阅读说明：本技术 (+)-α-二氢丁苯那嗪在治疗运动障碍中的用途 (Use of (+) -alpha-dihydrotetrabenazine for the treatment of movement disorders ) 是由 安德鲁·约翰·达菲尔德 阿南特·潘迪亚 于 2018-03-29 设计创作，主要内容包括：本发明涉及低剂量的(+)-α-二氢丁苯那嗪在治疗运动障碍,如图雷特综合征中的用途。本发明提供了(+)-α-二氢丁苯那嗪或其药学上可接受的盐在治疗有需要的受试者的运动障碍的方法中的用途,所述方法包括给予所述受试者初始日剂量的(+)-α-二氢丁苯那嗪或其药学上可接受的盐步骤,其中所述初始日剂量是与0.5mg至5mg的(+)-α-二氢丁苯那嗪游离碱相对应的(+)-α-二氢丁苯那嗪或其药学上可接受的盐的量,对所述受试者进行临床评价,保持所述初始日剂量,增加或减少所述剂量,或者停止所述治疗。所述方法旨在达到最佳日剂量。(The present invention relates to the use of low doses of (+) - α -dihydrotetrabenazine in the treatment of movement disorders, such as tourette's syndrome. The present invention provides the use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, in a method of treating a movement disorder in a subject in need thereof, the method comprising the step of administering to the subject an initial daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, wherein the initial daily dose is the amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg to 5mg of (+) - α -dihydrotetrabenazine free base, clinically evaluating the subject, maintaining the initial daily dose, increasing or decreasing the dose, or stopping the treatment. The method aims at achieving an optimal daily dose.)

Use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, in a method of treating a movement disorder in a subject in need thereof, the method comprising the steps of:

(a) administering to the subject an initial daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, wherein the initial daily dose is an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, that corresponds to 0.5mg to 5mg of (+) - α -dihydrotetrabenazine free base;

(b) performing a clinical evaluation of the subject to understand the efficacy and side effects of the treatment;

(c) when said clinical assessment (b) has determined that an increased daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is required, administering an increased daily dose that is greater than said initial daily dose by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg to 5mg of (+) - α -dihydrotetrabenazine free base; or, when said clinical assessment (b) has determined that an increase in daily dose is not required, maintaining said initial daily dose, decreasing said dose, or discontinuing said treatment;

(d) (ii) when an increasing daily dose has been administered, performing a further clinical evaluation of the subject to understand the efficacy and side effects of the treatment with the increasing daily dose;

(e) administering a further increased daily dose, which is greater than the daily dose of the preceding day, by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg to 5mg of (+) - α -dihydrotetrabenazine free base, when said further clinical assessment (d) has determined that a further increased daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is required; or, when said clinical assessment has determined that no further increase in daily dose is required, maintaining said daily dose on the previous day, decreasing said daily dose on the previous day or discontinuing said treatment; and

(f) optionally repeating steps (d) and (e) as necessary until an optimal daily dose is reached.

2. The use of (+) - α -dihydrotetrabenazine according to claim 1, wherein the initial daily dose is an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg to 3mg of (+) - α -dihydrotetrabenazine free base.

3. The use of (+) - α -dihydrotetrabenazine according to claim 2, wherein the initial daily dose is an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg, 1mg, 1.5mg or 2mg of (+) - α -dihydrotetrabenazine free base.

4. The use according to any one of claims 1 to 3 for the use of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, wherein the increased daily dose in step (c) is increased by an amount of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to 0.5mg to 3mg of (+) - α -dihydrotetrabenazine free base compared to the initial daily dose.

5. The (+) - α -dihydrotetrabenazine according to claim 4 or a pharmaceutically acceptable salt thereof, wherein the increased daily dose in step (c) is increased by an amount of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to 0.5mg, 1mg, 1.5mg or 2mg of (+) - α -dihydrotetrabenazine free base compared to the initial daily dose.

6. The use of (+) - α -dihydrotetrabenazine according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the further increased daily dose in step (e) is increased by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg to 3mg of (+) - α -dihydrotetrabenazine free base, as compared to the daily dose on the preceding day.

7. The use of (+) - α -dihydrotetrabenazine according to claim 6, wherein the further increased daily dose in step (e) is increased by an amount of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to 0.5mg, 1mg, 1.5mg or 2mg of (+) - α -dihydrotetrabenazine free base, as compared to the daily dose of the preceding day.

8. The use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1 to 7, wherein said treatment comprises said administration of a maximum (e.g. optimized) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to no more than 20mg of (+) - α -dihydrotetrabenazine free base.

9. The use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, as claimed in claim 8, wherein said treatment comprises said administration of a maximum (e.g. optimized) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to no more than 10mg of (+) - α -dihydrotetrabenazine free base.

10. The use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, wherein the treatment comprises determining the approximate weight of the subject and:

(i) administering a maximum (e.g. optimized) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to between 2mg and 7.5mg (+) - α -dihydrotetrabenazine free base when the subject weighs between 30kg and 50 kg;

(ii) administering a maximum (e.g. optimized) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, when the subject weighs between 50kg and 75kg, said dose corresponding to between 5mg and 10mg of (+) - α -dihydrotetrabenazine free base;

(iii) administering a maximum (e.g., optimized) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, when the subject weighs between 75kg and 95kg, said dose corresponding to between 7.5mg and 15mg of (+) - α -dihydrotetrabenazine free base; or

(iv) Administering a maximum (e.g. optimized) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to between 15mg and 20mg of (+) - α -dihydrotetrabenazine free base, when the subject weighs more than 95kg, the amount of (+) - α -dihydrotetrabenazine administered per day being between 15mg and 20 mg.

Use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, in a method of treating a movement disorder in a subject in need thereof, the treatment comprising administering to the subject an effective amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, wherein the effective amount corresponds to an amount of (+) - α -dihydrotetrabenazine free base of 0.05mg/kg to 0.3mg/kg per day.

12. The use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, wherein the daily dose, daily amount, or effective amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, administered to the subject is sufficient to produce 50% to 85% blockade of VMAT2 protein in the subject.

13. The use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, as claimed in claim 12, wherein the daily dose, daily amount, or effective amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, administered to the subject is sufficient to produce between 50% and 85% blockade of VMAT2 protein in the subject.

14. The use of (+) - α -dihydrotetrabenazine according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein the movement disorders are selected from the group consisting of tardive dyskinesia, tourette syndrome and huntington's disease.

15. The use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, as claimed in claim 14, wherein the movement disorder is tourette's syndrome.

16. The use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, as claimed in claim 14, wherein the movement disorder is huntington's disease.

17. The use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 16, wherein the (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily.

18. The use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1 to 17, wherein the (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is not administered in combination with a therapeutically effective amount of amantadine.

19. The use of (+) - α -dihydrotetrabenazine according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein the subject is a human subject aged 5 to 16 years who weighs 80kg or less, such as weighs in the range of 17 to 70 kg.

20. A unit dosage form comprising from 0.5mg to 3mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in a method as defined in any one of claims 1 to 19.

22. The invention as defined in any one of embodiments 1.1 to 1.175 herein.

Technical Field

The present invention relates to the use of low doses of (+) - α -dihydrotetrabenazine in the treatment of movement disorders, such as Tourette's syndrome.

Background

Dyskinesias generally fall into two categories: hyperkinetic dyskinesia and hypokinetic dyskinesia. Hyperkinetic movement disorders are caused by increased muscle activity and can cause abnormal and/or excessive movement, including tremors, dystonia, chorea, tics, myoclonus, and behavioral nodules.

Hyperkinetic dyskinesias are usually psychogenic and are caused by inappropriate regulation of amine neurotransmitters in the basal ganglia.

Tourette's syndrome is a specific hyperkinetic movement disorder, a hereditary neurological disorder characterized by a variety of physiological and vocal tics. Tics are usually repetitive, but also random, being body movements or vocal twitches. Vocal tics may take a variety of forms, including repeating one's own voice, another's voice, or other sounds. The onset usually occurs in childhood and continues to puberty and adulthood.

Although able to temporarily suppress tourette's syndrome-associated tics, affected persons typically suppress tics for only a limited period of time. There is currently no effective treatment covering all types of tics in all patients, but some agents have been developed to suppress tics.

Dopamine receptor antagonists are known to have a tic-suppressing effect on patients with tourette's syndrome, and there are currently a number of dopamine receptor antagonists used to suppress tourette's syndrome tics, such as fluphenazine, risperidone, haloperidol, and pimozide.

Type 2 vesicular monoamine transporters (VMAT2) are membrane proteins that transport monoamine neurotransmitters (e.g., dopamine, 5-hydroxytryptamine, and histamine) from the cytosol to synaptic vesicles. Inhibition of this protein can block the release of dopamine from presynaptic neurons, leading to depletion of dopamine levels in the brain.

VMAT2 inhibitors may be used to treat symptoms of tourette's syndrome.

Tetrabenazine (chemical name: 1,3,4,6,7,11 b-hexahydro-9, 10-dimethoxy-3- (2-methylpropyl) -2H-benzo (α) quinolizin-2-one) was used as a drug since the end of the 50 s of the 20 th century. Originally used as antipsychotic drugs, tetrabenazine is currently used in the treatment of hyperkinetic movement disorders such as huntington's disease, hemitoses, senile chorea, tics, tardive dyskinesia and tourette's syndrome, as detailed for example in Jankovic et al, am.j.psychiatry (1999) month 8; 156(8) 1279-1281 and Jankovic et al Neurology (1997) month 2; 48(2):358-62.

The main pharmacological effect of tetrabenazine is to reduce the supply of monoamines such as dopamine, 5-hydroxytryptamine and norepinephrine in the central nervous system by inhibiting the human vesicular monoamine transporter subtype 2(hVMAT 2). The drug is also capable of blocking postsynaptic dopamine receptors.

The central effects of tetrabenazine are quite similar to those of reserpine, but unlike reserpine tetrabenazine lacks activity at the VMAT1 transporter. The lack of VMAT1 transporter activity means that tetrabenazine has a peripheral activity lower than that of reserpine and therefore does not produce VMAT 1-related side effects such as hypotension.

Tetrabenazine is an effective and safe drug for the treatment of various hyperkinetic dyskinesias, and has not been found to cause tardive dyskinesia compared to typical antipsychotics. However, tetrabenazine does exhibit some dose-related side effects including causing depression, parkinson's disease, lethargy, stress or anxiety, insomnia and in rare cases antipsychotic malignancy, see for example the introductory part of WO2016/127133 (neuroendocrine biology).

The chemical structure of tetrabenazine is as follows.

This compound has chiral centers on the carbon atoms at the 3 and 11b positions, and therefore, theoretically coexists in four isomeric forms, as shown below.

The stereochemistry of each isomer is defined using the "R-S" nomenclature developed by Cahn, Ingold and Prelog, as described in Jerry March, advanced organic chemistry, 4 th edition, John Wiley and Sons, New York, 1992, page 109-. In this patent application, the designations "R" or "S" are listed in order of the position numbers of the carbon atoms. Thus, for example, RS is a shorthand notation for 3R,11 bS. Similarly, when three chiral centers are present, as in dihydrotetrabenazine described below, the designation "R" or "S" is listed in the order of carbon atoms 2, 3 and 11 b. Thus, the 2R,3S,11bS isomer is abbreviated as RSS, etc.

The commercial tetrabenazine is a racemic mixture of the RR and SS isomers, with RR and SS appearing to be the most stable thermodynamic isomers.

Tetrabenazine is poorly bioavailable and is highly variable. Tetrabenazine achieves extensive metabolism through first-pass metabolism, with little or no prototype tetrabenazine typically detected in urine. It is well known that at least some of the metabolites of tetrabenazine are dihydrotetrabenazine formed by reduction of the 2-keto group of tetrabenazine.

Dihydrotetrabenazines (chemical name: 2-hydroxy-3- (2-methylpropyl) -1,3,4,6,7,11 b-hexahydro-9, 10-dimethoxybenzo (a) quinolizine) have three chiral centers and can therefore exist as any of the following eight optical isomers:

sun et al describe the synthesis and characterization of eight dihydrotetrabenazine isomers (Eur.J.Med.chem. (2011), 1841-1848).

Of the eight dihydrotetrabenazine isomers, the four isomers are derived from the more stable RR and SS isomers of the parent tetrabenazine, i.e., the RRR, SSs, SRR, and RSS isomers.

The RRR and SSS isomers are commonly referred to as "alpha" dihydrotetrabenazine, and the RRR and SSS isomers are also referred to as (+) -alpha-dihydrotetrabenazine and (-) -alpha-dihydrotetrabenazine, respectively. The alpha isomer is characterized by the 2-and 3-hydroxy and 2-methylpropyl substituents in trans relative orientation-as detailed in, for example, Kilbourn et al, Chirality,9:59-62(1997) and Brossi et al, Helv.Chim.acta., vol.XLI, No.193, pp1793-1806 (1958).

The SRR and RSS isomers are commonly referred to as "beta" dihydrotetrabenazine, and the SRR and RSS isomers are also referred to as (+) -beta-dihydrotetrabenazine and (-) -beta-dihydrotetrabenazine, respectively. The beta isomer is characterized by a cis relative orientation of the hydroxyl groups at the 2-and 3-positions and the 2-methylpropyl substituent.

Although dihydrotetrabenazine is believed to be directly related to the activity of the drug, no published studies have been published to date, including evidence demonstrating which of the various stereoisomers of dihydrotetrabenazine is relevant to its biological activity. More specifically, no published studies have demonstrated which stereoisomers are associated with the ability of tetrabenazine to treat movement disorders (e.g. tourette's syndrome).

Schwartz et al, in rabbits, dogs and humans, studied the metabolism of tetrabenazine (biochem. Pharmacol (1996),15: 645-. Schwartz et al identified nine metabolites, five of which were unbound and four of which were bound to glucuronic acid. The five unbound metabolites are alpha-and beta-dihydrotetrabenazine, their two oxidized analogs (2-methylpropyl side chain to hydroxyl) and oxybutylazine (2-methylpropyl side chain to hydroxyl). The four combined metabolites were all 9-hydroxy compounds obtained by demethylation of 9-methoxy. The chirality of various metabolites has not been studied, and in particular the chirality of each of the α -and β -isomers has not been disclosed.

Scherman et al demonstrated the stereospecificity of the binding of the racemates alpha-and beta-dihydrotetrabenazine to VMAT2 (mol. pharmacol. (1987),33, 72-77). It is reported that in vitro studies, α -dihydrotetrabenazine has 3-4 times higher affinity for pheochromoid granule monoamine transporters than β -isomer. However, Scherman et al do not teach resolution testing of the individual enantiomers of alpha-and beta-dihydrotetrabenazine.

Mehvar et al reported studies of tetrabenazine or dihydrotetrabenazine concentration in rat brain following tetrabenazine or dihydrotetrabenazine administration (J.pharm.Sci. (1987),76(6), 461-. This study showed that dihydrotetrabenazine, although more polar, is able to cross the blood brain barrier. However, stereochemical studies of dihydrotetrabenazine have not been published.

Mehvar et al reported pharmacokinetic studies of tetrabenazine and dihydrotetrabenazine following tetrabenazine administration in four patients with tardive dyskinesia (Drug Metabolism and Disposition (1987),15:2, 250-. Oral administration of tetrabenazine results in low plasma concentrations of tetrabenazine but relatively high concentrations of dihydrotetrabenazine. However, the stereochemistry of dihydrotetrabenazine in vivo has not been reported.

Roberts et al describe pharmacokinetic studies of tetrabenazine and its hydroxy metabolites in patients treated with non-autonomic dyskinesias (Eur. J. Clin. Pharmacol. (1986),29: 703-708). Roberts et al reported that after oral administration, tetrabenazine is extensively metabolized, resulting in very low plasma concentrations of tetrabenazine, but very high concentrations of its hydroxy metabolites. Although the identity of the hydroxymetabolite is not described, they believe that high concentrations of the hydroxymetabolite in plasma may be therapeutically important (as the metabolite is known to be pharmacologically active) and, in combination with the Schwartz et al report (supra), the association of the cis-trans isomers (i.e., the β and α isomers) may be therapeutically more important than the parent drug.

The Michael Kilbourn team at the Michigan medical college published a series of studies on dihydrotetrabenazine isomers. Therefore, Kilbourn et al describe the use of (+/-) - α [11C ] -dihydrotetrabenazine as a live imaging agent for VMAT2 binding studies (Med. chem. Res. (1994),5: 113-.

Kilbourn et al performed competitive binding studies with [3H ] -tetrabenazine, investigating the in vitro tuberculosis affinity of (+) -, (-) -and (+/-) -alpha-DHTBZ (Eur. J. Pharmacol (1995)278, 249-252). Binding studies gave a Ki value of 0.97nM for (+) - α -dihydrotetrabenazine and 2.2 μ M for (-) - α -dihydrotetrabenazine, indicating a stronger binding affinity of the (+) - α isomer to the VMAT2 receptor than for the (-) α isomer. However, there has been no report or conclusion on the effect of these two isoforms in the treatment of movement disorders, such as Tourette's syndrome.

Kilbourn et al also determined the absolute configuration of (+) - α -dihydrotetrabenazine and concluded that it has the 2R,3R,11bR configuration shown above (Chirality (1997)9: 59-62). They also mention the above-mentioned articles published by Schwartz et al and Mehvar et al, which indicate that alpha-and beta-dihydrotetrabenazine may be pharmacologically active in the human brain, but they do not draw clear conclusions about the precise stereochemical properties of the active metabolites of tetrabenazine.

Kilbourn et al also proposed the use of (+) - α - [11C ] -dihydrotetrabenazine as a reagent for detecting specific in vivo binding of VMAT receptors in the "infusion balance" method (Synapse (2002),43: 188-. They found that (-) - α - [11C ] -dihydrotetrabenazine produced a homogeneous brain distribution, which is consistent with previous observations that this enantiomer has low VMAT affinity.

Sun et al (supra) studied the VMAT2 binding affinities of all eight dihydrotetrabenazine isomers. They found that all the dextrorotatory enantiomers showed greater binding activity of VMAT2 than the corresponding levorotatory enantiomer, with the (+) - α -isomer being most active. However, Sun et al did not investigate the relative efficacy of each isomer in treating dyskinesias (e.g., tourette's syndrome).

WO 2015/120110(Auspex) describes sustained release formulations which may include a variety of different pharmacological agents, including tetrabenazine and dihydrotetrabenazine. WO 2015/120110 discloses generally that the formulation may include 5mg to 30mg of tetrabenazine or dihydrotetrabenazine, more specifically a sustained release formulation including tetrabenazine or dihydrotetrabenazine in amounts of 7.5mg, 12.5mg, 15mg, 25mg, 30mg and 50 mg. However, no specific disclosure of a formulation containing (+) - α -dihydrotetrabenazine is provided.

Furthermore, there is no working example of dihydrotetrabenazine; only the formulation containing tetrabenazine.

WO 2006/053067(Prestwick) describes the use of amantadine and a tetrabenazine compound, which may be tetrabenazine or dihydrotetrabenazine, in combination to treat hyperkinetic movement disorders. WO 2006/053067 discloses that dihydrotetrabenazine may be administered in an amount of 10-400mg per day (although no examples are provided to demonstrate that low value doses of this range are still effective) and also describes a pharmaceutical composition containing only 10 mg. WO 2006/053067 does not specifically combine any specific isomer of dihydrotetrabenazine with these amounts and, more specifically, does not disclose the specific use of 10mg (+) - α -dihydrotetrabenazine. WO 2006/053067 provides no experimental data.

WO 2011/153157(Auspex pharmaceuticals) describes deuterated forms of dihydrotetrabenazine. This publication describes various deuterated forms of dihydrotetrabenazine, but provides only information that allows the synthesis of small amounts of the compound. Although it discloses racemic mixtures of d6- α -dihydrotetrabenazine and d6- β -dihydrotetrabenazine, these mixtures are not decomposed nor the properties of the respective (+) and (-) isomers have been investigated. Likewise, WO 2014/047167(Auspex pharmaceuticals) describes some deuterated forms of tetrabenazine and derivatives thereof. In addition, the respective (+) and (-) isomers of the deuterated forms of alpha-and beta-dihydrotetrabenazine have not been isolated or studied.

Thus, it is not clear which dihydrotetrabenazine isomer has been correlated with the therapeutic effects of tetrabenazine to date.

It is still somewhat unclear to date whether (+) - α -dihydrotetrabenazine produces an effective therapeutic effect in the treatment of movement disorders such as tourette's syndrome, and no side effects such as those described above occur. For example, although WO2016/127133 (neuroendocrine biology) mentions that Kilbourn et al published in Chirality (supra) show that (+) - α -dihydrotetrabenazine is an active metabolite of tetrabenazine. Reference is also made to the reports of the studies by Login et al ((1982), Ann. neurology 12:257-62) and Reches et al (J. Pharmacol. exp. Ther. (1983),225:515-521), which show that tetrabenazine inhibits presynaptic and postsynaptic dopamine receptors in rat brain. It is suggested in WO2016/127133 that the "off-target" activity of tetrabenazine may be associated with some of the observed side effects of tetrabenazine.

As mentioned above, tetrabenazine is known to have a number of dose-related side effects including causing depression and parkinson's disease (see WO2016/127133 for details.) these side effects also appear to be caused by VMAT2 inhibition and it is therefore difficult to distinguish the therapeutic effect of tetrabenazine from the tetrabenazine derivatives obtained from the side effects (see M ü ler for details, "breakthrough pharmaceutical status of valiphenazine for treating tardive dyskinesia", Expert opin. investig. drugs (2015),24(6), pp.737-742).

To avoid or reduce the tetrabenazine-related side effects, a valine ester precursor drug of (+) - α -dihydrotetrabenazine was developed, the international non-proprietary drug name of which is valine (Valbenazine). The structure of valine benazine is as follows:

(+) - α -dihydrotetrabenazine is reacted with carboxybenzyloxy-L-valine in dichloromethane and 4-Dimethylaminopyridine (DMAP) in the presence of N, N-Dicyclohexylcarbodiimide (DCC) to produce the intermediate 2-benzyloxycarbonylamino-3-methylbutanoic acid (2R,3R,1bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyridin [2,1- α ] isoquinolin-2-yl ester as described in US 8039627. The carbobenzoxy protecting group is then removed by hydrogenation of palladium at the carbon position of the intermediate to give the valbenazine.

M ü ller ("breakthrough drug status of valiphenazine for treating tardive dyskinesia", expetpopin. investig. drugs (2015),24(6), pp.737-742) describes a phase IIB clinical study of valiphenazine ("KINECT 1") in subjects with tardive dyskinesia although a 100 mg/day dose of valiphenazine (equivalent to 76mg of (+) - α -dihydrotetrabenazine) was observed to reduce symptoms, subjects receiving 50 mg/day of valiphenazine (equivalent to 38mg of (+) - α -dihydrotetrabenazine) did not have any significant signs of improvement in the Abnormal Involuntary Motor Scale (AIMS) score.

In the same article, a further study ("KINECT 2") was conducted, with subjects having an initial dose of 25 mg/day and subsequent dose ranges increasing to 75 mg/day. At the end of the study, 21 out of 34 subjects given valphenazine reached a dose of 75 mg/day as measured (O' Brien et al, "Kinect 2: NBI-98854 treatment for moderate to severe tardive dyskinesia" Mov. disorder.2014; 29(Suppl1): 829). This analysis does not provide details of abnormal involuntary movements reduction in subjects receiving a 75 mg/day dose at the end of the trial and subjects receiving a 25 mg/day or 50 mg/day dose at the end of the trial.

O' Brien et al further reported a phase III trial of valiphenazine ("KINECT 3 valiphenazine (NBI-98854) randomized double-blind placebo controlled phase 3 trial (PL 02.003)" Neurology (2016),86(16), Supplement PL02.003) for the treatment of tardive dyskinesia, investigating the changes in abnormal involuntary movements of tardive dyskinesia patients following daily administration of 40mg or 80mg of valiphenazine. They found that 80 mg/day of valiphenazine could significantly improve abnormal involuntary movement scores and concluded that 80 mg/day of valiphenazine could significantly improve tardive dyskinesia.

WO2015/171802 (Neurocrine biosciences) describes a method of treating a hyperkinetic disease by administering a therapeutic agent capable of producing a (+) - α -dihydrotetrabenazine concentration in plasma and a Cmax of between 15ng/ml and 60ng/ml over eight hours with a Cmin of at least 15 ng/ml. Although WO2015/171802 suggests that this could be achieved by administration of (+) - α -dihydrotetrabenazine, the experiments described in WO2015/171802 only provide data on the levels of (+) - α -dihydrotetrabenazine that are achieved following administration of valiphenazine. The results of example 1 of WO2015/171802 show that 30ng/ml of (+) - α -dihydrotetrabenazine in plasma is a suitable target and exposure below 15ng/ml is suboptimal in the general population with Tardive Dyskinesia (TD). In example 2 of WO2015/171802, it is disclosed that a 50mg dose of valbenazine appears to maintain the desired (+) - α -dihydrotetrabenazine levels in plasma.

W02016/210180(Neurocrine organisms) discloses the use of VMAT2 inhibitors for the treatment of various neurological diseases. (+) - α -dihydrotetrabenazine is mentioned as an example of a VMAT2 inhibitor and a therapeutic agent is disclosed that provides plasma concentrations similar to those described in W02015/171802. The VMAT2 inhibitory compounds specifically exemplified in W02016/210180 are valiphenazine and [ (2R,3S,11bR) -9, 10-dimethoxy-3- (2-methylpropyl) -1H,2H,3H,4H,6H,7H,11 bH-pyridine [2, 1-. alpha ] isoquinolin-2-yl ] methanol.

Disclosure of Invention

The present study shows that (+) - α -dihydrotetrabenazine itself has the chemical name "(R, R, R) -3-isobutyl-9, 10-dimethyloxy-1, 3,4,5,7,11 b-hexahydro-2H-pyridin [2,1- α ] isoquinolin-2-yl ester", having the formula (I),

it is effective in the treatment of dyskinesias at doses well below those predicted in the literature (e.g. WO 2015/171802) and is used at such low doses as to avoid or minimize tetrabenazine-related adverse effects.

More specifically, experiments conducted in this disclosure demonstrate that administration of (+) - α -dihydrotetrabenazine is itself effective in treating movement disorders (e.g., Tourette's syndrome), and that the dose of (+) - α -dihydrotetrabenazine is much lower than the dose of valiphenazine required in WO2015/171802 e.

Furthermore, contrary to the teaching of WO2015/171802, it has been found that effective results are obtained by administering a dose of (+) - α -dihydrotetrabenazine such that the plasma concentration does not exceed 15ng/mL within 8 hours.

The use of low doses is expected to reduce the biological side effects associated with tetrabenazine and tetrabenazine derivatives, including parkinson's disease and depression.

One advantage of using (+) - α -dihydrotetrabenazine itself, as compared to the prodrug valiphenazine, is that it avoids the two additional synthetic steps and the additional purification steps required to produce from (+) - α -dihydrotetrabenazine to valiphenazine. Furthermore, the release of active (+) - α -dihydrotetrabenazine in plasma is not limited by the rate of degradation of the prodrug.

Another unexpected advantage of using a low dose of (+) - α -dihydrotetrabenazine is that experiments conducted by the inventors have shown that normal movement is not affected, although dyskinesias of the type found in dyskinesias are reduced or inhibited by the drug. This is in contrast to risperidone, a commonly used drug for the treatment of dyskinesia, where levels of both normal and abnormal movements are reduced.

Based on these results, it is envisioned that low doses of (+) - α -dihydrotetrabenazine may be useful in the prevention or treatment of disease states and conditions in which tetrabenazine is currently used or proposed, among others. Thus, by way of example, and without limitation, it is envisaged that low doses of (+) - α -dihydrotetrabenazine may be used in the treatment of hyperkinetic movement disorders, such as huntington's disease, hemitoseisis, senile chorea, tic disorders, tardive dyskinesia, dystonia, in particular tourette's syndrome.

In accordance with the present disclosure, a subject can be initially administered a very low dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof (e.g., 0.5mg to 5mg), and, where necessary and desirable, the therapeutic effect of the initial dose is evaluated prior to increasing the dose. Thus, starting from a very low initial dose, titration measurements can be performed on a subject to determine the optimal dose for a particular dyskinesia. This initial low dose is much lower than the lowest dose of tetrabenazine currently in clinical use.

Accordingly, in a first aspect (example 1.1), the present disclosure provides a method of treating dyskinesia in a subject in need thereof, said treatment comprising the steps of:

(a) administering to the subject an initial daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, wherein the initial daily dose is an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg to 5mg of (+) - α -dihydrotetrabenazine free base.

(b) Performing a clinical evaluation of the subject to understand the efficacy and side effects of the treatment;

(c) administering an increased daily dose, which is greater than the initial daily dose, by an amount of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to between 0.5mg and 5mg of (+) - α -dihydrotetrabenazine free base, when the clinical assessment (b) has determined that an increased daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is required; or, when said clinical assessment has determined that an increase in daily dose is not required, maintaining said initial daily dose, decreasing said dose, or discontinuing said treatment;

(d) (ii) when an increasing daily dose has been administered, performing a further clinical evaluation of the subject to understand the efficacy and side effects of the treatment with the increasing daily dose;

(e) administering a further increased daily dose, which is greater than the daily dose of the preceding day, by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg to 5mg of (+) - α -dihydrotetrabenazine free base, when said further clinical assessment (d) has determined that a further increased daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is required; or, when said clinical assessment has determined that no further increase in daily dose is required, maintaining said daily dose on the previous day, decreasing said daily dose on the previous day or discontinuing said treatment; and

(f) optionally repeating steps (d) and (e) as necessary until an optimal daily dose is reached.

In a specific embodiment of the above method, there is provided:

1.2 the method according to embodiment 1.1, wherein said initial daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is an amount corresponding to 0.5mg to 3mg of (+) - α -dihydrotetrabenazine free base.

1.3 the method according to embodiment 1.2, wherein said initial daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is an amount corresponding to 0.5mg to 2mg of (+) - α -dihydrotetrabenazine free base.

1.4 the method according to example 1.2, wherein said initial daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is an amount corresponding to 0.5mg, 1mg, 1.5mg or 2mg of (+) - α -dihydrotetrabenazine free base.

1.5 the method according to embodiment 1.4, wherein said initial daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is an amount corresponding to 0.5mg of (+) - α -dihydrotetrabenazine free base.

1.6 the method according to embodiment 1.4, wherein said initial daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is an amount corresponding to 1mg of (+) - α -dihydrotetrabenazine free base.

1.7 the method according to example 1.4, wherein said initial daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is an amount corresponding to 1.5mg of (+) - α -dihydrotetrabenazine free base.

1.8 the method according to embodiment 1.4, wherein said initial daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is an amount corresponding to 2mg of (+) - α -dihydrotetrabenazine free base.

1.9 the method according to any one of embodiments 1.1 to 1.8, wherein the increased daily dose in step (c) is increased by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5 to 3mg of (+) - α -dihydrotetrabenazine free base, compared to the initial daily dose.

1.10 the method according to embodiment 1.9, wherein the increased daily dose in step (c) is increased by an amount of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to 0.5mg to 2mg of (+) - α -dihydrotetrabenazine free base compared to the initial daily dose.

1.11 the method according to embodiment 1.10, wherein the increased daily dose in step (c) is increased by an amount of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to 0.5mg, 1mg, 1.5mg or 2mg of (+) - α -dihydrotetrabenazine free base compared to the initial daily dose.

1.12 the method of embodiment 1.11, wherein the increased daily dose in step (c) is increased by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg (+) - α -dihydrotetrabenazine free base, compared to the initial daily dose.

1.13 the method of embodiment 1.11, wherein the increased daily dose in step (c) is increased by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 1mg (+) - α -dihydrotetrabenazine free base, compared to the initial daily dose.

1.14 the method of embodiment 1.11, wherein the increased daily dose in step (c) is increased by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 1.5mg of (+) - α -dihydrotetrabenazine free base, compared to the initial daily dose.

1.15 the method of embodiment 1.11, wherein the increased daily dose in step (c) is increased by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 2mg of (+) - α -dihydrotetrabenazine free base, compared to the initial daily dose.

1.16 the method according to any one of embodiments 1.1 to 1.15, wherein the further increased daily dose in step (e) is increased by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg to 3mg of (+) - α -dihydrotetrabenazine free base, compared to the daily dose of the preceding day.

1.17 the method of embodiment 1.16 wherein the further increased daily dose in step (e) is increased by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg to 2mg of (+) - α -dihydrotetrabenazine free base, compared to the daily dose of the preceding day.

1.18 the method of embodiment 1.17 wherein the further increased daily dose in step (e) is increased by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg, 1mg, 1.5mg or 2mg of (+) - α -dihydrotetrabenazine free base, as compared to the daily dose of the preceding day.

1.19 the method of embodiment 1.18 wherein the further increased daily dose in step (e) is increased by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 0.5mg of (+) - α -dihydrotetrabenazine free base, compared to the daily dose of the preceding day.

1.20 the method of embodiment 1.18 wherein the further increased daily dose in step (e) is increased by the amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 1mg (+) - α -dihydrotetrabenazine free base, compared to the daily dose of the preceding day.

1.21 the method of embodiment 1.18 wherein the further increased daily dose in step (e) is increased by an amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 1.5mg of (+) - α -dihydrotetrabenazine free base, compared to the daily dose of the preceding day.

1.22 the method of embodiment 1.18 wherein the further increased daily dose in step (e) is increased by the amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 2mg of (+) - α -dihydrotetrabenazine free base, compared to the daily dose of the preceding day.

1.23 the method according to any one of embodiments 1.1 to 1.22, wherein the treatment comprises administering a maximum (e.g. optimal) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to no more than 20mg of (+) - α -dihydrotetrabenazine free base.

1.24 the method according to example 1.23, wherein the treatment comprises administering a maximum (e.g. optimised) daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, said amount corresponding to no more than 17.5mg of (+) - α -dihydrotetrabenazine free base.

1.25 the method according to example 1.23, wherein the treatment comprises administering a maximum (e.g. optimised) daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, said amount corresponding to no more than 15mg of (+) - α -dihydrotetrabenazine free base.

1.26 the method according to example 1.23, wherein the treatment comprises administering a maximum (e.g. optimised) daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, said amount corresponding to no more than 12.5mg of (+) - α -dihydrotetrabenazine free base.

1.27 the method according to example 1.23, wherein the treatment comprises administering a maximum (e.g. optimised) daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, said amount corresponding to no more than 10mg of (+) - α -dihydrotetrabenazine free base.

1.28 the method according to example 1.23, wherein the treatment comprises administering a maximum (e.g. optimised) daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, said amount corresponding to no more than 9mg of (+) - α -dihydrotetrabenazine free base.

1.29 the method according to example 1.23, wherein the treatment comprises administering a maximum (e.g. optimised) daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, said amount corresponding to no more than 8mg of (+) - α -dihydrotetrabenazine free base.

1.30 the method according to example 1.23, wherein the treatment comprises administering a maximum (e.g. optimised) daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, said amount corresponding to no more than 7.5mg of (+) - α -dihydrotetrabenazine free base.

1.31 the method according to example 1.23, wherein the treatment comprises administering a maximum (e.g. optimised) daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, said amount corresponding to no more than 7mg of (+) - α -dihydrotetrabenazine free base.

1.32 the method according to example 1.23, wherein the treatment comprises administering a maximum (e.g. optimised) daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, said amount corresponding to no more than 6mg of (+) - α -dihydrotetrabenazine free base.

1.33 the method according to example 1.23, wherein the treatment comprises administering a maximum (e.g. optimised) daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, said amount corresponding to no more than 5mg of (+) - α -dihydrotetrabenazine free base.

1.34 the method of example 1.23 wherein the treatment comprises administering a maximum (e.g. optimized) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to no more than 4mg of (+) - α -dihydrotetrabenazine free base.

1.35 the method according to example 1.23, wherein the treatment comprises administering a maximum (e.g. optimised) daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, said amount corresponding to no more than 3mg of (+) - α -dihydrotetrabenazine free base.

1.36 the method of example 1.23 wherein the treatment comprises administering a maximum (e.g. optimized) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to no more than 2.5mg of (+) - α -dihydrotetrabenazine free base.

At least initially, the amount of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof to be administered to a subject is determined by determining the weight of said subject and then administering a dose appropriate to the weight of said subject. Thus, in a further embodiment, the present disclosure provides: 1.37 the method according to any one of embodiments 1.1 to 1.23, wherein the treatment comprises determining the approximate body weight of the subject and:

(i) administering a maximum (e.g. optimized) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, when the subject weighs between 30kg and 50kg, said dose corresponding to between 2mg and 7.5mg of (+) - α -dihydrotetrabenazine free base;

(ii) administering a maximum (e.g. optimized) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, when the subject weighs between 50kg and 75kg, said dose corresponding to between 5mg and 10mg of (+) - α -dihydrotetrabenazine free base;

(iii) administering a maximum (e.g. optimized) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, when the subject weighs between 75kg and 95kg, said dose corresponding to between 7.5mg and 15mg of (+) - α -dihydrotetrabenazine free base; or

(iv) Administering a maximum (e.g. optimized) daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 15mg to 20mg of (+) - α -dihydrotetrabenazine free base, when the subject weighs more than 95kg, the amount of (+) - α -dihydrotetrabenazine administered per day being 15mg to 20 mg.

1.38 a method of treating a movement disorder in a subject in need thereof, said treatment comprising administering to said subject an effective amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, wherein:

(i) (ii) when the subject weighs between 30kg and 50kg, the effective amount is a daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to between 2mg and 7.5mg of (+) - α -dihydrotetrabenazine free base;

(ii) (ii) when the subject weighs between 50kg and 75kg, the effective amount is a daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to between 5mg and 10mg of (+) - α -dihydrotetrabenazine free base;

(iii) (ii) when the subject weighs 75kg to 95kg, the effective amount is a daily dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, corresponding to 7.5mg to 15mg of (+) - α -dihydrotetrabenazine free base; or

(iv) When the subject weighs more than 95kg, the effective amount is a daily dose of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to 15mg to 20mg of (+) - α -dihydrotetrabenazine free base, the amount of (+) - α -dihydrotetrabenazine per day being 15mg to 20 mg.

1.39A method of treating a movement disorder in a subject in need thereof, said treatment comprising administering to said subject an effective amount of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, wherein said effective amount corresponds to an amount of (+) - α -dihydrotetrabenazine free base of between 0.05mg/kg and 0.3mg/kg per day.

1.40 the method according to embodiment 1.39, wherein the effective amount corresponds to an amount of (+) - α -dihydrotetrabenazine free base of 0.1mg/kg to 0.2mg/kg per day.

The amount of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof administered is determined by the desired plasma concentration of (+) - α -dihydrotetrabenazine to be achieved in the subject or the desired level of blockade of VMAT2 protein. Accordingly, the present disclosure also provides:

a method of treating a movement disorder in a subject in need thereof, wherein the treatment comprises administering to the subject a therapeutically effective amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, wherein the effective amount is sufficient to provide a mean plasma Cc of (+) - α -dihydrotetrabenazine when measured over a three hour period_avgThe concentration is in the range of 3ng/ml to 15 ng/ml.

1.42 the method of any one of embodiments 1.1 to 1.40, wherein the daily dose, daily amount, or effective amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, administered to the subject is sufficient to cause a blockade level of 50% to 85% of VMAT2 protein in the subject.

1.43 the method of any one of embodiments 1.1 to 1.40, wherein the daily dose, daily amount, or effective amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, administered to the subject is sufficient to cause a blockade level of 55% to 85% of VMAT2 protein in the subject.

1.44 the method of embodiment 1.42 or 1.43, wherein treating comprises administering to the subject a dose of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, sufficient to cause a level of blockade of 70% to 85% of VMAT2 protein in the subject (or in the brain of the subject, as the case may be).

In further embodiments, the present disclosure provides:

1.45 the method according to any one of embodiments 1.1 to 1.44, wherein the (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is administered to the subject once daily.

1.46 the method according to any one of embodiments 1.1 to 1.44, wherein the (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is administered to the subject twice daily.

1.47 the method according to any one of embodiments 1.1 to 1.46, wherein the (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is not administered in combination with a therapeutically effective amount of amantadine.

1.48 the method of embodiment 1.47 wherein the (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is not administered in combination with any amount of amantadine.

1.49 the method according to any one of embodiments 1.1 to 1.48, wherein the (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is administered as a non-sustained release dosage form or a delayed release dosage form (e.g. an immediate release unit dosage form).

1.50 the method according to any one of embodiments 1.1 to 1.49, wherein the (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is administered orally.

1.51 the method of embodiment 1.50 wherein the (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is administered in the form of a tablet, capsule, solution, syrup or suspension.

1.51A the method of embodiment 1.50 wherein the (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is administered in the form of a tablet.

1.51B the method of embodiment 1.50 wherein the (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is administered in the form of a solution.

1.51C the method of embodiment 1.50, wherein the (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is administered in the form of a syrup.

1.51D the method of embodiment 1.50 wherein the (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is administered in the form of a suspension.

1.52 the method of embodiment 1.50 wherein the (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, is administered in the form of a capsule.

Use of 52A (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, in a method as defined in any one of examples 1.1 to 1.52.

Use of 52B (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament according to the method defined in any one of examples 1.1 to 1.52.

The present disclosure also provides an innovative low dose unit dosage form containing (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof. Thus, in a further embodiment, the present disclosure provides:

1.53A unit dosage form comprising from 0.5mg to 20mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.54 a unit dosage form according to example 1.53, formulated for oral administration.

1.55 the unit dosage form of example 1.54, which is a capsule or tablet.

1.56 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising 1 to 20mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.57 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising from 2mg to 20mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.58 the unit dosage form of any one of embodiments 1.53 to 1.55, comprising 0.5 to 10mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.59 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising 0.5 to 7.5mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.60 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising from 1mg to 10mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.61 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising 1 to 7.5mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.62 the unit dosage form of any one of embodiments 1.53 to 1.55, comprising from 3mg to 20mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.63 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising from 2mg to 15mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.64 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising from 3mg to 15mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.65 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising from 4mg to 15mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.66 the unit dosage form of any one of embodiments 1.53 to 1.55, comprising 5 to 15mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.67 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising about 0.5mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.68 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising about 1mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.69 the unit dosage form of any one of embodiments 1.53 to 1.55 comprising about 1.5mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.70 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising about 2mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.71A unit dosage form according to any one of embodiments 1.53 to 1.55, comprising about 2.5mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.72 the unit dosage form of any one of embodiments 1.53 to 1.55, comprising about 3mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.73 the unit dosage form of any one of embodiments 1.53 to 1.55, comprising about 3.5mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.74 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising about 4mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.75 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising about 4.5mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.76 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising about 5mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.77 the unit dosage form of any one of embodiments 1.53 to 1.55, comprising about 7.5mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.78 the unit dosage form of any one of embodiments 1.53 to 1.55, comprising about 10mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.79 the unit dosage form of any one of embodiments 1.53 to 1.55, comprising about 12.5mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.80 the unit dosage form of any one of embodiments 1.53 to 1.55, comprising about 15mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.81 the unit dosage form according to any one of embodiments 1.53 to 1.55 comprising 0.5 to 3mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.82 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising 0.5 to 2mg of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.83 the unit dosage form according to any one of embodiments 1.53 to 1.55, comprising from 1mg to 3mg (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

1.84 the method according to any one of embodiments 1.1 to 1.52, wherein the (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof is administered as a unit dosage form according to any one of embodiments 1.53 to 1.83.

The methods and unit dosage forms defined and described above are generally useful for treating hyperkinetic movement disorders, such as Huntington's disease, hemitoseisis, senile chorea, tic disorders, tardive dyskinesia, dystonia, myoclonus, and Tourette's syndrome.

More specifically, the unit dosage form described above is used for the treatment of a hyperkinetic movement disorder selected from the group consisting of tic disorders, tardive dyskinesia and tourette's syndrome.

In a particular embodiment, the unit dosage form described above is used for 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 term "treatment" as used herein for treating a disease or disorder generally relates to treatments and therapies that achieve some desired therapeutic effect, such as inhibition of the development of the condition, and includes slowing of the rate of progression, halting of the rate of progression, amelioration of the condition, reduction or alleviation of at least one symptom associated with or caused by the condition being treated, and healing of the condition. When the treated hyperkinetic movement disorder is tourette's syndrome, treatment of the disorder may be associated with a reduction in the incidence or severity of tics.

Thus, in a further embodiment, the present disclosure also provides:

1.85 the method according to any one of embodiments 1.1 to 1.52 and 1.84, wherein the dyskinesia is selected from tardive dyskinesia, tourette's syndrome, and huntington's disease.

1.86 the method of embodiment 1.85, wherein the movement disorder is tourette's syndrome.

1.87 the method of embodiment 1.85, wherein the dyskinesia is huntington's disease.

1.88 the method of embodiment 1.85 wherein the movement disorder is tardive dyskinesia.

As described above, the inventors have found that low dose treatment with (+) - α -dihydrotetrabenazine helps to block the VMAT2 receptor in the treatment of dyskinesias. Thus, in a further embodiment, the present disclosure provides:

use of (+) - α -dihydrotetrabenazine in a method of treating a movement disorder, wherein the treatment comprises administering to a subject an amount of (+) - α -dihydrotetrabenazine of from 0.5mg to 20mg per day.

1.90A method of treating a movement disorder in a subject in need thereof (e.g. a mammalian subject, such as a human) comprising administering to the subject an amount of (+) - α -dihydrotetrabenazine of from 0.5mg to 20mg per day.

Use of 91(+) - α -dihydrotetrabenazine in a method of treating a movement disorder comprising administering to said subject an amount of (+) - α -dihydrotetrabenazine of from 0.5mg to 20mg per day.

In a further embodiment, there is also provided:

1.92 use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine of from 1mg to 20mg per day.

1.93 use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine of from 2mg to 20mg per day.

1.94 use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine of from 3mg to 20mg per day.

1.95 use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine of from 2mg to 15mg per day.

1.96 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine of from 3mg to 15mg per day.

1.97 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine of from 5mg to 15mg per day.

1.98 use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine of from 5mg to 10mg per day.

1.99 the use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine of about 5mg per day.

1.100 use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine of about 7.5mg per day.

1.101 use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine of about 10mg per day.

1.102 use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine of about 12.5mg per day.

1.103 use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine of about 15mg per day.

In each case, the specified amount of (+) - α -dihydrotetrabenazine may be administered once daily or several times daily (e.g., twice daily), unless the context indicates otherwise.

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

Part of a typical chronic treatment regimen is the administration of (+) - α -dihydrotetrabenazine. Thus, the (+) - α -dihydrotetrabenazine may be administered to a patient for a treatment period of at least one week, more typically, at least two weeks, or at least one month, typically more than one month. The treatment period can be more than six months, or can extend to years if the patient responds well to the treatment.

The chronic treatment regimen may involve daily administration of (+) - α -dihydrotetrabenazine, or the treatment regimen may include days without administration of (+) - α -dihydrotetrabenazine.

The dose administered to the subject may vary during the treatment. For example, the initial dose may be increased or decreased depending on the subject's response to the treatment. For example, the subject may be tested for tolerance to (+) - α -dihydrotetrabenazine by administering a lower initial dose, after which the dose is increased as necessary to a maximum daily intake of 20 mg. Alternatively, the initial daily dose administered to the subject may be selected to give the expected degree of blockade of VMAT2, and a lower maintenance dose may be subsequently administered for the remainder of the treatment period, and an increased dose may be selected if the subject's response to the treatment indicates that an increased dose is necessary.

The amount of (+) - α -dihydrotetrabenazine required to achieve the desired therapeutic effect may depend on the body weight of the subject being treated. The amount of (+) - α -dihydrotetrabenazine administered to said subject may be expressed in mg/kg, wherein said kg is related to the body weight of said subject receiving the treatment. Thus, the appropriate dose may be calculated by multiplying the value of mg/kg by the weight of the subject being treated. Accordingly, the present disclosure also provides:

1.104 use of (+) - α -dihydrotetrabenazine in a method of treating a movement disorder, wherein the treatment comprises administering to the subject a daily dose of (+) - α -dihydrotetrabenazine of 0.01mg/kg to 0.5mg/kg such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.105A method of treating a movement disorder in a subject in need thereof (e.g., a mammalian subject such as a human) comprising administering to the subject a daily dose of (+) - α -dihydrotetrabenazine of 0.01mg/kg to 0.5mg/kg such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g., 1mg to 20 mg).

1.106 use of (+) - α -dihydrotetrabenazine in the manufacture of a medicament for use in the treatment of movement disorders, said treatment comprising administering to said subject a dose of (+) - α -dihydrotetrabenazine of from 0.01mg/kg to 0.5mg/kg such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of from 0.5mg to 20mg (e.g. from 1mg to 20 mg).

In a further embodiment, there is also provided:

1.107 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject 0.01mg/kg to 0.3mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.108 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject 0.02mg/kg to 0.3mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.109 the use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject 0.03mg/kg to 0.3mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.110 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject 0.04mg/kg to 0.3mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.111 the use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject 0.05mg/kg to 0.3mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.112 the use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject 0.02mg/kg to 0.2mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.113 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject 0.03mg/kg to 0.2mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.114 the use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject 0.04mg/kg to 0.2mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.115 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject 0.05mg/kg to 0.2mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.116 the use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein the treatment comprises administering to the subject 0.02mg/kg to 0.1mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.117 the use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject 0.03mg/kg to 0.1mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.118 the use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein the treatment comprises administering to the subject 0.04mg/kg to 0.1mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

1.119 the use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein the treatment comprises administering to the subject 0.05mg/kg to 0.1mg/kg (+) - α -dihydrotetrabenazine per day such that the total amount of (+) - α -dihydrotetrabenazine administered per day is in the range of 0.5mg to 20mg (e.g. 1mg to 20 mg).

In each of the above aspects and embodiments, (+) - α -dihydrotetrabenazine may be administered as the free base or as a pharmaceutically acceptable salt. In one embodiment, the (+) - α -dihydrotetrabenazine is administered as a pharmaceutically acceptable salt. In another embodiment, the (+) - α -dihydrotetrabenazine is administered as the free base. Calculating the amount of (+) - α -dihydrotetrabenazine from said free base, or when said (+) - α -dihydrotetrabenazine is present in the form of a pharmaceutically acceptable salt, the amount of (+) - α -dihydrotetrabenazine is the amount of (+) - α -dihydrotetrabenazine free base present in said pharmaceutically acceptable salt.

The present inventors have found that the plasma levels of (+) - α -dihydrotetrabenazine required for effective treatment of hyperkinetic dyskinesia can be significantly lower than the plasma levels achieved by administration of valphenazine as described in WO 2015/171802.

Thus, in another aspect (1.120), the present disclosure provides:

use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, in a method of treating a movement disorder; or

A method of treating dyskinesia in a subject in need thereof (e.g. a mammalian subject such as a human); or

The use of (+) - α -dihydrotetrabenazine for the preparation of a medicament for use in the treatment of dyskinesias;

wherein the treatment comprises administering to the subject a therapeutically effective amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, sufficient to achieve a mean plasma concentration C within five hours_avgValues were in the range of 2ng/ml to 15 ng/ml.

In one embodiment (1.121), the present disclosure provides:

use of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, in a method of treating a movement disorder; or

A method of treating dyskinesia in a subject in need thereof (e.g. a mammalian subject such as a human); or

The use of (+) - α -dihydrotetrabenazine for the preparation of a medicament for use in the treatment of dyskinesias;

whereinThe treatment comprises administering to the subject a therapeutically effective amount of (+) -alpha-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, sufficient to achieve a mean plasma concentration C within three hours_avgValues were in the range of 3ng/ml to 15 ng/ml.

Complete blockade of VMAT2 is undesirable because it can lead to unwanted side effects, such as parkinson's disease. The present disclosure provides plasma concentrations of (+) - α -dihydrotetrabenazine that are effective in treating movement disorders, but do not block VMAT2 resulting in parkinson's disease and similar side effects. The level of VMAT2 blockade can be determined by competitive binding studies using Positron Emission Tomography (PET). The proportion of occupied binding sites was determined by co-administering radioligand with the compound of interest at varying concentrations (see, e.g., Mattews et al, "positron emission tomography for drug development", Br. J. Clin. Pharmacol., 73:2, 175-.

Accordingly, the present disclosure provides:

1.122(+) - α -dihydrotetrabenazine for use in a method of treating a movement disorder, wherein the treatment comprises administering to a subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause 90% blockade of VMAT2 protein in the subject.

1.123A method of treating dyskinesia in a subject in need thereof (e.g., a mammalian subject such as a human being) which comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause 90% blockade of VMAT2 protein in said subject.

Use of (+) - α -dihydrotetrabenazine in the manufacture of a medicament for use in the treatment of a movement disorder, the method comprising administering to the subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause 90% blockade of VMAT2 protein in the subject.

In further embodiments, the present disclosure provides:

1.125 the use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade of 85% of said VMAT2 protein in said subject.

1.126 the use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade of 80% of said VMAT2 protein in said subject.

1.127 the use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade of 75% of said VMAT2 protein in said subject.

1.128 the use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade of 70% of said VMAT2 protein in said subject.

1.129 the use, method, or use of (+) - α -dihydrotetrabenazine as described herein, wherein the treatment comprises administering to the subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade of between 25% and 85% of the VMAT2 protein in the subject.

1.130 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade in said subject of between 30% and 80% of said VMAT2 protein.

1.131 uses, methods or uses of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade in said subject of between 35% and 75% of said VMAT2 protein.

1.132 the use, method, or use of (+) - α -dihydrotetrabenazine as described herein, wherein the treatment comprises administering to the subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade in the subject of between 35% and 70% of the VMAT2 protein.

1.133 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to said subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade in said subject of between 40% and 75% of said VMAT2 protein.

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

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

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

1.137 the use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to a subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade of said VMAT2 protein of between 45% and 80% in said subject.

1.138 the use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administering to a subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade of said VMAT2 protein in said subject of between 50% and 80%.

139 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to a subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade of 55% to 80% of said VMAT2 protein in said subject.

1.140 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein said treatment comprises administering to a subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade in said subject of between 30% and 70% of said VMAT2 protein.

1.141 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein the treatment comprises administration to the subject in need thereof, wherein the method comprises administering to the subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade of 30% to 65% of the VMAT2 protein in the subject.

1.142 the use, method or use of (+) - α -dihydrotetrabenazine as described herein wherein said treatment comprises administration to said subject in need thereof, wherein said method comprises administering to the subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade of 30% to 60% of said VMAT2 protein in said subject.

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

1.144 the use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein the treatment comprises administration to the subject in need thereof, wherein the method comprises administering to the subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a blocking level of 40% to 75% of the VMAT2 protein in the subject.

1.145 use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein the treatment comprises administration to the subject in need thereof, wherein the method comprises administering to the subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a level of blockade of 40% to 70% of the VMAT2 protein in the subject.

1.146 the use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprises administering to the subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a blocking level of 40% to 65% of the VMAT2 protein in the subject.

1.147 the use, method or use of (+) - α -dihydrotetrabenazine as described herein, wherein the treatment comprises administration to the subject in need thereof, wherein the method comprises administering to the subject an amount of (+) - α -dihydrotetrabenazine sufficient to cause a blocking level of 40% to 60% of the VMAT2 protein in the subject.

In further embodiments of the present disclosure, in particular, it is contemplated that low doses of (+) - α -dihydrotetrabenazine may be useful in the treatment of hyperkinetic movement disorders in juvenile subjects aged 5 to 16 years.

Accordingly, the present disclosure also provides:

1.148(+) - α -dihydrotetrabenazine for use in a method of treating hyperkinetic movement disorders in a juvenile subject aged 5 to 16 years, wherein the treatment comprises administering to the subject 0.5mg to 12.5mg (+) - α -dihydrotetrabenazine per day.

1.149A method of treating hyperkinetic movement disorder in a juvenile subject from 5 to 16 years old in need thereof (e.g., a mammalian subject such as a human), wherein said treatment comprises administering to said subject from 0.5mg to 12.5mg per day of (+) - α -dihydrotetrabenazine.

Use of 150(+) - α -dihydrotetrabenazine in the manufacture of a medicament for use in the treatment of movement disorders, said treatment comprising administering to a subject aged 5 to 16 years 0.5mg to 12.5mg (+) - α -dihydrotetrabenazine per day.

In a further embodiment, there is provided:

1.151 use of (+) - α -dihydrotetrabenazine in a method or use as defined in any one of examples 1.148 to 1.150, wherein the treatment comprises administering to the subject 0.5mg to 10mg of (+) - α -dihydrotetrabenazine per day.

1.152 use of (+) - α -dihydrotetrabenazine in a method or use as defined in any of examples 1.148 to 1.150 wherein the treatment comprises administering to the subject 0.5mg to 8mg of (+) - α -dihydrotetrabenazine per day.

Use of 153(+) - α -dihydrotetrabenazine in a method or use as defined in any one of examples 1.148 to 1.150, wherein the treatment comprises administering to the subject 0.5mg to 7.5mg (+) - α -dihydrotetrabenazine per day.

Use of 154(+) - α -dihydrotetrabenazine in a method or use as defined in any one of examples 1.148 to 1.150, wherein the treatment comprises administering to the subject 0.5mg to 7mg (+) - α -dihydrotetrabenazine per day.

Use of 1.155(+) - α -dihydrotetrabenazine in a method or use as defined in any one of examples 1.148 to 1.150 wherein said treatment comprises administering to said subject 0.5mg to 6mg (+) - α -dihydrotetrabenazine per day.

1.156(+) - α -dihydrotetrabenazine for use in a method or use as defined in any of examples 1.148 to 1.150 wherein the treatment comprises administering to the subject 0.5mg to 5mg (+) - α -dihydrotetrabenazine per day.

1.157 use of (+) - α -dihydrotetrabenazine in a method or use as defined in any one of examples 1.148 to 1.150, wherein the treatment comprises administering to the subject from 1mg to 12.5mg of (+) - α -dihydrotetrabenazine per day.

1.158(+) - α -dihydrotetrabenazine for use in a method or use as defined in any one of examples 1.148 to 1.150, wherein the treatment comprises administering to the subject from 1mg to 10mg (+) - α -dihydrotetrabenazine per day.

1.159(+) - α -dihydrotetrabenazine for use in a method or use as defined in any one of examples 1.148 to 1.150 wherein said treatment comprises administering to said subject from 1mg to 8mg (+) - α -dihydrotetrabenazine per day.

Use of 160(+) - α -dihydrotetrabenazine in a method or use as defined in any one of examples 1.148 to 1.150, wherein the treatment comprises administering to the subject 1mg to 7.5mg (+) - α -dihydrotetrabenazine per day.

1.161 use of (+) - α -dihydrotetrabenazine in a method or use as defined in any one of examples 1.148 to 1.150, wherein the treatment comprises administering to the subject from 1mg to 7mg of (+) - α -dihydrotetrabenazine per day.

Use of 162(+) - α -dihydrotetrabenazine in a method or use as defined in any one of examples 1.148 to 1.150, wherein the treatment comprises administering to the subject 1mg to 6mg (+) - α -dihydrotetrabenazine per day.

Use of 163(+) - α -dihydrotetrabenazine in a method or use as defined in any one of examples 1.148 to 1.150, wherein said treatment comprises administering to said subject 1mg to 5mg (+) - α -dihydrotetrabenazine per day.

Use of 164(+) - α -dihydrotetrabenazine in a method or use as defined in any one of examples 1.148 to 1.150, wherein said treatment comprises administering to said subject about 2.5mg (+) - α -dihydrotetrabenazine per day.

1.165 use of (+) - α -dihydrotetrabenazine in a method or use as defined in any of examples 1.148 to 1.150 wherein said treatment comprises administering to said subject about 5mg of (+) - α -dihydrotetrabenazine per day.

Use of 166(+) - α -dihydrotetrabenazine in a method or use as defined in any one of examples 1.148 to 1.150, wherein said treatment comprises administering to said subject about 7.5mg (+) - α -dihydrotetrabenazine per day.

Use of 167(+) - α -dihydrotetrabenazine in a method or use as defined in any one of examples 1.148 to 1.150, wherein the treatment comprises administering to the subject about 10mg of (+) - α -dihydrotetrabenazine per day.

In each of examples 1.148 to 1.167, the human subject receiving (+) - α -dihydrotetrabenazine treatment is from 5 to 16 years of age. The subject will typically not weigh more than 80kg, for example a body weight in the range 17kg to 70 kg.

In other embodiments (example 1.168), the (+) - α -dihydrotetrabenazine is administered to adolescents weighing 20 to 65 kg.

In other embodiments (example 1.169), the (+) - α -dihydrotetrabenazine is administered to adolescents weighing 20 to 60 kg.

In one embodiment (example 1.170), the subject is between 5 and 8 years of age and the amount of (+) - α -dihydrotetrabenazine administered is between 0.5 and 5mg per day.

In another embodiment (example 1.171), the subject is 9 to 12 years of age and the amount of (+) - α -dihydrotetrabenazine administered is 1mg to 8mg per day.

In a further example (example 1.172), the subject is 13 to 16 years of age and the amount of (+) - α -dihydrotetrabenazine administered is 2mg to 12.5mg per day.

In a further embodiment (embodiment 1.173), the use of (+) - α -dihydrotetrabenazine, the method or use as defined in any one of embodiments 1.148 to 1.172, may comprise steps (a), (b) and optional steps (c), (d), (e) and (f) as defined in any one of embodiments 1.1 to 1.36.

In the methods and uses of each of examples 1.1 through 1.52B and 1.85 through 1.174, the amount of (+) - α -dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, required to be administered to a subject depends to some extent on the rate of metabolism of the compound by the subject.

The metabolism of many drugs (about 25% of all currently prescribed drugs) involves the cytochrome P4502D 6(CYP2D6) enzyme, which is expressed primarily in the liver.

Approximately 7% of the population have a slow-acting form of the enzyme, and 7% have an ultrafast-acting form. Thirty-five percent of the population are carriers of the non-functional CYP2D6 allele.

Thus, the subject may be classified according to:

people with metabolic dysfunction-little or no CYP2D6 function;

medium-metabolizing populations-metabolizing drugs at a rate intermediate between those with poor metabolism and those with rapid metabolism;

tachymetabotropic populations-having normal CYP2D6 function;

ultrafast metabolising populations-expressing multiple copies of the CYP2D6 and therefore being more functional than normal CYP2D 6.

Therefore, there is considerable variation in the efficiency and amount of CYP2D6 enzyme produced between individuals. Thus, for drugs metabolized by CYP2D6, some people (people with ultra-rapid metabolism) will eliminate the drugs quickly, while others (people with poor metabolism) will eliminate them slowly. If the drug is metabolized too quickly, the efficacy of the drug may be reduced, while if the drug is metabolized too slowly, toxicity may result.

A number of commercial diagnostic tests are available to determine whether a subject belongs to the rapid metabolism population or the hypometabolism population, including the CYP2D6 genotyping test provided by Genelex Labs LLC (Seattle, WA 98121, USA) and Trimgen Corporation (Sparks, Maryland 21152, USA).

Thus, in each of the methods and uses described herein, for example in examples 1.1 to 1.52B and 1.85 to 1.173, the use or method may comprise a step comprising performing an assay on a subject to determine the CYP2D6 status of the subject, and then using the assay result as a factor in determining the amount of (+) - α -dihydrotetrabenazine or a pharmaceutically acceptable salt thereof administered to the subject. Thus, fast-metabolizing populations may be administered a given range of high-value amounts, while slow-metabolizing populations may be administered smaller amounts.

In each of the foregoing examples 1.1 through 1.173, the unit dosage form (or the substance administered in the method) includes no more than 20% by weight of any other isomer of dihydrotetrabenazine relative to the (+) - α -dihydrotetrabenazine; more commonly, no more than 10% by weight of any other isomer of dihydrotetrabenazine is included relative to the (+) - α -dihydrotetrabenazine; preferably no more than 5% by weight of any other isomer of dihydrotetrabenazine is included relative to the (+) - α -dihydrotetrabenazine; more preferably, no more than 2% by weight of any other isomer of dihydrotetrabenazine is included relative to the (+) - α -dihydrotetrabenazine.

Thus, the (+) - α -dihydrotetrabenazine typically has an isomeric purity of at least 80%.

The term "isomeric purity" in this context refers to the amount of (+) - α -dihydrotetrabenazine 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 (+) - α -dihydrotetrabenazine, then the isomeric purity is 90%.

The isomer purity of the disclosed (+) -alpha-dihydrotetrabenazine may be 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%.

Salt (salt)

The (+) - α -dihydrotetrabenazine may be present as the free base or as a salt. Unless the context indicates otherwise, all references herein to (+) - α -dihydrotetrabenazine include (+) - α -dihydrotetrabenazine as the free base and as a salt thereof.

In one embodiment (embodiment 1.174), the (+) - α -dihydrotetrabenazine as defined in any of embodiments 1.1 to 1.173 is in the form of the free base.

In another embodiment (embodiment 1.175), the (+) - α -dihydrotetrabenazine as defined in any of embodiments 1.1 to 1.173 is in the form of a salt.

These salts are generally acid addition salts.

The salts may be synthesized from the parent compound by conventional chemical methods, for example "pharmaceutical salts: properties, selection and application (P.Heinrich Stahl, eds., Camile G.Wermuth, eds., ISBN: 3-90639-. Typically, such salts can be prepared by reacting the compound in the free base form with the acid in water or an organic solvent or a mixture of the two; usually, nonaqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used.

Acid addition salts can be formed in the form of a variety of acids, including inorganic and organic acids. Examples of acid addition salts include salts formed from acids selected from the group consisting of: acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+) camphoric acid, camphorsulfonic acid, (+) - (1S) -camphoric acid-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, 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), alpha-ketoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, gluconic acid, and the like, 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, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) -L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid, as well as acylated amino acids and cation exchange resins.

The salt forms of the compounds of the present disclosure are typically pharmaceutically acceptable salts, examples of which are discussed in Berge et al, 1977, "pharmaceutically acceptable salts" (j.pharm.sci. vol. 66, pages 1-19). However, salts which are not pharmaceutically acceptable may also be prepared as intermediates and then converted to pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts may also form part of the present disclosure, for example, may be useful in the purification or isolation of the compounds described in the present disclosure.

Isotope of carbon monoxide

The (+) -alpha-dihydrotetrabenazine may comprise one or moreMultiple isotopic substitutions and the introduction of a particular element, including all isotopes of the element within the range. For example, the introduction of hydrogen is included in the scope thereof¹H、²H, (D) and³h (T). Also, the introduction of carbon and oxygen is included in the range thereof¹¹C、¹²C、¹³C and¹⁴c and¹⁶o and¹⁸O。

typically, the (+) - α -dihydrotetrabenazine of the present disclosure does not include isotopes above its natural abundance (e.g.¹¹C or³H)。

In one embodiment, the percentage of deuterium atoms in (+) - α -dihydrotetrabenazine on said total hydrogen atoms is less than 2%, more typically less than 1%, more typically less than 0.1%, preferably less than 0.05%, and most preferably no more than 0.02%.

Similarly, the introduction of a particular functional group also includes isotopic variations within its scope unless the context indicates otherwise.

The isotope may be radioactive or non-radioactive. In one embodiment of the disclosure, the (+) - α -dihydrotetrabenazine is free of radioisotopes. The compounds are preferably for therapeutic use. However, in another embodiment, the (+) - α -dihydrotetrabenazine may comprise one or more radioisotopes.

Compounds containing such radioisotopes may be useful in diagnostic terms.

Solvates

(+) - α -dihydrotetrabenazine may form solvates.

An example of a solvate is one formed by combining a non-toxic pharmaceutically acceptable solvent molecule (hereinafter solvent) with a solid state structure (e.g., crystal structure) of a compound described in the present disclosure. Examples of such solvents include water, alcohols (e.g., ethanol, isopropanol, and butanol), and dimethyl sulfoxide. Solvates may be prepared by recrystallization of the compounds described in the present disclosure with a solvent or a mixture of solvents containing the solvent. In any given case, the crystals of the compound may be analyzed by well-known standard techniques, such as thermogravimetric analysis (TGE), Differential Scanning Calorimetry (DSC) and X-ray crystallography, to determine whether a solvate has formed.

The solvate may be a stoichiometric solvate or a non-stoichiometric solvate.

Particular solvates are hydrates, specific examples of hydrates include hemihydrate, monohydrate, and dihydrate.

A more detailed discussion of solvates and methods of preparation and characterization is provided IN Bryn et al, solid-state chemistry of drugs, second edition, published by SSCI (West Lafayette, IN, USA) (1999, ISBN 0-967-06710-3).

In addition, the compounds of the present disclosure may be anhydrous, rather than exist in the form of hydrates. Thus, in another embodiment, the (+) - α -dihydrotetrabenazine is in anhydrous form.

Drawings

FIG. 1 is a graph of percentage of VMAT2 binding versus body weight following administration of doses of 7.5mg, 15mg, and 22.5mg of (+) - α -dihydrotetrabenazine to a human subject.

FIG. 2 is a graph of the percentage of VMAT2 bound versus the amount of (+) - α -dihydrotetrabenazine administered to a human subject in mg/kg body weight.

Figure 3 shows the mean total locomotor distance of rats treated with placebo (with or without induction of phenylpropylamine) and treated with 0.5, 1, 1.5 and 2mg/kg doses of (+) - α -dihydrotetrabenazine and 1mg/kg dose of risperidone, as described in example 2 of study 1 below.

Figure 4 shows the mean total stereotypical behavior of rats treated with placebo (with or without induction of phenylpropylamine) and treated with 0.5, 1, 1.5 and 2mg/kg doses of (+) - α -dihydrotetrabenazine and 1mg/kg dose of risperidone, as described in example 2 of study 1 below.

Figure 5 shows the mean total locomotor distance of rats treated with placebo (with or without induction of phenylpropylamine) and treated with 0.1mg/kg and 0.25mg/kg doses of (+) - α -dihydrotetrabenazine and 1mg/kg risperidone, as described in example 2 of study 2, below.

Figure 6 shows the mean total stereotypical behavior of rats treated with placebo (with or without induction of phenylpropylamine) and treated with 0.1mg/kg and 0.25mg/kg doses of (+) - α -dihydrotetrabenazine and 1mg/kg risperidone, as described in example 2 of study 2, below.

Figure 7 shows the mean total locomotor distance of non-amphetamine-induced rats treated with placebo, either a 2.5mg/kg or 5mg/kg dose of (+) - α -dihydrotetrabenazine, and a 1mg/kg dose of risperidone, as described in example 2 of study 3, below.

Figure 8 shows the average total stereotypical behavior of non-amphetamine-induced rats treated with placebo, either a 2.5mg/kg or 5mg/kg dose of (+) - α -dihydrotetrabenazine, and a 1mg/kg dose of risperidone, as described in example 2 of study 3, below.

Figure 9 shows the mean total locomotor distance of amphetamine-induced rats treated with placebo, either at doses of 1mg/kg or 1.5mg/kg (+) - α -dihydrotetrabenazine and valphenazine, respectively, and a dose of 1mg/kg risperidone, as described in example 2 of study 4, below.

Figure 10 shows the average total stereotypical behavior of rats when amphetamine-induced rats were treated with placebo, either at doses of 1mg/kg or 1.5mg/kg (+) - α -dihydrotetrabenazine and valphenazine, respectively, and a dose of 1mg/kg risperidone, as described in example 2 of study 4, below.

Detailed Description

Method for preparing (+) -alpha-dihydrotetrabenazine

With tetrabenazine as a raw material, (+) -alpha-dihydrotetrabenazine (compound of formula (I)) can be prepared according to the synthetic route shown in scheme 1.

Racemic tetrabenazine (3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyridin [2,1- α ] isoquinolin-2-yl ester) contains the RR and SS isomers of tetrabenazine and is reduced with sodium borohydride to give a mixture of four dihydrotetrabenazine isomers, the racemic mixture of α -dihydrotetrabenazine (RRR and SSs isomers) constituting the major product and the racemic mixture of β -dihydrotetrabenazine (SRR and RSS isomers) constituting the minor product. The β -dihydrotetrabenazine can be removed during the initial purification process, e.g. by chromatography or recrystallization, and the racemic α -dihydrotetrabenazine is then decomposed (e.g. by recrystallization from di-p-tolyl-L-tartaric acid or (R) - (-) -camphorsulfonic acid or by chiral chromatography) to give (+) - α -dihydrotetrabenazine (I) ((2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyridin [2,1, α ] isoquinolin-2-ol). The stereochemistry of (+) - α -dihydrotetrabenazine can be determined, for example, by the formation of crystalline forms of the salt (e.g., the mesylate salt) and by X-ray crystallography of the identified structure.

(+) - α -dihydrotetrabenazine can also be prepared according to Yao et al, preparation and evaluation of the VMAT2 inhibitor tetrabenazine isomer and eight dihydrotetrabenazine isomers (eur.j.med.chem., (2011), 46, pp.1841-1848).

Pharmaceutical preparation

In each of examples 1.1 to 1.175, wherein the compound is administered as a pharmaceutical unit dosage form or other pharmaceutical ingredient, the pharmaceutical ingredient of the present disclosure may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, ophthalmic, otic, rectal, vaginal, or transdermal administration. If the composition is for parenteral administration, it can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery to the target organ or tissue by injection, infusion or other means.

Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, troches, syrups, solutions, sprays, powders, granules, elixirs and suspensions, sublingual tablets, sprays, wafers or patches and buccal patches.

A specific group of pharmaceutical dosage forms used according to examples 1.1 to 1.175 includes tablets, capsules, solutions, syrups, suspensions and gels.

Pharmaceutical compositions containing dihydrotetrabenazine as described in the present disclosure may be formulated according to known techniques, as described in, for example, the complete Reminden pharmaceutical Specification, Mack publishing company, Easton, Pa., USA.

Thus, a tablet composition may comprise a unit dose of the active compound together with an inert diluent or carrier, such as a sugar or sugar alcohol, for example lactose, sucrose, sorbitol or mannitol; and/or non-sugar derived diluents such as sodium carbonate, calcium phosphate, talc, calcium carbonate, or cellulose or derivatives thereof, such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starch, such as corn starch. Tablets may also contain standard ingredients as binders and excipients, for example, polyvinylpyrrolidone, disintegrants (e.g., swelling cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and foaming agents (e.g., citrate/bicarbonate mixtures). Such adjuvants are well known and need not be discussed in detail herein.

Capsule formulations may be of the hard or soft gelatin variety and may contain the active ingredient in solid, semi-solid or liquid form. Gelatin capsules may be made from animal gelatin or its synthetic or plant derivatives.

The solid dosage forms (e.g., tablets, capsules, etc.) may be coated or uncoated, but typically have a coating, such as a protective film coating (e.g., wax or varnish) or a release control coating. The coating (e.g. Eudragit)^TMType polymers) can be designed to release (+) - α -dihydrotetrabenazine at a desired location within the gastrointestinal tract. Thus, the coating may be selected to degrade under the particular pH conditions of the gastrointestinal tract to selectively release the compound in the stomach or the ileum or duodenum.

The release controlling coating may be designed to release (+) - α -dihydrotetrabenazine at a rate such that a therapeutically effective plasma concentration is maintained for at least 2 hours, more typically for at least 3 hours, such as for at least 4 hours or at least 5 hours.

The composition may comprise a plurality of individual units, such as pellets or mini-tablets, wherein each unit comprises (+) - α -dihydrotetrabenazine and each unit may be coated with a release controlling agent.

Instead of or in addition to the coating, the drug may be present in a solid matrix comprising a release controlling agent, e.g. a slow release agent, which may be adapted to selectively release the compound under conditions of varying pH in the gastrointestinal tract. Alternatively, the matrix material or sustained release coating may take the form of an erodible polymer (e.g., a maleic anhydride polymer) that is substantially continuously released as the dosage form passes through the gastrointestinal tract.

Topical compositions include ointments, creams, sprays, patches, gels, drops and implants (e.g., intraocular implants). Such ingredients may be formulated according to known methods.

The ingredients for parenteral administration are usually present in the form of sterile aqueous or oily solutions or fine suspensions, or may be provided in the form of finely divided sterile powders for ready-to-use with sterile water for injection.

Examples of formulations for rectal or intravaginal administration include suppositories and suppositories, which may be composed, for example, of a mouldable or waxy material containing the active compound.

The composition for inhalation administration may be in the form of an inhalable powder composition or a liquid or powder spray and may be administered in standard form using a powder inhaler device or an aerosol dispensing device. Such devices are well known. For administration by inhalation, the powder formulations will generally comprise the active compound and an inert solid powder diluent (e.g. lactose).

Specific pharmaceutical ingredients of the present disclosure are selected from:

a sublingual ingredient;

intranasal;

a pill or tablet providing a release kinetics corresponding to a zero order release of the active compound;

a pill or tablet providing a constant rate release (zero order) after the first rapid release of the active compound;

pellets or tablets providing a mixture of first and zero order release of the active compound; and

a pill or tablet providing a combination of zero order and first order release of the active compound; and optionally, a further release profile of the active compound selected from the second, third and fourth release profiles and combinations thereof.

The pills and tablets prepared to provide the above type of release kinetics may be prepared according to methods well known to the skilled person; for example, the complete pharmaceutical book of Reminden (supra) and Reminden: pharmaceutical technology and practice (21 st edition, 2006, ISBN 0-7817-4673-6).

The compounds of the present disclosure are typically presented in unit dosage form and, therefore, typically contain sufficient compound to provide the desired level of biological activity. The amounts are as described above.

The active compound is administered to a subject (patient), e.g., a human or animal patient, in need thereof in an amount sufficient to achieve the desired therapeutic effect.

Examples of the invention

The following non-limiting examples illustrate the synthesis and properties of (+) - α -dihydrotetrabenazine of the present disclosure.

Example 1

Five human volunteers were administered orally a fixed amount of (+) - α -dihydrotetrabenazine. Four of the volunteers collected blood samples 30, 60, 120 and 180 minutes after dosing. The fifth volunteer did not take a blood sample. After 60 minutes of dosing, PET scans were started and stopped at 120 minutes of dosing.

The experiment was performed at doses of 7.5mg, 15mg and 22.5 mg.

Results

Table 1 shows the (+) - α -dihydrotetrabenazine plasma concentrations (in nanograms per milliliter) at 0.5, 1, 1.5, 2, and 3 hours after administration of doses of 7.5mg, 15mg, and 22.5mg to five human subjects. Table 2 shows the percentage of block of VMAT2 in five subjects following administration of doses of 7.5mg, 15mg and 22.5mg of (+) - α -dihydrotetrabenazine.

TABLE 1

BLQ-below quantitative range; ND-not detected

TABLE 2

Although higher (+) - α -dihydrotetrabenazine plasma concentrations were observed at a given dose in lighter weight subjects, it can be seen that at least 50% of the blockade of VMAT2 was observed at doses as low as 7.5mg even in heavier weight individuals, while the percent binding of VMAT2 was significantly higher in lighter weight individuals. It was also observed that mean plasma levels below 15ng/ml resulted in at least 50% of VMAT2 binding during PET scanning.

The data indicate that very low doses of (+) - α -dihydrotetrabenazine (resulting in plasma concentrations below 15ng/ml) can still result in higher levels of VMAT2 blockade.

The data for subjects 1 to 5 were used to generate a graph of the percentage of VMAT2 binding versus body weight at the three dose levels (figure 1) and a graph of the percentage of VMAT2 binding versus the amount of (+) - α -dihydrotetrabenazine administered (in mg/kg body weight) (figure 2). The data of subject 6 were somewhat abnormal and were not included in either figure 1 or figure 2.

Based on the above data, FIG. 1 shows the percentage of VMAT2 binding versus body weight for each (+) - α -DHTBZ dose (7.5mg, 15mg, and 22.5 mg). It is seen that there is a good correlation between body weight and percent VMAT2 binding for a given dose.

Based on the above data, figure 2 shows the percentage of VMAT2 binding as a function of the amount of (+) - α -DHTBZ administered to the subject per kg body weight. It is seen that there is a good correlation between the amount of (+) - α -DHTBZ per kg body weight administered to the subject and the percentage of VMAT2 binding.

Thus, the amount of (+) - α -DHTBZ that needs to be administered to provide a given level of VMAT2 binding is expected to depend largely on the body weight of the subject.

Example 2 comparison of the Effect of Dihydrotetrabenazin and Risperidone on Primatine-induced excitatory locomotion

The dopaminergic model of tourette's syndrome uses systemic or local administration of dopamine agonists, such as amphetamine. After amphetamine injection, the experimental animals showed stereotypical behavior. In particular, the dopaminergic system associated with tourette's syndrome can be stimulated with amphetamine in wild-type mice and rats, and the resulting hyperactivity and stereotypical behavior can be reversed with dopamine antagonists (e.g. risperidone and haloperidol) (tourette's syndrome-animal model screen, Charles river discovery Research Services, Finland).

Amphetamines elevate extracellular levels of dopamine in the brain of mice and other species of animals and produce concomitant performance. At relatively low doses (1.2 ng/kg i.p.), amphetamine increases locomotor activity, stops locomotion, and gives way to a resting position with highly repetitive rapid head movements. This post-stimulation non-motor phase is called focal stereotypy. The engraving may last for more than an hour, often followed by a period of exercise stimulation (Schiorring 1997).

It is known that administration of dopamine agonists (e.g. amphetamine) results in behavioral stereotype and sensorimotor gating interruptions. Furthermore, dopaminergic, cholinergic (TANs) and HDC models (pressure and/or post amphetamine injection) also showed an increase in stereotypical behavior (Yao et al, 2016).

Amphetamine-induced stereotypy was also evaluated as a model of dyskinesia status, tardive dyskinesia (see rubivisis et al (1972)).

The atypical antipsychotic risperidone is commonly used to treat tourette's syndrome and has been identified as perhaps the best atypical antipsychotic to suppress tics (j.d. walkup, tourette's syndrome drug guide, published in 2008, national tourette's syndrome association), with a lower risk of potential motor side effects than haloperidol and fluoropiperazine.

To compare the effects of dihydrotetrabenazine and risperidone on the excitatory locomotion in both the phenylpropylamine-induced and non-phenylpropylamine-induced rats, three studies were conducted, which for the reasons mentioned above are favorable models for tourette's syndrome and other movement disorders.

Materials and methods

Device

Open laboratory site, Med Associates Inc

1ml plastic syringe, Terumo. Reference numbers: SS-01T1

15G animal feeding needle, Instech Solomon, class No.: 72-4446

Sartorius mechanical electronic scale model a22101, Sartorius weighing Technology, germany

27G needle, Terumo Myjector, 0.5ml, reference number: 8300010463

3ml plastic syringe, Soft-Ject, reference number: 8300005761

BD Microtainer K2EDTA tube, reference number: 365975

Matrix 0.75ml, Alphanum tube, Thermo Scientific, reference number: 4274

Microplate apparatus, single plate 24 wells, 10ml, reference number: 734-1217

Heraeus Fresco 17, Thermo electronics, cryogenic centrifuge

Laboratory animal

All animal experiments were performed according to the National Institute of Health (NIH) guidelines for the management and use of laboratory animals, and approved by the Finland national animal testing Committee. Male CD (Charles River Laboratories, Germany) for the experiment ranged in weight from 200-250g (weight at arrival 165-200 g). Animals were kept in a standard temperature (22 + -1 deg.C) and light controlled environment (light from seven am to eight pm) with optional access to food and water.

Method of producing a composite material

The rats were tested for voluntary activity in an open laboratory setting. In the rat photoperiod, open field experiments were performed under conditions where normal light was evenly distributed to the experimental site. The activity path of the rat was recorded with an activity monitor (med.

The placebo, placebo-amphetamine, (+) -alpha-DHTBZ or risperidone were administered prior to the LMA trial. The rat was placed in the center of the test site and its 60 minute path was recorded.

Endpoint, blood sample and tissue treatment

Within 10 minutes after the end of the experiment, excess CO was used₂The experimental animals were euthanized. Except for placebo rats, each rat was subjected to a cardiac puncture method to collect a terminal blood sample, and 0.5ml of blood was collected using a syringe connected to an 18G needle and then transferred to a precooled K syringe₂EDTA microtubes. Mix EDTA and blood by inverting the tube several times. The tubes were then immediately placed on wet ice, centrifuged at 4 ℃ for 2 minutes (Heraeus Fresco 17, 9.6X 1000G/10X 1000RPM) within 10-15 minutes of collection, and 200. mu.l of plasma were collected according to the sample plot and placed in 96-well plates on dry ice (matrix technologies Screenmaterials, 0.75ml Alphanumeric round bottom storage tubes, PP).

After blood sampling, the neck was dislocated at the base of the skull. Brains were collected and weighed. The weight of the brain was recorded and the brain was cryopreserved in 24-well plates on dry ice.

The plasma and brain samples were stored at-80 ℃ until analysis for submission or destruction.

Study 1

The effect of (+) - α -dihydrotetrabenazine administered at doses of 0.5mg/kg to 2mg/kg and risperidone at 1mg/kg on stereotypical behavior and locomotor distance in rats was studied.

The animals were grouped as follows:

group 1: 10 rats were given placebo (t 0min) and placebo (t 30min)

Group 2: 10 rats were given placebo (t 0min) and amphetamine (t 30min)

Group 3: 10 rats were given 0.5mg/kg (+) - α -DHTBZ (t ═ 0min) and amphetamine (t ═ 30min)

Group 4: 10 rats were given 1mg/kg (+) - α -DHTBZ (t ═ 0min) and amphetamine (t ═ 30min)

Group 5: 10 rats were given 1.5mg/kg (+) - α -DHTBZ (t ═ 0min) and amphetamine (t ═ 30min)

Group 6: 10 rats were given 2mg/kg (+) - α -DHTBZ (t ═ 0min) and amphetamine (t ═ 30min)

Group 7: 10 rats were given 1mg/kg risperidone (t ═ 0min) and amphetamine (t ═ 30min)

Results

1. Distance of movement

Rats given placebo, 0.5mg/kg (+) - α -DHTBZ, 1mg/kg (+) - α -DHTBZ, 1.5mg/kg (+) - α -DHTBZ, 2mg/kg (+) - α -DHTBZ or 1mg/kg risperidone were first subjected to the LMA test for 30 minutes and then to the second LMA test for 60 minutes after placebo or amphetamine challenge. During the test period, the resulting autonomic activity was evaluated at 3min intervals and overall. Fig. 3 shows the normalized total movement distance over the test time.

The placebo-amphetamine group was significantly different compared to the placebo-placebo group. The placebo-placebo group, 0.5mg/kg (+) - α -DHTBZ group, 1mg/kg (+) - α -DHTBZ group, 1.5mg/kg (+) - α -DHTBZ group, 2mg/kg (+) - α -DHTBZ group, and 1mg/kg risperidone group were significantly different compared to the placebo-amphetamine group.

2. Carving behavior

Rats given placebo, 0.5mg/kg (+) - α -DHTBZ, 1mg/kg (+) - α -DHTBZ, 1.5mg/kg (+) - α -DHTBZ, 2mg/kg (+) - α -DHTBZ or 1mg/kg risperidone were first subjected to the LMA test for 30 minutes and then to the second LMA test for 60 minutes after placebo or amphetamine challenge. During the test, the resulting cliche activity was evaluated at 3min intervals and overall. Figure 4 shows the normalized total stereotype behavior over the time of the experiment.

The placebo-amphetamine group, the 0.5mg/kg (+) - α -DHTBZ group, and the 1.5mg/kg (+) - α -DHTBZ group were significantly different compared to the placebo-placebo group. The placebo-placebo group, 0.5mg/kg (+) - α -DHTBZ group, 1mg/kg (+) - α -DHTBZ group, 1.5mg/kg (+) - α -DHTBZ group, 2mg/kg (+) - α -DHTBZ group, and 1mg/kg risperidone group were significantly different compared to the placebo-amphetamine group.

Conclusion

The study evaluated the effect of 0.5mg/kg, 1mg/kg, 1.5mg/kg and 2mg/kg (+) - α -DHTBZ and 1mg/kg risperidone on the autonomously functioning of the phenylpropylamine-induced male CD rats.

All of the trial doses of (+) - α -DHTBZ and 1mg/kg risperidone resulted in reduced locomotor activity compared to the placebo-amphetamine group. All of the trial doses of (+) - α -DHTBZ and 1mg/kg risperidone resulted in a reduction in stereotypy compared to the placebo-amphetamine group. These two parameters tested indicate that (+) - α -DHTBZ has similar sedative effects as risperidone.

Study 2

The effect of (+) - α -dihydrotetrabenazine administered at doses of 0.1mg/kg to 0.25mg/kg and risperidone at 1mg/kg on stereotypy behavior and locomotor distance in rats was studied.

The animals were grouped as follows:

group 1: 10 rats were given placebo (t 0min) and placebo (t 30min)

Group 2: 10 rats were given placebo (t 0min) and amphetamine (t 30min)

Group 3: 10 rats were given 0.1mg/kg (+) - α -DHTBZ (t ═ 0min) and amphetamine (t ═ 30min)

Group 4: 10 rats were given 0.25mg/kg (+) - α -DHTBZ (t ═ 0min) and amphetamine (t ═ 30min)

Group 5: 10 rats were given 1mg/kg risperidone (t ═ 0min) and amphetamine (t ═ 30min)

Results

1. Distance of movement

Rats given placebo, 0.1mg/kg (+) - α -DHTBZ, 0.25mg/kg (+) - α -DHTBZ or 1mg/kg risperidone were first subjected to LMA test for 30 minutes and then to a second LMA test for 60 minutes after placebo or amphetamine challenge. During the test period, the resulting autonomic activity was evaluated at 3min intervals and overall. Fig. 5 shows the normalized total movement distance over the test time.

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

2. Carving behavior

Rats given placebo, 0.1mg/kg (+) - α -DHTBZ, 0.25mg/kg (+) - α -DHTBZ or 1mg/kg risperidone were first subjected to LMA test for 30 minutes and then to a second LMA test for 60 minutes after placebo or amphetamine challenge. During the test, the resulting cliche activity was evaluated at 3min intervals and overall. Figure 6 shows the normalized total stereotype behavior over the time of the experiment.

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

Conclusion

The study evaluated the effect of 0.1mg/kg, (+) - α -DHTBZ at 0.25mg/kg and risperidone at 1mg/kg on the independent activity of the phenylpropylamine-induced male CD rats.

Both 0.25mg/kg (+) - α -DHTBZ and 1mg/kg risperidone resulted in reduced locomotor activity compared to the placebo-amphetamine group. All of the trial doses of (+) - α -DHTBZ and 1mg/kg risperidone resulted in a reduction in stereotypy compared to the placebo-amphetamine group.

Study 3

The effects of (+) - α -dihydrotetrabenazine and risperidone on non-amphetamine-induced rats were studied.

The animals were grouped as follows:

group 1: 10 rats given placebo

Group 2: 10 rats, 2.5mg/kg (+) -alpha-DHTBZ

Group 3: 10 rats, 5mg/kg (+) -alpha-DHTBZ

Group 4: 10 rats given 1mg/kg risperidone

Results

In non-induced rats, the total locomotion and stereotypical behavior of rats given the placebo was comparable to rats given (+) - α -dihydrotetrabenazine (see figures 7 and 8 for details). However, both total locomotion and total stereotypical behavior were reduced in the rats given risperidone.

Study 4

The effect of the administration of 1mg/kg and 1.5mg/kg doses of (+) - α -dihydrotetrabenazine and valphenazine and 1mg/kg risperidone on the stereotypical behavior and the locomotor distance of rats was studied.

The animals were grouped as follows:

group 1: 10 rats were given placebo (t 0min) and placebo (t 30min)

Group 2: 10 rats were given placebo (t 0min) and amphetamine (t 30min)

Group 3: 10 rats were given 1mg/kg (+) - α -DHTBZ (t ═ 0min) and amphetamine (t ═ 30min)

Group 4: 10 rats were given 1.5mg/kg (+) - α -DHTBZ (t ═ 0min) and amphetamine (t ═ 30min)

Group 5: 10 rats were given 1mg/kg of valphenazine (t ═ 0min) and amphetamine (t ═ 30min)

Group 6: 10 rats were given 1.5mg/kg of valphenazine (t ═ 0min) and amphetamine (t ═ 30min)

Group 7: 10 rats were given 1mg/kg risperidone t 0min and amphetamine (t 30min)

Results

1. Distance of movement

Rats given placebo, (+) -alpha-DHTBZ, valphenazine or risperidone were first subjected to LMA trials for 30 minutes and then to a second LMA trial for 60 minutes after placebo or amphetamine challenge. During the test period, the resulting autonomic activity was evaluated at 3min intervals and overall. Fig. 9 shows the normalized total movement distance over the test time.

Compared with the placebo-amphetamine group, the placebo-placebo group, (+) -alpha-DHTBZ (1mg/kg and 1.5mg/kg) group, the valiphenazine (1mg/kg and 1.5mg/kg) group and the 1mg/kg risperidone group were significantly different.

2. Carving behavior

Rats given placebo, 0.1mg/kg (+) - α -DHTBZ, 0.25mg/kg (+) - α -DHTBZ or 1mg/kg risperidone were first subjected to LMA test for 30 minutes and then to a second LMA test for 60 minutes after placebo or amphetamine challenge. During the test, the resulting cliche activity was evaluated at 3min intervals and overall. Figure 10 shows the normalized total stereotype behavior over the time of the experiment.

Compared with the placebo-amphetamine group, the placebo-placebo group, (+) -alpha-DHTBZ (1mg/kg and 1.5mg/kg) group, the valiphenazine (1mg/kg and 1.5mg/kg) group and the 1mg/kg risperidone group were significantly different.

Conclusion

The study evaluated the effect of 1mg/kg and 1.5mg/kg (+) - α -DHTBZ and valiphenazine and 1mg/kg risperidone on the independent activity of the phenylpropylamine-induced male CD rats.

Compared to the placebo-amphetamine group, (+) - α -DHTBZ at 1mg/kg and 1.5mg/kg resulted in reduced autonomic activity. All of the trial doses of (+) - α -DHTBZ resulted in a reduction in stereotypy compared to the placebo-amphetamine group and the corresponding dose of valiphenazine.

Evaluation of

Studies 1 and 2 in example 2 show that (+) - α dihydrotetrabenazine at doses as low as 0.1mg/kg has a reducing effect on the movement of the rat induced by phenylpropylamine. Thus, it is expected that such low dose regimens may also be helpful in treating hyperkinetic dyskinesias in humans.

Study 3 in example 2 shows that after administration of a low dose of (+) - α -dihydrotetrabenazine, normal movement is not affected, although the type of abnormal movement found in dyskinesias is reduced or inhibited by the drug. This is in contrast to risperidone, a commonly used drug for the treatment of dyskinesias, where levels of both normal and abnormal movements are reduced.

Study 4 in example 2 shows that the therapeutic efficacy of (+) - α -dihydrotetrabenazine is higher than that of valbenazine.

Principle of equivalence

It will be evident that various modifications and changes may be made to the specific embodiments of the invention described above without departing from the broader principles of the disclosure. All such modifications and variations are intended to be included herein.