade of VMAT2 protein of greater than 20% in a subject any of the above unit dosage forms, pharmaceutical combinations, methods or uses, comprising administering to a subject the unit dosage form or combination in an amount sufficient for the above.

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein the treatment causes a level of blockade of VMAT2 protein of greater than 30% in a subject any of the above unit dosage forms, pharmaceutical combinations, methods or uses, comprising administering to a subject the unit dosage form or combination in an amount sufficient for the above.

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein the treatment causes a level of blockade of VMAT2 protein of greater than 40% in a subject any of the above unit dosage forms, pharmaceutical combinations, methods or uses, comprising administering to a subject the unit dosage form or combination in an amount sufficient for the above.

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein the treatment causes a level of blockade of VMAT2 protein of less than 90% in the subject any of the above unit dosage forms, pharmaceutical combinations, methods or uses, comprising administering to a subject the unit dosage form or combination in an amount sufficient for the above.

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein the treatment causes a level of blockade of VMAT2 protein of less than 85% in the subject any of the above unit dosage forms, pharmaceutical combinations, methods or uses, comprising administering to a subject the unit dosage form or combination in an amount sufficient for the above.

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein the treatment causes a level of blockade of VMAT2 protein of less than 80% in a subject any of the above unit dosage forms, pharmaceutical combinations, methods or uses, comprising administering to a subject the unit dosage form or combination in an amount sufficient for the above.

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein the treatment causes a level of blockade of VMAT2 protein of less than 75% in the subject any of the above unit dosage forms, pharmaceutical combinations, methods or uses, comprising administering to a subject the unit dosage form or combination in an amount sufficient for the above.

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein the treatment causes a level of blockade of VMAT2 protein of less than 70% in the subject any of the above unit dosage forms, pharmaceutical combinations, methods or uses, comprising administering to a subject the unit dosage form or combination in an amount sufficient for the above.

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein treatment is between 20% and 90% (e.g., between 20% and 90%) in subjects A unit dosage form, pharmaceutical combination, method or use as described above, comprising administering to a subject an amount of the unit dosage form or combination sufficient to cause a blocking level of VMAT2 protein of between %).

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein treatment is between 30% and 80% (e.g., 30% and 80%) in subjects A unit dosage form, pharmaceutical combination, method or use as described above, comprising administering to a subject an amount of the unit dosage form or combination sufficient to cause a blocking level of VMAT2 protein of between %).

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein treatment is between 30% and 75% (e.g., between 30% and 75%) in subjects A unit dosage form, pharmaceutical combination, method or use as described above, comprising administering to a subject an amount of the unit dosage form or combination sufficient to cause a blocking level of VMAT2 protein of between %).

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein treatment is between 30% and 70% (e.g., between 30% and 70%) in subjects A unit dosage form, pharmaceutical combination, method or use as described above, comprising administering to a subject an amount of the unit dosage form or combination sufficient to cause a blocking level of VMAT2 protein of between %).

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein treatment is between 30% and 65% (e.g., 30% and 65%) in subjects A unit dosage form, pharmaceutical combination, method or use as described above, comprising administering to a subject an amount of the unit dosage form or combination sufficient to cause a blocking level of VMAT2 protein of between %).

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein treatment is between 30% and 60% (e.g., between 30% and 60%) in subjects A unit dosage form, pharmaceutical combination, method or use as described above, comprising administering to a subject an amount of the unit dosage form or combination sufficient to cause a blocking level of VMAT2 protein of between %).

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein treatment is between 40% and 80% (e.g., 40% and 80%) in subjects A unit dosage form, pharmaceutical combination, method or use as described above, comprising administering to a subject an amount of the unit dosage form or combination sufficient to cause a blocking level of VMAT2 protein of between %).

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein treatment is between 40% and 75% (e.g., 40% and 75%) in subjects A unit dosage form, pharmaceutical combination, method or use as described above, comprising administering to a subject an amount of the unit dosage form or combination sufficient to cause a blocking level of VMAT2 protein of between %).

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein treatment is between 40% and 70% (e.g., 40% and 70%) in subjects A unit dosage form, pharmaceutical combination, method or use as described above, comprising administering to a subject an amount of the unit dosage form or combination sufficient to cause a blocking level of VMAT2 protein of between %).

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein treatment is between 40% and 65% (e.g., 40% and 65%) in subjects A unit dosage form, pharmaceutical combination, method or use as described above, comprising administering to a subject an amount of the unit dosage form or combination sufficient to cause a blocking level of VMAT2 protein of between %).

- A unit dosage form for use, a pharmaceutical combination for use, a method or use described herein wherein treatment is between 40% and 60% (e.g., 40% and 60%) in subjects A unit dosage form, pharmaceutical combination, method or use as described above, comprising administering to a subject an amount of the unit dosage form or combination sufficient to cause a blocking level of VMAT2 protein of between %).

In each of the foregoing aspects and embodiments of the invention relating to the combination of dihydrotetrabenazine (a) and (b) and/or (c), typically the combination is not administered with a therapeutically effective amount of amantadine. More specifically, the combination is not administered with any amount of amantadine.

For example, with respect to pharmaceutical unit dosage forms, typically the unit dosage form does not contain a therapeutically effective amount of amantadine, more particularly the pharmaceutical unit dosage form does not contain any amount of amantadine.

Further, in each of the foregoing aspects and embodiments of the invention relating to the combination of dihydrotetrabenazine (a) and (b) and/or (c), the pharmaceutical unit dosage form is a sustained release or delayed release dosage form It may be other than

Thus, for example, the combination of dihydrotetrabenazine (a) and (b) and/or (c) can be administered as an immediate release unit dosage form.

Free Base and Salts In each of the foregoing aspects and embodiments of the invention, all references herein to individual isomers of dihydrotetrabenazine are the free base thereof, unless the context indicates otherwise. and salt.

Salts are typically acid addition salts.
Salts are described in Pharmaceutical Salts: Properties, Selection, and Use, P.M. Heinrich Stahl (ed.), Camille G.; Wermuth (ed.), ISBN: 3-90639-026-8, Hardcover, page 388, August, 2002, from the parent compound by conventional chemical methods. Generally, such salts can be prepared by reacting the free base form of the compound with an acid in water or an organic solvent, or a mixture of the two, generally ether, acetone, ethyl acetate, ethanol, isopropanol. , or non-aqueous media such as acetonitrile are used.

Acid addition salts can be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g. L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid. , butanoic acid, (+)camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfone acids, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g. D-glucuronic acid ), glutamic acid (e.g. L-glutamic acid), α-oxoglutarate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, (+)-L-lactic acid, (±)-DL -lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5- disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, selected from the group consisting of sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid, and acylated amino acids and cation exchange resins and salts formed with acids such as

The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, examples of pharmaceutically acceptable salts can be found in Berge et al. , 1977, "Pharmaceutically Acceptable Salts", J. Am. PharmSci. , Vol. 66, pp. 1-19. However, non-pharmaceutically acceptable salts can also be prepared as intermediate forms, which are then converted to pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms may also be useful, for example in the purification or isolation of compounds of the invention, and form part of this invention.

The isomers of dihydrotetrabenazine may contain one or more isotopic substitutions and references to a particular element include within its scope all isotopes of the element. For example, reference to hydrogen includes within its scope ¹ H, ² H (D), and ³ H (T). Similarly, references to carbon and oxygen each include within its scope ¹¹ C, ¹² C, ¹³ C and ¹⁴ C and ¹⁶ O and ¹⁸ O.

Typically, the dihydrotetrabenazine isomers of the present invention do not contain isotopes (eg, ¹¹ C or ³ H) in amounts greater than their natural abundance.

In one embodiment, the percentage of total hydrogen atoms in (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine that are deuterium atoms is less than 2%, more typically 1% less than, more usually less than 0.1%, preferably less than 0.05% and most preferably 0.02% or less.

In a similar fashion, references to particular functional groups also include isotopic variations within their scope unless the context indicates otherwise.

Isotopes can be radioactive or non-radioactive. In one embodiment of the invention, the isomers of dihydrotetrabenazine are radioisotope-free. Such compounds are preferred for therapeutic use. However, in another embodiment, one or more of the isomers of dihydrotetrabenazine may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in diagnostic situations.

A reference to an isomer of dihydrotetrabenazine includes any solvate formed by the compound.

Examples of solvates are formed by incorporating molecules of non-toxic pharmaceutically acceptable solvents (hereinafter referred to as solvating solvents) into the solid state structure (e.g., crystal structure) of the compounds of the invention. It is a solvate. Examples of such solvents include water, alcohols (eg ethanol, isopropanol and butanol) and dimethylsulfoxide. Solvates can be prepared by recrystallizing the compound from a solvent or a mixture of solvents containing the solvating solvent. Whether solvates are formed in any given instance can be determined by analyzing crystals of the compound by well known standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography. can be determined by analyzing using

Solvates may 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 methods used to make and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, 2nd ed., SSCI, Inc., West Lafayette, IN, USA. , 1999, ISBN 0-967-06710-3.

Alternatively, rather than existing as a hydrate, the compounds of the invention may be anhydrous. Thus, in another embodiment, one or more of the isomers of dihydrotetrabenazine is in anhydrous form.

Methods of Preparation of Dihydrotetrabenazine Isomers (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine can be prepared from tetrabenazine according to the synthetic route shown in Scheme 1.

Racemic tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1,a]isoquinoline- containing the RR and SS isomers of tetrabenazine 2-one) with sodium borohydride, the racemic mixture of α-dihydrotetrabenazine (RRR and SSS isomers) constitutes the major product and the racemic mixture of β-dihydrotetrabenazine (SRR and A mixture of four dihydrotetrabenazine isomers was obtained in which the RSS isomer) constituted the by-product. β-Dihydrotetrabenazine can be removed during the initial purification procedure, for example by chromatography or recrystallization, and racemic α-dihydrotetrabenazine can then be converted to diastereoisomers by chiral chromatography or reaction with a chiral acid. Separation can be achieved by well-known methods such as separation by formation of isomeric salts followed by recrystallization.

For example, by recrystallizing the racemic mixture with di-p-toluoyl-L-tartaric acid or (R)-(-)-camphorsulfonic acid, or by chiral chromatography, the (+)-α-dihydrotetrabenazine isomerism Form (I) (((2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1,a]isoquinoline- 2-ol) can be obtained.

The (−)-α-dihydrotetrabenazine isomers (−)-α-dihydrotetrabenazine isomers (−)-α-dihydrotetrabenazine isomers (−)-α-dihydrotetrabenazine isomers (−)-α-dihydrotetrabenazine isomers (−)-α-dihydrotetrabenazine isomers ( I) ((2S,3S,11bS)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1,a]isoquinolin-2-ol ) can be obtained.

(+)-α-Dihydrotetrabenazine and (−)-α-dihydrotetrabenazine are also described in Yao et al. Preparation and Characterization of Tetrabenazine Enantiomers and All Eight Stereoisomers of Dihydrotetrabenazine"), Eur. J. Med. Chem. , (2011), 46, pp. 1841-1848.

(+)-β-Dihydrotetrabenazine (compound of formula (III)) can be prepared from tetrabenazine according to the synthetic route shown in Scheme 2.

Racemic tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1,a], including the RR and SS isomers of tetrabenazine isoquinolin-2-one) is reduced with sodium borohydride, the racemic mixture of β-dihydrotetrabenazine (SRR and RSS isomers) constitutes the major product, and the racemic mixture of α-dihydrotetrabenazine ( A mixture of four dihydrotetrabenazine isomers was obtained in which the RRR and SSS isomers) constituted by-products. α-Dihydrotetrabenazine is removed during the first purification procedure, e.g. -(-)-Camphorsulfonic acid recrystallization or by chiral chromatography) to give (+)-β-dihydrotetrabenazine (III) ((2S,3R,11bR)-3-isobutyl-9, 10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1,a]isoquinolin-2-ol) is obtained. The stereochemical configuration of (+)-β-dihydrotetrabenazine can be determined by forming a salt, eg, the crystalline form of the mesylate salt, and identifying the structure by X-ray crystallography.

(+)-α-Dihydrotetrabenazine, (−)-α-dihydrotetrabenazine and (+)-β-dihydrotetrabenazine are described by Yao et al. , "Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors". Eur. J. Med. Chem. , (2011), 46, pp. 1841-1848.

Once prepared and purified, (+)-β-dihydrotetrabenazine, (−)-α-dihydrotetrabenazine and, if present, (+)-α-dihydrotetrabenazine, or Each salt can be mixed in the required proportions.

Pharmaceutical Formulations and Methods of Treatment The pharmaceutical unit dosage form of the present invention can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, ophthalmic, aural, rectal, intravaginal, or transdermal administration. When the compositions are intended for parenteral administration, they may be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, or by direct delivery to a target organ or tissue by injection, infusion or other means of delivery. can be formulated for

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. Includes patch.

Specific examples of pharmaceutical unit dosage forms containing a combination of the invention are capsules and tablets.

Pharmaceutical unit dosage forms containing a combination of the invention can be formulated according to well known techniques, see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

Tablet compositions thus comprise a unit dosage of an active compound combination in an inert diluent or carrier such as a sugar or sugar alcohol such as lactose, sucrose, sorbitol or mannitol; sodium carbonate, calcium phosphate, talc, calcium carbonate), or cellulose or derivatives thereof (eg, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose), and starch (eg, corn starch)). Tablets may also contain binders and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricants (e.g. stearates), preservatives (e.g. parabens). , antioxidants (e.g. BHT), buffers (e.g. phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. . Such excipients are well known and need not be discussed at length here.

Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active ingredient in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant-derived equivalents thereof.

Solid dosage forms (e.g. tablets, capsules, etc.) may be coated or uncoated, but typically have a coating, e.g. a protective film coating (e.g. wax or varnish) or a release controlling coating . Coatings (eg, Eudragit™-type polymers) can be designed to release the active ingredient at a desired location within the gastrointestinal tract. Thus, the coating can be selected to degrade at specific pH conditions within the gastrointestinal tract, thereby selectively releasing the compound within the stomach or ileum or duodenum.

Alternatively, or in addition to a coating, the isomers of dihydrotetrabenazine, or pharmaceutically acceptable salts thereof, that make up the combinations of the present invention can be treated with release controlling agents, e.g. It can be presented in a solid matrix containing a release retardant that can be adapted to selectively release the compound under conditions of alkalinity. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (eg, a maleic anhydride polymer) that erodes substantially continuously as the dosage form passes through the gastrointestinal tract.

Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (eg intraocular inserts). Such compositions can be formulated according to known methods.

Compositions for parenteral administration are typically provided as sterile aqueous or oily solutions or microsuspensions, or as finely divided sterile powders for constitution extemporaneously with sterile water for injection. can be provided in the form

Formulations for rectal or vaginal administration include, for example, pessaries and suppositories which may be formed of a moldable or waxy material containing the active compound.

Compositions for administration by inhalation can take the form of inhalable powder compositions or liquid or powder sprays and can be administered in standard form using powder inhaler or aerosol dispensing devices. Such devices are well known. For administration by inhalation, powder formulations typically contain a combination of dihydrotetrabenazine isomers, or a pharmaceutically acceptable salt thereof, together with an inert solid powder diluent (eg, 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 are one or more pharmaceutical excipients processed (e.g., compressed to form tablets or capsules) to form a pharmaceutical composition such as a unit dosage form. It can be provided as a mixture that is added before filling). 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 may be separately formulated into different granules, pellets, microbeads, or mini-tablets and then combined and processed to give the pharmaceutical composition. (eg, by filling into capsules or compressing to form tablets). As another alternative, different isomers of dihydrotetrabenazine isomers may be contained in different layers in a multi-layer tablet.

A particular pharmaceutical composition of the invention is a composition 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 an initial fast release of the active compound followed by a constant rate release (zero order);
- pellets or tablets formulated to provide a mixture of first 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; Optionally higher order release of the active compound selected from secondary, tertiary and quaternary release and combinations thereof.

Pellets and tablets formulated to provide the type of release kinetics defined above are described, for example, in Remington's Pharmaceutical Sciences (Id.) and "Remington-The Science and Practice of Pharmacy, 21st Edition, 2006, ISBN 0-7817-4673-6 according to methods well known to those skilled in the art.

The combinations of the invention are generally provided in a pharmaceutical unit dosage form, and as such typically contain sufficient of the compounds to provide the desired level of biological activity, as described above.

The inventive combination is administered to a subject (patient) in need thereof (eg, a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect, as described above.

Figure 1 shows that in amphetamine-challenged rats, vehicle (with or without amphetamine challenge) and (-)-α-dihydrotetrabenazine at 2.5 mg/kg, as described in Example 2, Study 1 below. and risperidone at a dose of 1 mg/kg.

Figure 2 depicts vehicle (with or without amphetamine challenge) and (−)-α-dihydrotetrabenazine at a dose of 2.5 mg/kg in amphetamine-challenged rats, as described in Example 2, Study 1 below. and risperidone at a dose of 1 mg/kg.

Figure 3 shows that vehicle (with or without amphetamine challenge) and (+)-α-dihydrotetrabenazine at 0.1 mg/kg and 0 in amphetamine-challenged rats, as described in Example 2, Study 2 below. Figure 3 shows the average total distance traveled by rats when treated with a dose of .25 mg/kg and with risperidone at a dose of 1 mg/kg.

Figure 4 shows that vehicle (with or without amphetamine challenge) and (+)-α-dihydrotetrabenazine at 0.1 mg/kg and 0 in amphetamine-challenged rats, as described in Example 2, Study 2 below. .25 mg/kg dose and risperidone at a dose of 1 mg/kg mean total stereotypic behavior by rats treated.

FIG. 5 depicts vehicle (with or without amphetamine challenge) and (−)-α-dihydrotetrabenazine at a dose of 2 mg/kg in amphetamine-challenged rats, as described in Example 2, Study 3 below. with a combination of (+)-α-dihydrotetrabenazine at a dose of 2 mg/kg and (−)-α-dihydrotetrabenazine at a dose of 2 mg/kg and risperidone at a dose of 1 mg/kg. Mean total distance traveled by rats when

FIG. 6 depicts vehicle (with or without amphetamine challenge) and (−)-α-dihydrotetrabenazine at a dose of 2 mg/kg in amphetamine-challenged rats, as described in Example 2, Study 3 below. with a combination of (+)-α-dihydrotetrabenazine at a dose of 2 mg/kg and (−)-α-dihydrotetrabenazine at a dose of 2 mg/kg and risperidone at a dose of 1 mg/kg. Shows the average total stereotypic behavior of rats when

FIG. 7 shows the effects of vehicle (with or without amphetamine challenge) and (+)-α-dihydrotetrabenazine at various ratios in amphetamine-challenged rats, as described in Example 2, Study 4 below. Figure 3 shows mean total distance traveled in rats treated with a combination of (-)-α-dihydrotetrabenazine and risperidone at a dose of 1 mg/kg.

Figure 8 shows the effect of vehicle (with or without amphetamine challenge) and (+)-α-dihydrotetrabenazine at various ratios in amphetamine-challenged rats, as described in Example 2, Study 4 below. Shown is the average gross stereotypic behavior of rats treated with a combination of (−)-α-dihydrotetrabenazine and risperidone at a dose of 1 mg/kg.

Figure 9 shows vehicle (with or without amphetamine challenge), (+)-β-dihydrotetrabenazine, and (+)- Shown is the mean total distance traveled by rats treated with a combination of α-dihydrotetrabenazine and (+)-β-dihydrotetrabenazine.

Figure 10 depicts vehicle (with or without amphetamine challenge), (+)-β-dihydrotetrabenazine, and (+)- Shown is the average total stereotypic behavior of rats treated with a combination of α-dihydrotetrabenazine and (+)-β-dihydrotetrabenazine.

Figure 11 shows vehicle (with or without amphetamine challenge), (+)-α-dihydrotetrabenazine alone, (-)- (+)-α-dihydrotetrabenazine in combination with β-dihydrotetrabenazine, (+)-β-dihydrotetrabenazine in combination with (-)-α-dihydrotetrabenazine, (-)-β- of rats treated with (+)-β-dihydrotetrabenazine in combination with dihydrotetrabenazine and (+)-α-dihydrotetrabenazine in combination with (+)-β-dihydrotetrabenazine. Shows the average total distance traveled.

Figure 12 shows vehicle (with or without amphetamine challenge), (+)-α-dihydrotetrabenazine alone, (-)- (+)-α-dihydrotetrabenazine in combination with β-dihydrotetrabenazine, (+)-β-dihydrotetrabenazine in combination with (-)-α-dihydrotetrabenazine, (-)-β- of rats treated with (+)-β-dihydrotetrabenazine in combination with dihydrotetrabenazine and (+)-α-dihydrotetrabenazine in combination with (+)-β-dihydrotetrabenazine. Stereotypic behavior (distance over time) is shown.

The following non-limiting examples illustrate the synthesis and properties of the compositions of the invention.

Example 1
Investigation of the properties of dihydrotetrabenazine metabolites formed after administration of tetrabenazine to human subjects. A pharmacokinetic study was performed to determine plasma concentrations of α and +/-β dihydrotetrabenazine. The data are summarized below.

Table 1 summarizes the pharmacokinetic data obtained after a single oral administration of tetrabenazine (fasting, N = 08) at the 25 mg dose level.
Table 1

Table 2 summarizes the pharmacokinetic data obtained after repeated oral administration of tetrabenazine (fasting, N = 07) at the 25 mg dose level.
Table 2

The data presented in Tables 1 and 2 demonstrate that in humans the major metabolites are the (−)-α-dihydrotetrabenazine isomer, which is essentially the active ingredient as a VMAT2 binder, and the (+)-α- It demonstrates that the (+)-β-dihydrotetrabenazine isomer is significantly less active than the dihydrotetrabenazine isomer. (−)-β-dihydrotetrabenazine and (+)-α-dihydrotetrabenazine were shown to be minor metabolites

The data suggest that (+)-α-dihydrotetrabenazine is not the major contributor to tetrabenazine's therapeutic properties. Conversely, (+)-α-dihydrotetrabenazine may contribute a relatively minor contribution to the therapeutic properties of tetrabenazine.

Example 2
Investigation of the effects of the combination of (+)-α-dihydrotetrabenazine and (-)-α-dihydrotetrabenazine on locomotor and stereotypic movements in rats (+)-α-dihydrotetrabenazine and (-) )-α-dihydrotetrabenazine combination on locomotor and stereotypic locomotion in rats, the individual (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine isomers compared with the effect of

Materials and methods
Facilities Open field arena, Med Associates Inc.
1 ml plastic syringe, Terumo Ref: SS-01T1
Animal Feeding Needle 15G, Instech Solomon, Cat: 72-4446
Sartorius Mechatronics Scale A22101, Sartorius Weighting Technology, Germany
Needle 27G Terumo Myjector, 0,5 ml, Ref: 8300010463
3 ml plastic syringe, Soft-Ject, Ref: 8300005761
BD Microtainer K2EDTA tube Ref: 365975
Matrix 0,75 ml, Alphanum Tubes, Thermo Scientific, Ref: 4274
Microplate Devices, Uniplate 24 well, 10 ml, Ref: 734-1217
Thermo Electron Corp. Heraeus Fresco 17, refrigerated centrifuge

All animal experiments were conducted in accordance with the US National Institutes of Health (NIH) guidelines for the care and use of laboratory animals and were approved by the National Animal Experiment Board, Finland. Male CDs (Charles River Laboratories, Germany) in the weight range of 200-250 g (165-200 g upon arrival) were used in the experiments. Animals were housed at standard temperature (22±1° C.) in a light-controlled environment (lighting from 7 am to 8 pm) with ad libitum access to food and water.

Methods Locomotor activity of rats was tested in an open field arena. The open field test was performed under normal lighting evenly distributed over the test chamber during the rat light cycle. The rat's trajectory was recorded by an activity monitor (Med. Associates Inc.).

Vehicle, amphetamine, (+)-α-DHTBZ, (−)-α-DHTBZ, (+)-β-DHTBZ, (−)-β-DHTBZ or risperidone were administered prior to LMA testing. The rat was placed in the center of the arena and the path was recorded for 30 minutes. After 30 minutes of testing, vehicle or amphetamine was administered, rats were placed in the center of the arena, and paths were recorded for 60 minutes, total testing time was 90 minutes.

Animals were euthanized by an overdose of _CO2 within 10 minutes of the end of endpoint, blood samples and tissue processing test. Terminal blood samples were collected by cardiac puncture from all compound-treated rats from each group except vehicle rats. 0.5 ml of blood was collected with a syringe attached to an 18G needle and transferred into pre-chilled K2-EDTA microfuge tubes. The EDTA microtube was inverted several times to mix the EDTA and blood. Then immediately place the tube in wet ice, centrifuge (Heraeus Fresco 17) (9.6x 1000 G/10x 1000 RPM, +4°C, 2 min) within 10-15 min of collection and place on dry ice according to sample map. 200 μl of plasma was collected in the top 96-tube plate (Matrix Technologies ScreenMates 0.75 ml Alphaundic Round-Bottom Storage tubes, PP).

After blood collection, the neck was dislocated at the base of the skull and the brain was harvested and weighed. Brain weights were recorded and brains were frozen on dry ice on 24-well plates.

Plasma and brain samples were stored at −80° C. on dry ice until sent for analysis.

test 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 (−)-α-DHTBZ 2.5 mg/kg (t=0 min) and amphetamine (t=30 min) Group 4: Risperidone 1 mg/kg (t= 0 min) and 10 rats treated with amphetamine (t=30 min)

Results 1. Distance Traveled Rats dosed with either vehicle, (−)-α-DHTBZ 2.5 mg/kg or risperidone 1 mg/kg were subjected to the LMA test for the first 30 minutes and then 60 minutes after vehicle or amphetamine challenge. . Locomotor activity obtained was evaluated in 3-minute bins as a total over the test period. The normalized total distance traveled over the test time is shown in FIG.

Vehicle-amphetamine and (−)-α-DHTBZ 2.5 mg/kg were significantly different when compared to the vehicle-vehicle group. Vehicle-vehicle and risperidone 1 mg/kg were significantly different when compared to the vehicle-amphetamine group.

2. Stereotypic Behavior Rats dosed with either vehicle, (−)-α-DHTBZ 2.5 mg/kg or risperidone 1 mg/kg were subjected to the LMA test for an initial 30 minutes and then 60 minutes after vehicle or amphetamine challenge. bottom. Stereotypic behavior obtained was assessed in 3-minute bins and as a total over the test period. Normalized total stereotypic behavior over test time is shown in FIG.

Vehicle-amphetamine and (−)-α-DHTBZ 2.5 mg/kg were significantly different when compared to the vehicle-vehicle group. Vehicle-vehicle and risperidone 1 mg/kg were significantly different when compared to the vehicle-amphetamine group.

Conclusions This study evaluated the effects of (−)-α-DHTBZ at a dose of 2.5 mg/kg and risperidone at a dose of 1 mg/kg on amphetamine-induced locomotion in male CD rats.

A dose of 2.5 mg/kg (−)-α-DHTBZ did not result in decreased locomotor activity or decreased stereotypies when compared to the vehicle-amphetamine group. Rats given (−)-α-DHTBZ at a dose of 2.5 mg/kg were less concerned with what was going on around them. Rats administered (−)-α-DHTBZ were equally active when compared to animals administered vehicle-amphetamine, indicating that (−)-α-DHTBZ has a sedative effect similar to risperidone. suggested not to.

test 2
After administration of (+)-α-dihydrotetrabenazine at 0.1 mg/kg to 0.25 mg/kg and risperidone at 1 mg/kg to rats, effects on stereotypic behavior and movement distance were investigated.

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 (+)-α-DHTBZ 0.1 mg/kg (t=0 min) and amphetamine (t=30 min) Group 4: (+)-α-DHTBZ 10 rats treated with 0.25 mg/kg (t=0 min) and amphetamine (t=30 min) Group 5: treated with risperidone 1 mg/kg (t=0 min) and amphetamine (t=30 min) 10 rats with

Results 1 Distance Traveled Rats dosed with either vehicle, (+)-α-DHTBZ 0.1 mg/kg, (+)-α-DHTBZ 0.25 mg/kg, or risperidone 1 mg/kg were treated with vehicle or amphetamine challenge. After that, the LMA test was performed first for 30 minutes and then for 60 minutes. Locomotor activity obtained was evaluated in 3-minute bins as a total over the test period. The normalized total distance traveled over the test time is shown in FIG.

Vehicle-vehicle, (+)-α-DHTBZ 0.25 mg/kg and risperidone 1 mg/kg were significantly different when compared to the vehicle-amphetamine group.

2 Stereotypic Behavior Rats dosed with either vehicle, (+)-α-DHTBZ 0.1 mg/kg, (+)-α-DHTBZ 0.25 mg/kg, or risperidone 1 mg/kg were challenged with vehicle or amphetamine. After that, the LMA test was performed first for 30 minutes and then for 60 minutes. Stereotypic behavior obtained was assessed in 3-minute bins and as a total over the test period. Total stereotypic behavior normalized over test time is shown in FIG.

Vehicle-vehicle, (+)-α-DHTBZ 0.1 mg/kg, (+)-α-DHTBZ 0.25 mg/kg and risperidone 1 mg/kg were significantly different when compared to the vehicle-amphetamine group.

Conclusions This study evaluated the effects of 0.1 mg/kg and 0.25 mg/kg doses of (+)-α-DHTBZ and 1 mg/kg dose of risperidone on amphetamine-induced locomotion in male CD rats.

(+)-α-DHTBZ 0.25 mg/kg and risperidone 1 mg/kg produced lower locomotor activity when compared to the vehicle-amphetamine group. Both (+)-α-DHTBZ and 1 mg/kg risperidone at the tested doses produced decreased stereotypies when compared to the vehicle-amphetamine group.

test 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 (+)-α-DHTBZ 2 mg/kg (t=0 min) and amphetamine (t=30 min) Group 4: (+)-α-DHTBZ 2 mg/kg 10 rats treated with (−)-α-DHTBZ 2 mg/kg (t=0 min) and amphetamine (t=30 min) at kg Group 5: Risperidone 1 mg/kg (t=0 min) and amphetamine (t = 30 min) 10 rats treated with

Outcome 1 Distance Traveled Vehicle, combination of (+)-α-DHTBZ 2 mg/kg, (−)-α-DHTBZ 2 mg/kg and (+)-α-DHTBZ 2 mg/kg or risperidone 1 mg/kg administered The LMA test was performed on rats that were tested for 30 minutes first and then 60 minutes after vehicle or amphetamine challenge. Locomotor activity obtained was evaluated in 3-minute bins as a total over the test period. The normalized total distance traveled over the test time is shown in FIG.

Vehicle-amphetamine was significantly different when compared to the vehicle-vehicle group. Vehicle-vehicle, (+)-α-DHTBZ 2 mg/kg, combination of (−)-α-DHTBZ 2 mg/kg and (+)-α-DHTBZ 2 mg/kg and risperidone 1 mg compared to vehicle-amphetamine group /kg combination was significantly different.

2 Stereotypic Behavior Vehicle, (+)-α-DHTBZ 2 mg/kg, (−)-α-DHTBZ 2 mg/kg combined with (+)-α-DHTBZ 2 mg/kg or risperidone 1 mg/kg The LMA test was performed on rats that were tested for 30 minutes first and then 60 minutes after vehicle or amphetamine challenge. Stereotypic behavior obtained was assessed in 3-minute bins as a total over the test period. Total stereotypic behavior normalized over test time is shown in FIG.

Vehicle-vehicle, (+)-α-DHTBZ 2 mg/kg, combination of (−)-α-DHTBZ 2 mg/kg and (+)-α-DHTBZ 2 mg/kg, and risperidone compared to vehicle-amphetamine group 1 mg/kg was significantly different.

Conclusions In this study, the compounds (+)-α-DHTBZ at a dose of 2 mg/kg, (+)-α-DHTBZ and (-) -α-DHTBZ combination and the effects of risperidone at a dose of 1 mg/kg were evaluated.

A test dose of (+)-α-DHTBZ, a combination of (+)-α-DHTBZ and (−)-α-DHTBZ at a dose of 2 mg/kg, and risperidone 1 mg/kg compared to the vehicle-amphetamine group , resulted in lower locomotor activity. A test dose of (+)-α-DHTBZ, a combination of (+)-α-DHTBZ and (−)-α-DHTBZ at a dose of 2 mg/kg, and risperidone 1 mg/kg compared to the vehicle-amphetamine group , resulted in a decrease in stereotypic behavior.

Although the (−)-α-isomer has been shown to reduce the decrease in locomotor activity induced very little, if at all, amphetamine-induced locomotor activity is associated with (+) Rats treated with a combination of -α-DHTBZ and (−)-α-DHTBZ had less than rats treated with (+)-α-DHTBZ alone.

test 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: A group of 10 rats treated with (+)-α-DHTBZ 0.5 mg/kg (t=0 min) and (−)-α-DHTBZ 0.5 mg/kg and amphetamine (t=30 min) 4: Group 5 of 10 rats treated with (+)-α-DHTBZ 1.0 mg/kg (t=0 min) and (-)-α-DHTBZ 0.5 mg/kg and amphetamine (t=30 min) : Group 6 of 10 rats treated with (+)-α-DHTBZ 1.0 mg/kg (t=0 min) and (−)-α-DHTBZ 1.0 mg/kg and amphetamine (t=30 min): 10 rats treated with (+)-α-DHTBZ 1.5 mg/kg (t=0 min) and (−)-α-DHTBZ 1.0 mg/kg and amphetamine (t=30 min)

Results 1 Distance Traveled Vehicle, combination of (+)-α-DHTBZ 0.5 mg/kg and (−)-α-DHTBZ 0.5 mg/kg, (+)-α-DHTBZ 1 mg/kg and (−)-α -DHTBZ 0.5 mg/kg, (+)-α-DHTBZ 1 mg/kg and (−)-α-DHTBZ 1 mg/kg, or (+)-α-DHTBZ 1.5 mg/kg and (−)-α-DHTBZ 1 mg/kg )-α-DHTBZ 1 mg/kg combination, the LMA test was performed first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Locomotor activity obtained was evaluated in 3-minute bins as a total over the test period. The normalized total distance traveled over the test time is shown in FIG.

Vehicle-vehicle, (+)-α-DHTBZ, combination of (+)-α-DHTBZ 0.5 mg/kg and (-)-α-DHTBZ 0.5 mg/kg compared to vehicle-amphetamine group, ( +)-α-DHTBZ 1 mg/kg and (−)-α-DHTBZ 0.5 mg/kg, (+)-α-DHTBZ 1 mg/kg and (−)-α-DHTBZ 1 mg/kg and ( The combination of +)-α-DHTBZ 1.5 mg/kg and (-)-α-DHTBZ 1 mg/kg was significantly different.

2 Stereotypic behavior Vehicle, combination of (+)-α-DHTBZ 0.5 mg/kg and (−)-α-DHTBZ 0.5 mg/kg, (+)-α-DHTBZ 1 mg/kg and (−)-α -DHTBZ 0.5 mg/kg, (+)-α-DHTBZ 1 mg/kg and (−)-α-DHTBZ 1 mg/kg, or (+)-α-DHTBZ 1.5 mg/kg and (−)-α-DHTBZ 1 mg/kg )-α-DHTBZ 1 mg/kg combination underwent the LMA test first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Stereotypic behavior obtained was assessed in 3-minute bins and as a total over the test period. Normalized total stereotypic behavior over test time is shown in FIG.

The combination of (+)-α-DHTBZ 1 mg/kg and (−)-α-DHTBZ 0.5 mg/kg was significantly different when compared to the vehicle-vehicle group. Vehicle-vehicle, a combination of (+)-α-DHTBZ 0.5 mg/kg and (−)-α-DHTBZ 0.5 mg/kg, (+)-α-DHTBZ 1 mg/kg compared to the vehicle-amphetamine group. kg with (−)-α-DHTBZ 0.5 mg/kg, (+)-α-DHTBZ 1 mg/kg with (−)-α-DHTBZ 1 mg/kg, and (+)-α-DHTBZ 1 The combination of .5 mg/kg and (−)-α-DHTBZ 1 mg/kg was significantly different.

Conclusions In this study, 0.5 mg/kg + 0.5 mg/kg, 1 mg/kg + 0.5 mg of (+)-α-DHTBZ and (−)-α-DHTBZ on amphetamine-induced locomotion in male CD rats /kg, 1 mg/kg + 1 mg/kg and 1.5 mg/kg + 1 mg/kg dose combinations were evaluated.

The combination of (+)-α-DHTBZ and (−)-α-DHTBZ and risperidone 1 mg/kg in all tested combinations resulted in lower locomotor activity when compared to the vehicle-amphetamine group. The combination of (+)-α-DHTBZ and (−)-α-DHTBZ at all doses tested and risperidone 1 mg/kg resulted in decreased stereotypies when compared to the vehicle-amphetamine group.

There is an interaction between (+)-α-DHTBZ and (−)-α-DHTBZ that appears to affect the ability of (+)-α-DHTBZ to block amphetamine-induced hyperactivity .

(+)-α-DHTBZ at 1 mg/kg and (-)-α-DHTBZ at 0.5 mg/kg in combination with rats administered with (+)-α-DHTBZ at 1 mg/kg and A comparison of data from rats dosed with the 1 mg/kg combination of -DHTBZ demonstrated a lack of efficacy of the isolated (-)-α isomer, suggesting the use of the (-)-α isomer in combination therapy. It would not have been expected that an increase in the amount of 100 mg would result in a decrease in locomotion in the test rats.

test 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-DHTBZ 2.5 mg/kg (t=0 min) and amphetamine (t=30 min) Group 4: (+)-β-DHTBZ 5 mg/kg ( Group 5 of 10 rats treated with (t = 0 min) and amphetamine (t = 30 min): (+)-β-DHTBZ 2.5 mg/kg and (+)-α-DHTBZ 2.5 mg/kg (t = 0 min) and 10 rats treated with amphetamine (t = 30 min)

Results 1 Distance Traveled Vehicle, (+)-β-DHTBZ 2.5 mg/kg, (+)-β-DHTBZ 5 mg/kg or (+)-β-DHTBZ 2.5 mg/kg and (+)-α-DHTBZ Rats dosed with either 2.5 mg/kg underwent the LMA test first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Locomotor activity obtained was evaluated in 3-minute bins as a total over the test period. The normalized total distance traveled over the test time is shown in FIG.

Vehicle-amphetamine, (+)-β-DHTBZ 2.5 mg/kg and (+)-β-DHTBZ 5 mg/kg when compared to the vehicle-vehicle group. Vehicle-vehicle, (+)-β-DHTBZ 2.5 mg/kg and (+)-α-DHTBZ 2.5 mg/kg, (+)-β-DHTBZ 2.5 mg/kg compared with the vehicle-amphetamine group. The combination of kg and (+)-β-DHTBZ 5 mg/kg was significantly different.

2 stereotypies Vehicle, (+)-β-DHTBZ 2.5 mg/kg, (+)-β-DHTBZ 5 mg/kg or (+)-β-DHTBZ 2.5 mg/kg and (+)-α-DHTBZ Rats dosed with either 2.5 mg/kg underwent the LMA test first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Stereotypic behavior obtained was assessed in 3-minute bins as a total over the test period. Total stereotypic behavior normalized over test time is shown in FIG.

Vehicle-amphetamine, (+)-β-DHTBZ 2.5 mg/kg and (+)-β-DHTBZ 5 mg/kg were significantly different when compared to the vehicle-vehicle group. Vehicle-amphetamine group, (+)-β-DHTBZ 2.5 mg/kg and (+)-α-DHTBZ 2.5 mg/kg, (+)-β-DHTBZ 2.5 mg/kg when compared with vehicle-vehicle The combination of kg and (+)-β-DHTBZ 5 mg/kg was significantly different.

test 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 (+)-α-DHTBZ 1 mg/kg (t = 0 min) and amphetamine (t = 30 min) Group 4: (+)-α-DHTBZ 1 mg/kg + (-) -α-DHTBZ 1 mg/kg (t=0 min); and amphetamine (t=30 min) treated with 10 rats Group 5: (+)-α-DHTBZ 1 mg/kg + (−)-β-DHTBZ 1 mg /kg (t = 0 min and t = 30 min) Group 6 of 10 rats treated with amphetamine: (+)-β-DHTBZ 1 mg/kg + (−)-α-DHTBZ 1 mg/kg (t = 0 min) ) and amphetamine (t = 30 min) Group 7 of 10 rats: (+)-β-DHTBZ 1 mg/kg + (−)-β-DHTBZ 1 mg/kg (t = 0 min); Group 8 of 10 rats treated with (+)-α-DHTBZ 1 mg/kg + (+)-β-DHTBZ 1 mg/kg (t = 0 min); Group 9 of 10 treated rats: 10 rats treated with risperidone 1 mg/kg (t=0 min) and amphetamine (t=30 min)

Results 1 Distance Traveled Rats dosed with either vehicle or dihydrotetrabenazine were subjected to the LMA test initially for 30 min and then 60 min after vehicle or amphetamine challenge. Locomotor activity obtained was evaluated in 3-minute bins as a total over the test period. The total unnormalized distance traveled over the test time is shown in FIG.

Vehicle-amphetamine, (+)-β-DHTBZ 1 mg/kg + (−)-α-DHTBZ 1 mg/kg and (+)-β-DHTBZ 1 mg/kg + (−)-β- when compared to vehicle-vehicle group The DHTBZ 1 mg/kg group was significantly different. Vehicle-to-vehicle was significantly different for all groups 1 and 3-9 when compared to the vehicle-amphetamine group.

2 Stereotypic Behavior Rats dosed with either vehicle or dihydroterabenazine were subjected to the LMA test first for 30 minutes and then for 60 minutes after vehicle or amphetamine challenge. Stereotypic behavior obtained was assessed in 3-minute bins as a total over the test period. Total unnormalized stereotypic behavior over test time is shown in FIG.

Vehicle-amphetamine, (+)-β-DHTBZ 1 mg/kg + (−)-α-DHTBZ 1 mg/kg and (+)-β-DHTBZ 1 mg/kg + (−)-β- when compared to vehicle-vehicle group The DHTBZ 1 mg/kg group was significantly different. Vehicle-to-vehicle was significantly different for all groups 1 and 3-9 when compared to the vehicle-amphetamine group.

Comment Study 1 evaluated the effects of (−)-α-DHTBZ at a dose of 2.5 mg/kg and risperidone at a dose of 1 mg/kg on amphetamine-induced locomotion in male CD rats.

Administration of (−)-α-DHTBZ at a dose of 2.5 mg/kg did not result in decreased locomotor activity or decreased stereotypies when compared to the vehicle-amphetamine group. Rats given (−)-α-DHTBZ at a dose of 2.5 mg/kg were less concerned with what was going on in their surroundings. Rats given (−)-α-DHTBZ were equally active when compared to animals given vehicle-amphetamine, indicating that (−)-α-DHTBZ had similar behavioral effects to risperidone. suggests that it does not have

Study 2 evaluated the effects of (+)-α-DHTBZ 0.1 mg/kg and 0.25 mg/kg and risperidone 1 mg/kg on amphetamine-induced locomotor activity in male CD rats.

(+)-α-DHTBZ at 0.25 mg/kg and risperidone 1 mg/kg produced lower locomotor activity when compared to the vehicle-amphetamine group. (+)-α-DHTBZ and 1 mg/kg risperidone at both doses tested produced decreased stereotypies when compared to the vehicle-amphetamine group.

In Study 3, a dose of 2 mg/kg of (+)-α-DHTBZ, a dose of 2 mg/kg of the combination of (+)-α-DHTBZ and (−)-α-DHTBZ, and a dose of 1 mg/kg of risperidone on amphetamine-induced locomotor activity in male CD rats.

(+)-α-DHTBZ at all doses tested, (+)-α-DHTBZ in combination with (−)-α-DHTBZ at a dose of 2 mg/kg, risperidone at a dose of 1 mg/kg, vehicle- Locomotor activity decreased compared to the amphetamine group. (+)-α-DHTBZ at all doses tested, (+)-α-DHTBZ in combination with (−)-α-DHTBZ at a dose of 2 mg/kg, risperidone at a dose of 1 mg/kg, vehicle- Resulting in reduced stereotypies when compared to the amphetamine group.

(-)-α-isomer causes little, if any, reduction in locomotor activity induced in rats treated with a combination of (+)-α-DHTBZ and (−)-α-DHTBZ showed less amphetamine-induced locomotion than rats treated with (+)-α-DHTBZ alone.

(+)-α-DHTBZ and (−)-α-DHTBZ at 0.5 mg/kg + 0.5 mg/kg, 1 mg/kg + 0.5 mg/kg, 1 mg/kg + 1 mg/kg and 1 The effects of the combination at doses of .5 mg/kg plus 1 mg/kg on amphetamine-induced locomotor activity in male CD rats were evaluated.

The combination of (+)-α-DHTBZ and (−)-α-DHTBZ and risperidone 1 mg/kg in all tested combinations resulted in lower locomotor activity when compared to the vehicle-amphetamine group. The combination of (+)-α-DHTBZ and (−)-α-DHTBZ and risperidone 1 mg/kg at all doses tested resulted in decreased stereotypies when compared to the vehicle-amphetamine group.

Rats given a combination of (+)-α-DHTBZ at a dose of 1 mg/kg and (−)-α-DHTBZ at a dose of 0.5 mg/kg and (+)-α-DHTBZ at a dose of 1 mg/kg Considering the lack of efficiency of the isolated (-)-α isomer was demonstrated when comparing the data for rats administered a combination of DHTBZ and (−)-α-DHTBZ at a dose of 1 mg/kg. It was surprising, then, that increasing amounts of the (-)-α isomer in combination therapy resulted in decreased locomotor activity in the rats tested.

In study 5, (+)-β-DHTBZ 2.5 mg/kg and 5 mg/kg doses and (+)-α-DHTBZ 2.5 mg/kg doses and (+) on amphetamine-induced locomotor activity in male CD rats -β-DHTBZ 2.5 mg/kg dose combination effect was evaluated.

(+)-β-DHTBZ 2.5 mg/kg, (+)-β-DHTBZ 5 mg/kg, and (+)-α-DHTBZ 2.5 mg/kg and (+)-β-DHTBZ 2.5 mg/kg combination reduced locomotor activity when compared to the vehicle-amphetamine group. (+)-β-DHTBZ 2.5 mg/kg, (+)-β-DHTBZ 5 mg/kg, and (+)-α-DHTBZ 2.5 mg/kg and (+)-β-DHTBZ 2.5 mg/kg also resulted in decreased stereotypies when compared to the vehicle-amphetamine group. Rats given (+)-β-DHTBZ at a dose of 5 mg/kg were less concerned with what was going on around them, and rats receiving (+)-β-DHTBZ 5 mg/kg were observed to have tense extremities and partially lacked their righting reflex at the end of the trial.

In Study 6, (+)-α-DHTBZ 1 mg/kg dose, (+)-α-DHTBZ 1 mg/kg dose + (−)-α-DHTBZ 1 mg/kg dose combination, (+)-α-DHTBZ 1 mg /kg dose + (-)-β-DHTBZ 1 mg/kg dose combination, (+)-β-DHTBZ 1 mg/kg dose + (-)-α-DHTBZ 1 mg/kg dose combination, (+)-β- DHTBZ 1 mg/kg dose + (−)-β-DHTBZ 1 mg/kg dose combination, (+)-α-DHTBZ 1 mg/kg dose + (+)-β-DHTBZ 1 mg/kg dose combination, and Risperidone 1 mg/kg The effect of kg doses on amphetamine-induced locomotion in male CD rats was evaluated.

Vehicle, risperidone and all dihydrotetrabenazine containing resulted in lower locomotor activity and decreased stereotypic behavior when compared to the vehicle-amphetamine group.

Results from six trials suggest that the combination of (+)-β-dihydrotetrabenazine, (−)-α-dihydrotetrabenazine and (+)-α-dihydrotetrabenazine may be effective in treating movement disorders. Indicates that it is useful.

Equivalents It will be readily apparent that numerous modifications and variations may be made to the specific embodiments of the invention described above without departing from the underlying principles of the invention. All such modifications and variations are intended to be covered by this application.

Claims (37)

(a) (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, and (b) (−)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, and (c) ) (+)-α-dihydrotetrabenazine or a pharmaceutical combination comprising either or both of a pharmaceutically acceptable salt thereof. (a) (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof; and (b) (−)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof. Item 1. A pharmaceutical combination according to item 1. (a) (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof; and (c) (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof. Item 1. A pharmaceutical combination according to item 1. (a) (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof;
(b) (-)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof; and (c) (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof. Item 1. A pharmaceutical combination according to item 1. 35 to 75 parts by weight of (+)-β-dihydrotetrabenazine and 25 to 55 parts by weight of (+)-α-dihydrotetrabenazine or (−)-α-dihydrotetrabenazine or their A pharmaceutical combination according to any one of claims 1 to 4, comprising a mixture of α-dihydrotetrabenazines. (a) 40 to 65 parts by weight of (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, and (c) 40 to 65 parts by weight of (+)-α-dihydrotetrabenazine or 6. A pharmaceutical combination according to claim 5, comprising a pharmaceutically acceptable salt thereof. (a) 45 to 55 parts by weight of (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, and (c) 45 to 55 parts by weight of (+)-α-dihydrotetrabenazine or 7. A pharmaceutical combination according to claim 6, comprising a pharmaceutically acceptable salt thereof. (a) 45-65 parts by weight of (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof;
(b) 30-50 parts by weight of (-)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, and optionally,
7. A pharmaceutical combination according to claim 6, comprising (c) 0.1-5 parts by weight of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof. A pharmaceutical combination according to any one of claims 1 to 8 for use in medicine. A pharmaceutical unit dosage form comprising a pharmaceutically acceptable excipient and a pharmaceutical combination according to any one of claims 1-9. A pharmaceutical unit according to claim 10, wherein the total amount of (+)-β-dihydrotetrabenazine, (−)-α-dihydrotetrabenazine and (+)-α-dihydrotetrabenazine does not exceed 100 mg. dosage form. 12. A pharmaceutical unit dosage form according to claim 10 or 11 selected from (i) solid dosage forms such as capsules and tablets and (ii) liquid dosage forms such as solutions, syrups, suspensions and gels. 10. A method according to any one of claims 1 to 9 for use in the treatment of hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesias, dystonias and Tourette's syndrome. A pharmaceutical combination according to any one of claims 10-12 or a pharmaceutical unit dosage form according to any one of claims 10-12. 14. Use according to claim 13, wherein said use comprises administering to a subject an amount of said pharmaceutical combination or unit dosage form sufficient to cause a blocking level of VMAT2 protein in 20% to 90% of subjects. A pharmaceutical combination or unit dosage form for Pharmaceutical unit dosage containing a combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient shape. A combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in medicine. A combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in treating movement disorders or according to claim 15 pharmaceutical unit dosage form. A combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in a method of treating movement disorders, said method administering an effective therapeutic amount of the combination sufficient to provide a dosage of 1 mg to 20 mg of (+)-α-dihydrotetrabenazine per day to a subject (e.g., a human subject) in need thereof Any combination of the above, including A combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of movement disorders , 0.01 mg/kg to 0.3 mg/kg per day ( for example, between 0.01 mg/kg and 0.3 mg/kg). 20. Any one of claims 17-19, wherein the movement disorder is a hyperkinetic movement disorder selected from Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesias, dystonia and Tourette's syndrome. A combination for the uses described in . 21. The combination for use according to claim 20, wherein said movement disorder is Tourette's Syndrome. A combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of movement disorders , the above combination, wherein treatment comprises administering to the subject an amount of the combination sufficient to cause a block level of VMAT2 protein of 20% to 90% in the subject. 16. A pharmaceutical unit dosage form according to claim 15, wherein the combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine is not associated with any other isomer of dihydrotetrabenazine. Or a combination for use according to any one of claims 16-22. A pharmaceutical unit dosage form according to claim 15 or any one of claims 16 to 23, wherein the combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine is a racemic mixture. A combination for the uses described in . A pharmaceutical unit dosage form according to claim 15 or claims 16-23, wherein the combination of (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine is a scalemic mixture. A combination for use according to any one of A unit dosage form comprising (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein (+)-β-dihydrotetrabenazine with up to 20% by weight of any other dihydrotetrabenazine isomer relative to (+)-β-dihydrotetrabenazine. 27. The unit dosage form of claim 26, wherein the (+)-[beta]-dihydrotetrabenazine is associated with 1% or less of any other dihydrotetrabenazine isomer. Claim 26, comprising 1 mg to 200 mg (eg, between 1 mg and 200 mg) of (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. or the unit dosage form according to 27. (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. shape. A unit dosage form according to any one of claims 26 to 29 for use in the treatment of hyperkinetic movement disorder. (+)-β-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof for use in the treatment of hyperkinetic movement disorder. (+)-β-dihydrotetrabenazine for use in a method for the treatment of movement disorders, wherein the treatment comprises (+ (+)-β-dihydrotetrabenazine, comprising administering )-β-dihydrotetrabenazine to a subject. (+)-β-dihydrotetrabenazine for use in a method for the treatment of movement disorders, wherein said treatment is between 1 mg/kg and 10 mg/kg per day (e.g., 1 mg/kg and 10 mg/kg (+)-β-dihydrotetrabenazine, comprising administering to the subject an amount of (+)-β-dihydrotetrabenazine between ). (+)-β-dihydrotetrabenazine for use in a method for the treatment of movement disorders, wherein said treatment is sufficient to cause a level of blockade of VMAT2 protein of 20% to 90% in a subject amount of (+)-β-dihydrotetrabenazine to the subject. (+)-β-dihydrotetrabenazine for use according to any one of claims 31 to 34, wherein the (+)-β-dihydrotetrabenazine typically has an isomeric purity of at least 80%. Benazine. 31. A unit dosage form for use according to claim 30, wherein the hyperkinetic movement disorder is selected from Huntington's disease, hemiballismus, chorea, tic disorders, tardive dyskinesias, dystonia and Tourette's syndrome or (+)-β-Dihydrotetrabenazine for use according to claims 31-34. (+)-β-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for use in medicine.

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