EA040574B1 - MODIFIED RELEASE SOLID ORAL DOSAGE FORM CONTAINING PRIDOPIDINE - Google Patents

Description

The present application claims priority of US Provisional Application No. 62/050626, filed September 15, 2014, and US Provisional Application No. 61/930358, filed January 22, 2014, the entire contents of which are hereby incorporated by reference into this specification.

Throughout this application, reference is made to various publications by first author and year of publication. Full citations of such publications are provided in the section entitled References immediately before the claims. The contents of these publications are thus fully incorporated by reference into the present application for the purpose of a more complete description of the state of the art to which the invention pertains.

Background of the Invention

Pridopidine (Gantexil) is a unique compound developed for the treatment of patients with motor symptoms associated with Huntington's disease. Its chemical name is 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine and its Chemical Registry number is 882737-42-0 (US Publication No. US-2013-0267552-A1). Methods for synthesizing pridopidine and a pharmaceutically acceptable salt thereof are described in US Pat. No. 7,923,459. 6903120 claim Pridopidine for the treatment of Parkinson's disease, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychosis and hallucinosis, mood and anxiety disorders, sleep disorders, autism spectrum disorders, ADHD, Huntington's disease, age-related cognitive impairment and disorders associated with alcohol abuse and drug abuse.

Brief summary of the invention

The present invention provides a modified release solid oral dosage form comprising a therapeutically effective amount of pridopidin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable rate controlling excipient, wherein the solid oral dosage form provides an in vivo plasma pridopidin concentration profile having a C _max about 1400 ng/ml or less.

The present invention also provides a modified release solid oral dosage form comprising a therapeutically effective amount of pridopidin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable rate regulating excipient, and wherein the solid oral dosage form provides an in vivo plasma pridopidin concentration profile having C _max from about 244 to about 1002 ng/ml when administered as a single dose and from about 244 to about 1568 ng/ml when administered at steady state.

The present invention also provides a modified release solid oral dosage form comprising a therapeutically effective amount of pridopidin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable rate regulating excipient, and wherein the solid oral dosage form provides an in vivo plasma concentration profile of pridopidin, having a _Cmax less than that obtained by twice daily administration of an immediate-release solid oral dosage form which contains:

a) half the amount of pridopidine or a pharmaceutically acceptable salt thereof, or

b) 10 to 49% of the amount of pridopidine or a pharmaceutically acceptable salt thereof.

The claimed invention also provides a pharmaceutical composition comprising a modified release solid oral dosage form and one or more pharmaceutically acceptable carriers or excipients.

The claimed invention also provides a modified-release solid oral dosage form or pharmaceutical composition for use in the treatment of Huntington's disease, Parkinson's disease, iatrogenic and non-iatrogenic parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinosis, schizophrenic disorders or schizophreniform disorders, mood disorders or anxiety, manic-depressive illness, depression, obsessive-compulsive disorder, sleep disorders, autism spectrum disorders, ADHD, age-related cognitive impairment, alcohol and substance abuse, Alzheimer's disease, or Rett syndrome.

The claimed invention also provides a method for treating a patient suffering from a condition selected from Huntington's disease, Parkinson's disease, iatrogenic and non-iatrogenic parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinosis, schizophrenic disorders or schizophreniform disorders, mood and anxiety disorders, manic-depressive disorder, depression, obsessive-compulsive disorder, sleep disorders, autism spectrum disorders, ADHD, age-related cognitive impairment, alcohol and substance abuse, Alzheimer's disease and Rett's syndrome, wherein the method comprises administering a modified-release solid oral dosage form or a pharmaceutical composition to a patient in need thereof.

The invention also provides a method for treating a patient suffering from a neurodegenerative or dopamine related disease comprising administering once daily a solid

- 1 040574 oral dosage form or modified release pharmaceutical composition.

Brief description of several types of drawings

Fig. 1 - Geometric mean plasma concentration of pridopidine versus time from example 1.

Fig. 2 - Observed and predicted relationship between plasma pridopidine levels and AAQTcF; the line represents the average predicted values in the population.

Fig. 3 - The rate of dissolution in vitro dosage forms MB-1, MB-2 and MB-3.

Fig. 4 - Plasma concentration-time profiles of pridopidine after twice-daily single dose administration: GastroPlus method of confirmation: sham single dose of 22 mg pridopidine IR (IR), and comparison with data from the study. Fig. 4a is simulated data and FIG. 4b is data from the study.

Fig. 5 - Plasma concentration-time profiles of pridopidine after multiple doses twice daily: GastroPlus confirmation method: Simulated (steady state) pharmacokinetic (PK) (PK) profile after 45 mg pridopidine IR twice daily, and comparison with data from research. Fig. 5a is simulated data and FIG. 5b is data from the study.

Fig. 6 (a-b) Curves of mean plasma levels of pridopidine after oral administration of pridopidine as various formulations of MB and control NI, period 0-12h (a) and semi-log representation (b).

Detailed description of the invention

The present invention provides a modified release solid oral dosage form comprising a therapeutically effective amount of pidopidine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable rate regulating excipient, wherein the solid oral dosage form provides an in vivo plasma concentration profile of pidopidine having an average C _max is about 1400 ng/ml or less.

In one embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidin having a mean C _max of about 1157 ng/mL or less.

In one embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidin having a mean C _max of about 906 ng/mL or less.

In one embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidin having a mean C _max of about 499 ng/mL or less.

In one embodiment of the invention, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidin having a mean C _max of about 718 ng/mL or less, measured after administration of a single dose.

In one embodiment of the invention, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidin having a mean C _max of about 486 ng/mL or less, measured after administration of a single dose.

In one embodiment of the invention, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidin having a mean C _max of about 327 ng/mL or less, measured after administration of a single dose.

In one embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidin having a C _max of about 382 to about 1568 ng/mL.

In one embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidin having a C _max of about 244 ng/mL to about 1002 ng/mL. In another embodiment, the solid oral dosage form provides an in vivo plasma profile having a C _max between 244 and 813 ng/mL. In another embodiment, the solid oral dosage form provides an in vivo plasma profile having a C _max between 493 and 1002 ng/mL. In one embodiment, the solid oral dosage form provides an in vivo plasma profile having a C _max between 324 and 813 ng/mL. In one embodiment, the solid oral dosage form provides an in vivo plasma profile having a C _max between 871 and 1568 ng/mL.

In one embodiment, the solid oral dosage form provides an in vivo plasma profile having a C _max between 382 and 1287 ng/mL.

In one embodiment, the solid oral dosage form provides an in vivo plasma profile having a C _max between 639 and 1287 ng/mL.

In one embodiment of the invention, the average AUC _tau is about 5253 ng/ml or more. In another embodiment of the invention, the average AUC _tau is about 7178 ng/ml or more. In another embodiment of the invention, the average AUC _tau is about 14185 ng/ml or more. In another embodiment of the invention, the average AUC _tau is about 18065 ng/ml or more.

In one embodiment, the AUC _0-inf is about 2249 ng/ml or more. In another embodiment of the invention, the average AUC ₀ _ _inf is about 5043 ng/ml or more. In another embodiment of the invention, the average AUC ₀ _ _inf is about 7897 ng/ml or more. In another embodiment of the invention, the average AUC ₀ _ _inf is about 13594 ng/ml or more.

In one embodiment, the dosage form comprises from about 22.5 to about 350 mg of pridopidine, or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises from about 45 to about 300 mg of pridopidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the dosage form comprises from about 90 to about 250 mg of pridopidine, or a pharmaceutically acceptable salt thereof. In another embodiment of the invention, the dosage form includes at least about 90 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 100 mg of pridopidine, or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 125 mg of pridopidine, or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 135 mg of pridopidine, or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 150 mg of pridopidine, or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 180 mg or more of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 200 mg or more of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 225 mg or more of pridopidine or a pharmaceutically acceptable salt thereof. In one embodiment, the dosage form comprises at least about 250 mg of pridopidine, or a pharmaceutically acceptable salt thereof, or more. In another embodiment of the invention, the dosage form includes at least about 315 mg of pridopidine or its pharmaceutically acceptable salt or more. In another embodiment, the dosage form comprises about 90 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 100 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 125 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 135 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 150 mg of pridopidine or a pharmaceutically acceptable salt thereof.

In another embodiment, the dosage form comprises about 180 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 200 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 225 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 250 mg of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 315 mg of pridopidine or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, the in vivo plasma profile is assessed at steady state.

In one embodiment of the invention, the in vivo plasma profile is assessed after administration of a single dose.

The present invention also provides a modified release solid oral dosage form comprising a therapeutically effective amount of pidopidine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable rate regulating excipient, and wherein the solid oral dosage form provides an in vivo plasma concentration profile of pidopidine, having an average _Cmax less than the average _Cmax resulting from twice-daily administration of an immediate-release solid dosage form that contains:

a) half the amount of pridopidine or a pharmaceutically acceptable salt thereof, or

b) 10 to 49% of the amount of pridopidine or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is greater than 45 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least

- 3 040574 about 90 mg of pridopidine and the immediate release dosage form contains about 45 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 100 mg of pridopidine and the immediate release solid dosage form contains about 45 mg of pridopidine. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is at least about 125 mg of pridopidine and the immediate release solid oral dosage form contains about 45 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 135 mg of pridopidine and the immediate release solid oral dosage form contains about 45 mg of pridopidine. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is at least about 135 mg of pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of pridopidine. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is at least about 150 mg of pridopidine and the immediate release solid oral dosage form contains about 45 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 150 mg of pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 180 mg of pridopidine and the immediate release solid oral dosage form contains about 45 mg of pridopidine.

In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is at least about 180 mg of pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 180 mg of pridopidine and the immediate release solid oral dosage form contains about 90 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 200 mg of pridopidine and the immediate release solid oral dosage form contains about 45 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 200 mg of pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of pridopidine. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is at least about 200 mg of pridopidine and the immediate release solid oral dosage form contains about 90 mg of pridopidine. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is at least about 225 mg of pridopidine and the immediate release solid oral dosage form contains about 45 mg of pridopidine. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is at least about 225 mg of pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of pridopidine.

In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 225 mg of pridopidine and the immediate release solid oral dosage form contains about 90 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 225 mg of pridopidine and the immediate release solid oral dosage form contains about 112.5 mg of pridopidine. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is at least about 250 mg of pridopidine and the immediate release solid oral dosage form contains about 45 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 250 mg of pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 250 mg of pridopidine and the immediate release solid oral dosage form contains about 90 mg of pridopidine. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is at least about 250 mg of pridopidine and the immediate release solid oral dosage form contains about 112.5 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of pridopidine and the immediate release solid oral dosage form contains about 45 mg of pridopidine. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is at least about

- 4 040574

315 mg of pridopidine and an immediate release solid oral dosage form contains about 67.5 mg of pridopidine. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is at least about 315 mg of pridopidine and the immediate release solid oral dosage form contains about 90 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of pridopidine and the immediate release solid oral dosage form contains about 112.5 mg of pridopidine. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of pridopidine and the immediate release solid oral dosage form contains about 157.5 mg of pridopidine.

In another embodiment of the invention, the amount of pridopidine or a pharmaceutically acceptable salt thereof is about 90 mg. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is about 100 mg. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is about 125 mg. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is about 135 mg. In another embodiment, the amount of pridopidine, or a pharmaceutically acceptable salt thereof, is about 150 mg. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is about 180 mg. In another embodiment of the invention, the amount of pridopidine or a pharmaceutically acceptable salt thereof is about 200 mg. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is about 225 mg. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is about 250 mg. In another embodiment, the amount of pridopidine or a pharmaceutically acceptable salt thereof is about 315 mg.

In one embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidine having an average AUC _tau that is at least about 50% of the average AUC _tau provided by twice-daily administration of an immediate-release solid oral dosage form that contains half the amount of pridopidine or its pharmaceutically acceptable salt. In another embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidine having an average AUC _tau that is at least about 60% of the average AUC _tau provided by twice-daily administration of an immediate-release solid oral dosage form that contains half the amount of pridopidine or its pharmaceutically acceptable salt. In another embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidine having a mean AUCtau that is at least about 70% of the mean AUCtau provided by twice-daily administration of an immediate-release solid dosage form that contains half the amount of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidine having an average AUC _tau that is at least about 80% of the average AUC _tau provided by twice-daily administration of an immediate-release solid oral dosage form that contains half the amount of pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidine having an average AUCtau that is at least about 90% of the average AUCtau provided by twice-daily administration of an immediate-release solid oral dosage form that contains half the amount pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidine having an average AUC _tau that is at least about 95% of the average AUC _tau provided by twice-daily administration of an immediate-release solid oral dosage form that contains half the amount of pridopidine or a pharmaceutically acceptable salt thereof.

In one embodiment, the twice-daily administration of the immediate-release solid oral dosage form has a time interval between doses of 5-10 hours. h. In another embodiment, the twice-daily administration of the immediate-release solid oral dosage form has a dose interval of 6.5 hours. In another embodiment, the twice-daily administration of the immediate-release solid oral dosage form has a dose interval of 7 h.

In one embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidin having a mean C _max that is reduced

- 5 040574 as a percentage compared to the average C _max obtained as a result of the introduction of twice a day dosage form of immediate release, which contains half the amount of pridopidine or its pharmaceutically acceptable salt, where the percentage is at least 5%. In another embodiment of the invention, the percentage is at least 10%. In another embodiment of the invention, the percentage is at least 20%. In another embodiment of the invention, the percentage is at least 30%. In another embodiment of the invention, the percentage is at least 40%. In another embodiment of the invention, the percentage is at least 50%. In another embodiment of the invention, the percentage is at least 60%. In another embodiment of the invention, the percentage is at least 70%. In another embodiment of the invention, the percentage is at least 10 and 60%. In another embodiment of the invention, the percentage is from 20 to 50%. In another embodiment of the invention, the percentage is about 25%. In another embodiment of the invention, the percentage is about 35%. In another embodiment of the invention, the percentage is about 50%.

In one embodiment, the average time required to reach peak plasma, serum, or blood drug concentration after drug administration is greater than 2 hours. In another embodiment, the average time required to reach peak plasma drug concentration is serum or blood after drug administration is more than 4 hours.

In one embodiment of the invention, the pharmaceutically acceptable salt of pridopidine is the hydrochloride salt.

In another embodiment of the invention, the in vivo plasma profile is assessed at steady state.

In one embodiment of the invention, the in vivo plasma profile is assessed after administration of a single dose.

In one embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidine having a mean AUC ₀ _ _inf that is at least about 50% of the mean AUC ₀ _ _inf provided by twice-daily administration of the solid oral dosage form. immediate release, which contains half the amount of pridopidine or its pharmaceutically acceptable salt.

In one embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidine having a mean AUC ₀ _ _inf that is at least about 55% of the mean AUC ₀ _ _inf provided by twice-daily administration of the solid oral immediate dosage form. release, which contains half the amount of pridopidine or its pharmaceutically acceptable salt.

In one embodiment, the solid oral dosage form provides an in vivo plasma concentration profile of pridopidine having a mean AUC ₀ _ _inf that is at least about 75% of the mean AUC ₀ _ _inf provided by twice-daily administration of the immediate solid oral dosage form. release, which contains half the amount of pridopidine or its pharmaceutically acceptable salt.

In one embodiment of the invention, the solid oral dosage form releases no more than 50% of pridopidin after 1 hour when the oral dosage form is placed in an apparatus with a basket of 500 ml HCl 0.1 N at 37° C., rotating at 100 rpm. . In one embodiment, the solid oral dosage form releases no more than 75% of pridopidine after 3 hours when the oral dosage form is placed in a device with a basket of 500 ml HCl 0.1 N at 37° C. rotating at 100 rpm. for 120 minutes and then in buffered phosphate having a pH of 6.8 for 12 hours. in 500 ml HCl 0.1 N at 37°C rotating at 100 rpm for 120 minutes and then in buffered phosphate having a pH of 6.8 for 12 hours. form releases no more than 30% of pridopidine after 2 hours when the oral dosage form is placed in the instrument with a basket of 500 ml HCl 0.1 N at 37°C, rotating at 100 rpm for 120 minutes and then in fer phosphate having a pH of 6.8 for 12 hours. In another embodiment of the invention, the solid oral dosage form releases no more than 50% of pridopidin after 4 hours when the oral dosage form is placed in a device with a basket of 500 ml HCl 0.1 H at 37°C, rotating at 100 rpm for 120 minutes and then in buffered phosphate having a pH of 6.8 for 12 hours. In another embodiment, the solid oral dosage form releases no more than 65% pridopidine after 6 hours, when the oral dosage form is placed in the device with a basket in 500 ml HCl 0.1 N at 37°C, rotating at 100 rpm for 120 minutes and then in buffered phosphate having a pH of 6.8 , within 12 hours. In another

- 6 040574 embodiment of the invention, the solid oral dosage form releases at least 75% of pridopidin after 12 hours when the oral dosage form is placed in a device with a basket in 500 ml HCl 0.1 N at a temperature of 37°C, rotating at 100 vol./ min for 120 min and then in buffered phosphate having a pH of 6.8 for 12 h.

In one embodiment of the invention, the dosage form is in the form of a capsule. In another embodiment of the invention, the dosage form is the form of a tablet.

In one embodiment of the invention, the rate control aid is a polymeric material.

In one embodiment of the invention, the polymer may be hydrophobic or hydrophilic. In one embodiment, the polymeric material is selected from the group consisting of hydrogenated castor oil, polyethylene oxide, hydroxypropylcellulose (HPMC) ethylcellulose, hydroxypropylcellulose (HPC), polyvinyl alcohol (PVA), vinyl alcohol polymer, polyacrylates, polymethacrylates, ethyl acrylate-methyl methacrylate copolymers, glyceryl monostearate and mixtures thereof.

In one embodiment, the rate control aid is a combination of two or more polymeric materials, preferably wherein the rate control aid is a combination of at least hydroxypropyl methylcellulose (HPMC) and hydrogenated castor oil.

In one embodiment of the invention, the polymeric material is hydroxypropylmethylcellulose. In another embodiment of the invention, the polymeric material is hydrogenated castor oil.

In one embodiment, the total amount of rate-adjusting excipients is from about 8% to about 70% of the total weight of the dosage form, from about 10% to about 50% of the total weight of the dosage form, or from about 20% to about 50% of the total weight of the dosage form, about 30% to about 50%, or about 30% to about 40%, of the total weight of the dosage form.

In one embodiment of the invention, the polymeric material makes up 10 to 50% by weight of the solid oral dosage form.

In one embodiment of the invention, the polymeric material makes up 20 to 50% by weight of the solid oral dosage form. In another embodiment of the invention, the polymeric material comprises 30 to 50% by weight of the solid oral dosage form. In another embodiment of the invention, the polymeric material comprises 30 to 40% by weight of the solid oral dosage form. In another embodiment of the invention, the polymeric material comprises 35 to 40% by weight of the solid oral dosage form. In another embodiment of the invention, the polymeric material makes up at least 10% by weight of the solid oral dosage form. In another embodiment of the invention, the polymeric material makes up at least 20% by weight of the solid oral dosage form. In another embodiment of the invention, the polymeric material makes up at least 25% by weight of the solid oral dosage form. In another embodiment of the invention, the polymeric material makes up at least 30% by weight of the solid oral dosage form. In another embodiment of the invention, the polymeric material makes up at least 35% by weight of the solid oral dosage form. In another embodiment of the invention, the polymeric material makes up at least 40% by weight of the solid oral dosage form. In another embodiment of the invention, the polymeric material makes up at least 37% by weight of the solid oral dosage form. In another embodiment, the polymeric material makes up at least 38% by weight of the solid oral dosage form. In another embodiment of the invention, the polymeric material makes up at least 40% by weight of the solid oral dosage form.

In one embodiment, the modified release solid oral dosage form further comprises ethylcellulose.

In one embodiment, the total amount of ethylcellulose is from about 0.5 to about 10% of the total weight of the dosage form, from about 0.5 to about 7.2% of the total weight of the dosage form, from about 1.0 to about 5% of the total weight dosage form, from about 1.0 to about 3.0% of the total weight of the dosage form, from about 1.5 to about 3.0% of the total weight of the dosage form, or from about 1.5 to about 2.4% of the total weight of the dosage form .

In another embodiment, ethyl cellulose makes up about 1.5% by weight of the solid oral dosage form. In one embodiment of the invention, ethylcellulose is about 3.0 or about 2.4 wt.% solid oral dosage form.

In another embodiment of the invention, the polymeric material is hydroxypropyl methylcellulose and wherein the hydroxypropyl methylcellulose is about 38% by weight of the solid oral dosage form.

In one embodiment, the polymeric material is hydrogenated castor oil, and wherein the hydrogenated castor oil makes up about 38% by weight of the solid oral dosage form.

In one embodiment, the polymeric material is hydroxypropyl methylcellulose, wherein the hydroxypropyl methylcellulose is about 37% by weight of the solid oral dosage form and where ethylcellulose is from about 1.5% to about 3.0% by weight of the solid oral dosage form.

In one embodiment, the weight ratio of pridopidine or a pharmaceutically acceptable salt thereof to the rate-adjusting excipient is from about 0.2:1 to about 1:1, preferably from about 0.3:1 to about 0.8:1, more preferably from about 0.5:1 to about 0.7:1.

In one embodiment, the modified release solid oral dosage form further comprises a mucoadhesive.

In one embodiment, the mucoadhesive is selected from the group consisting of water-soluble and water-insoluble hydrophilic polymers, polymers that contain swellable networks, hydrogels, and polymers with groups that can cross-link with other polymers or with the mucosa, preferably the mucoadhesive is polyethylene oxide.

In one embodiment, pridopidine, or a pharmaceutically acceptable salt thereof, comprises from about 15% to about 60% by weight of the dosage form. In another embodiment, pridopidine, or a pharmaceutically acceptable salt thereof, comprises from about 25% to about 50% by weight of the dosage form.

In one embodiment, pridopidine, or a pharmaceutically acceptable salt thereof, makes up about 25% by weight of the dosage form.

The claimed invention also provides a pharmaceutical composition comprising a modified release solid oral dosage form and one or more pharmaceutically acceptable carriers or excipients.

In one embodiment of the invention, pharmaceutically acceptable carriers or excipients are selected from the group consisting of a binder, a filler, a plasticizer, a glidant and a lubricant, and mixtures thereof.

In one embodiment, the binder is selected from the group consisting of starch, peptized starch, polyethylene oxide, cellulose polymers, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and mixtures thereof.

In one embodiment, the filler is selected from the group consisting of microcrystalline cellulose, sugar globules, lactose, sorbitol, dextrose, sucrose, mannitol, dibasic or tribasic calcium phosphate, starch, retalac, and mixtures thereof.

In one embodiment of the invention, the filler is microcrystalline cellulose and is silicified microcrystalline cellulose.

In one embodiment of the invention, the filler is lactose. In another embodiment of the invention, the filler is a mixture of microcrystalline cellulose and lactose, and where the microcrystalline cellulose is silicified microcrystalline cellulose.

In one embodiment, the excipient comprises from 5 to about 64% by weight of the solid oral dosage form, from 10 to about 50% by weight of the solid oral dosage form, from 15 to about 45% by weight of the solid oral dosage form, from 20 to 40 wt.% solid oral dosage form, about 34 wt.% solid oral dosage form, about 16 wt.% solid oral dosage form, about 17 wt.% solid oral dosage form, or about 18 wt.% solid oral dosage form.

In one embodiment, the excipient is a mixture of silicified microcrystalline cellulose and lactose, wherein the silicified microcrystalline cellulose is about 16% by weight of the solid oral dosage form and lactose is about 17% or about 18% by weight of the solid oral dosage form. In one embodiment of the invention, the plasticizer is selected from the group consisting of polyethylene glycol, triethyl citrate, tributyl citrate, glycerol, dibutyl sebacate, triacetin, diethyl phthalate, and mixtures thereof.

In one embodiment of the invention, the glidant is selected from the group consisting of: starch, peptized starch, silicon dioxide, colloidal silicon dioxide, talc, and mixtures thereof.

In one embodiment of the invention, the glidant is colloidal silicon dioxide.

In one embodiment, the glidant comprises 0.2% to about 4% by weight of the solid oral dosage form, 0.4% to about 3% by weight of the solid oral dosage form, or 0.43% to about 2.0% by weight solid oral dosage form.

In one embodiment, the glidant comprises 1.7% to about 4% by weight of the solid oral dosage form, 1.7% to about 3% by weight of the solid oral dosage form, 1.7% to about 2.0% by weight of the solid oral dosage form, from 1.7 and 1.8 wt.% solid oral dosage form, about 1.7 wt.% solid oral dosage form, or about

1.8 wt.% solid oral dosage form.

In one embodiment, the lubricant is selected from the group consisting of sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate, glyceryl monostearate, and mixtures thereof.

In one embodiment of the invention, the lubricant is magnesium stearate.

In one embodiment, the lubricant comprises 0.3% to about 4% by weight of the solid oral dosage form, 0.5% to about 3% by weight of the solid oral dosage form, or 1.1% to about 2.0% by weight solid oral dosage form.

In one embodiment, the lubricant comprises 1.7% to about 4% by weight of the solid oral dosage form, 1.7% to about 3% by weight of the solid oral dosage form, 1.7% to about 2.3% by weight solid oral dosage form, from 1.8 to about 2.2 wt.% solid oral dosage form, or about 2 wt.% solid oral dosage form.

The claimed invention also provides a modified-release solid oral dosage form or pharmaceutical composition for use in the treatment of Huntington's disease, Parkinson's disease, iatrogenic and non-iatrogenic parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinosis, schizophrenic disorders or schizophreniform disorders, mood disorders and anxiety, manic-depressive disorders, depression, obsessive-compulsive disorders, sleep disorders, autism spectrum disorders, ADHD, age-related cognitive impairment, alcohol and substance abuse, Alzheimer's disease or Rett's syndrome.

The claimed invention also provides a method for treating a patient afflicted with a condition selected from Huntington's disease, Parkinson's disease, iatrogenic and non-iatrogenic parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinosis, schizophrenic disorders or schizophreniform disorders, mood and anxiety disorders, manic - depressive disorders, depression, obsessive-compulsive disorders, sleep disorders, autism spectrum disorders, ADHD, age-related cognitive impairment, alcohol and substance abuse, Alzheimer's disease or Rett's syndrome, where the method includes administering a modified-release solid oral dosage form or pharmaceutical composition to a patient in need thereof.

In one embodiment, two doses of the modified release solid oral form or pharmaceutical composition are administered to a patient and the interval between the two doses is about 24 hours.

In one embodiment of the invention, the patient is a human.

In one embodiment, the dosage form has the following in vivo concentrations of the plasma concentration profile of pridopidine at steady state: C _max from about 499 to about 1400 ng/mL, mean C _max from about 499 to about 1157 ng/ml, or mean C _max from about 906 to about 1157 ng/ml. The invention also provides a method for treating a patient afflicted with a neurodegenerative disease or a dopamine related disease, comprising once daily administration of a modified release solid oral dosage form or pharmaceutical composition.

In one embodiment of the invention, the modified release solid oral dosage form or pharmaceutical composition is adapted for once daily administration.

For the above embodiments of the invention, each embodiment of the invention described in the present description is provided as applicable to any of the other described embodiments of the invention. In addition, the elements cited in the embodiments of the pharmaceutical composition can be used in the embodiments of the methods and uses described in the present description.

Terms

As used herein, the term C refers to the plasma/serum/blood concentration of the active pharmaceutical ingredient or drug following administration of the drug, e.g., pridopidine, or a pharmaceutically acceptable salt thereof, in a biological sample, such as a patient sample (e.g., blood , plasma, serum and cerebrospinal fluid). The concentration of a drug in a biological sample can be determined by any standard test method known in the art. The term C includes concentration estimates such as C _min , C _max and C _ss (average steady state concentration) and allows calculation of PK parameters such as AUC. Usually the term C refers to the concentration in plasma, serum or blood.

As used herein, a stable state refers to a situation in which

- 9 040574 the amount of drug eliminated in each administration interval corresponds to the dose for such an interval. In one embodiment of the invention, steady state administration as used herein is reached after 7 days. In one embodiment of the invention, steady state administration as used herein is reached after 9 days. In one embodiment of the invention, steady state administration as used herein is reached after 14 days.

As used herein, the term C _max refers to the maximum concentration of a drug in plasma, serum, or blood following administration of a drug, eg, pridopidine, or a pharmaceutically acceptable salt thereof. C _max measured at steady state is sometimes referred to as C _max ,ss. Mean C _max c _max ,ss and mean C _max0 - _t are the mean of the respective C _max measured in a patient sample. In one embodiment of the invention, patient samples include four or more patients. Preferably, the sample should include ten patients or more.

As used herein, the term _Cmin refers to the minimum plasma, serum, or blood drug concentration following administration of a drug, such as pridopidine, or a pharmaceutically acceptable salt thereof. C _min measured at steady state is sometimes referred to as C _min , _ss .

As used herein, the term T _max refers to the time required to reach the maximum plasma, serum, or blood drug concentration (C _max ) following administration of a drug, such as pridopidine, or a pharmaceutically acceptable salt thereof. T _max measured at steady state is sometimes referred to as T _max ,ss.

As used herein, the term AUC refers to the area under the curve of plasma, serum, or blood concentration versus time.

As used herein, the terms AUCt and AUC ₀ _ _t refer to the area under the plasma, serum, or blood concentration versus time curve, where t is the last time point measured.

As used herein, the terms AUC _inf , AUC ₀ _ _inf , AUC , AUC ₀ .„ and AUC _infinity refer to the area under the curve of plasma, serum or blood concentration versus time extrapolated to infinity.

As used herein, the terms AUG _tau and AUG ₀ _ _tau refer to the area under the curve of plasma, serum, or blood drug concentration versus time over a single administration interval following administration of a drug such as pridopidine or a pharmaceutically acceptable salt thereof. The area under the curve is measured over time tau, where tau is the duration of the administration interval. The term AUC _tau ,ss evaluates exposure over a steady state administration interval. As used herein, tau is a 24-hour interval, which includes cases in which the drug is administered twice a day. Average AUG, average AUCt, average AUG ₀ . _t , mean AUG _inf , mean AUG _tau and mean AUC0- _tau are the means of the corresponding AUC estimated in a patient sample. In one embodiment, the patient samples include four or more patients. Preferably, the sample should include ten patients or more.

As used herein, single dose administration means that the drug is administered over a 24 hour interval, either once a day (1 r/d) or twice a day (2 r/d).

As used in the present description, the term immediate release or IR (IR) means that the release or release in the body of a drug, such as pridopidine or its pharmaceutically acceptable salt, from the dosage form (tablets, capsules, lozenges, etc.) occurs immediately or soon after administration, usually within minutes to several hours. For example, 80% of the drug may be dissolved within the first hour. The drug is released in a single action and the time of drug action is often limited.

As used herein, the term modified release or (MB)MR means that the release or release of a drug, such as pridopidine or a pharmaceutically acceptable salt thereof, from a dosage form (tablets, capsules, lozenges, etc.) has been modified such that the release rate is lower than in the unmodified or immediate release dosage form. The release of the drug takes place at a point in time after administration, or for a long period after administration, or at a specific target in the body. The release of the drug may occur over several hours or over several days in order to maintain a therapeutically effective plasma concentration of the drug. Modified release encompasses delayed release (release at a time point other than immediately after administration), sustained release (release over an extended period of time), sustained release (release rate of the drug is maintained over a period of time), and controlled release (release rate of the drug drug is adjusted to obtain a specific concentration profile of the drug in the body).

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As used herein, a slower dissolution profile is one in which the release or release of the drug from the dosage form is slower, i.e. drug release takes longer with a slower dissolution profile than with a faster dissolution profile.

As used herein, the term rate-adjusting excipient refers to an excipient or combination of excipients present in amounts sufficient to reduce the rate of release of a drug, such as pridopidine or a pharmaceutically acceptable salt thereof, from a dosage form. A rate-adjusting excipient or combination thereof controls the rate of release of the drug from the dosage form.

As used herein, the term at least one pharmaceutically acceptable rate regulating excipient or one or more pharmaceutically acceptable rate regulating excipients refers to the presence of one, two, three, four or more rate regulating excipients in a dosage form.

As used herein, the term pridopidin refers to the free base of pridopidin. In certain embodiments, pridopidine also includes any pharmaceutically acceptable salt, such as the HCl salt. Preferably, in any embodiments of the invention as described herein, pridopidine is in the form of its hydrochloride salt.

As used herein, the amount or dose of pridopidine, as measured in milligrams, refers to the milligrams of pridopidin base present in a formulation, regardless of the form of the formulation. A dosage of 90 mg of pridopidine means that the amount of pridopidine base in the preparation is 90 mg, regardless of the form of the preparation. Therefore, when in the form of a salt, for example the hydrochloride salt of pridopidine, the mass of salt required to provide a dose of 90 mg of pridopidine will be greater than a mg of pridopidine due to the presence of an additional salt ion.

As used herein, unit dose, unit dose, and unit dosage form(s) refers to the administration of a single drug.

As used herein, about in the context of a numerical value or range means ±10% of the numerical value or range specified or claimed.

As used in the present description, the term once a day means the introduction of a dose every 24 hours. As used herein, 1 p/d (QD) refers to once daily administration.

As used herein, reference to total dosage form weight refers to the total weight of the tablet (including any final shell), and in the case of a capsule, refers to the total weight of the contents of the capsule, excluding the weight of the capsule itself.

As used herein, the term bioavailability refers to the rate and extent to which an active pharmaceutical ingredient is absorbed from a dosage form and becomes available at the site of action.

A pharmacokinetic parameter, or combinations of such parameters, indicates the bioavailability of an active pharmaceutical ingredient such as pridopidine following administration of pridopidine or a pharmaceutically acceptable salt thereof. Such pharmacokinetic parameters are known to the person skilled in the art. Examples of such parameters include C _max , AUC, AUC _tau and T _max ..

The dosage forms of the present invention are formulated such that pridopidine or a pharmaceutically acceptable salt thereof has an in vitro dissolution profile that is slower than that of an immediate release (IR) formulation. Dosage forms of the present invention may contain immediate release, sustained or extended release or delayed release components, or combinations thereof.

Pridopidine or a pharmaceutically acceptable salt thereof in solid oral dosage forms of the present invention may be provided in a modified release form such as a modified, controlled or extended release (ER) form, with or without an immediate release (IR) component.

Modified release dosage forms can be prepared by, without limitation, providing lozenges of varying thickness so that the thinnest will release the drug first and the thickest last, including a slowly dissolving matrix or shell comprising an insoluble shell around a tablet or capsule with small holes to allow release. drug (by diffusion or solvation), controlling the release of the drug by diffusion through the shell or matrix or by erosion of the matrix or shell by a process dependent on, for example, a certain condition, such as the presence of enzymes or a certain pH. Modified release dosage forms contain higher amounts of drug than those present in unmodified or immediate release dosage forms.

Solid oral dosage forms of the present invention include all pharmaceutically acceptable salts of pridopidine. Preferably pridopidine is in the form of its hydrochloride salt.

The modified release solid oral dosage form of the present invention is suitable for administration in a single unit dosage form. Oral dosage forms for the purposes of the present invention include capsules, tablets, lozenges, granules, coated and uncoated powders, and combinations thereof. Optionally, if the dosage form is a capsule, pridopidine or a pharmaceutically acceptable salt thereof is provided in the form of coated or uncoated lozenges, granules, powders, mini-tablets, tablets or capsules.

As used herein, a polymeric material includes any polymer. Any suitable polymeric material can be used in accordance with the directions provided in the present description. The polymeric material may have any suitable configuration and may take any suitable form.

Dosage forms of the present invention may include mucoadhesives to slow the passage of the dosage form through the body so that the dosage form remains in the body long enough for all pridopidine to be released in the body.

Solid oral dosage forms of the present invention may further include one or more mucoadhesives. Mucoadhesives slow the passage of the dosage form through the body such that the dosage form remains in the body during the interval between administrations so that pridopidine or a pharmaceutically acceptable salt thereof is released in the body. Mucoadhesives are substances that adhere to biological tissues over a long period of time through interfacial forces. The biological tissue is the mucous membrane. Mucoadhesion develops when the mucoadhesive contacts and adheres to the membrane by wetting the mucoadhesive surface or by swelling of the mucoadhesive. Additional adhesion develops when the mucoadhesive penetrates the crevices of the membrane surface or when the mucoadhesive chains interact with those of the mucus on the membrane. Suitable mucoadhesives are polymers that are water-soluble or water-insoluble hydrophilic polymers, polymers that contain swellable networks, hydrogels, and polymers with groups that can cross-link to other polymers or to the mucosa.

Modified release solid oral dosage forms of the present invention may include at least one mucoadhesive with or without an immediate release component. For example, dosage forms of the present invention may include at least one mucoadhesive with a single sustained release component.

Silicified microcrystalline cellulose can be any commercially available form of such excipients, such as Prosolv® SMCC 90.

Hydroxypropyl methylcellulose (HPMC) may be a commercially available form of such a hydrophilic carrier, eg Methocel™ K100 Premium CR, Methocel DC2, Benecel ME 233P.

Spray dried lactose (SD), anhydrous lactose and lactose monohydrate can be used interchangeably throughout the present invention.

Colloidal silicon dioxide (CSD) is a colloidal silicon dioxide, usually obtained by vapor phase hydrolysis of a silicone compound such as silicon tetrachloride. The product as such is typically a powder that is commercially available from a number of sources including Degussa, Inc. (under the trade name Aerosil®); Cabot Corporation (under the trade name Cab-O-Sil); Huber Engineered Materials (Huber GL100 and GL200); Wacker (Wacker HDK®) and E.I. DuPont & Co. Colloidal silica is also known as colloidal silica, fumed silica, light anhydrous silicic acid, silicic anhydride, and fumed silica, among others. Many commercial CSD degrees are obtained by varying the manufacturing process.

Ethylcellulose can be added to the composition in the form of a dispersion, such as Surelease®.

The peptized starch may be any commercially available form of such material, such as Starch 1500®. LubriTose™ is lactose plus 2 to 10% glyceryl monostearate (GMS), LubriTose™ Yellow contains 10% GMS and LubriTose™ blue contains 2% GMS.

Tablets may contain suitable binders, lubricants, disintegrants, coloring agents, flavoring agents, flow inducing agents, melting agents and plasticizers. For example, for oral administration in tablet or capsule unit dosage form, the active drug component may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as xylose, gelatin, agar, starch, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like. Suitable binders include starch, gelatin, natural sugars such as cornstarch, natural or synthetic gums such as gum arabic, tragacanth or sodium alginate, povidone, polyvidone, carboxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, waxes, and the like. Glidants used in such dosage forms include silicon dioxide and the like. Lubricants used in such dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, stearic acid, sodium stearyl fumarate, talc, and the like. Disintegrating agents include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, sodium croscarmellose, sodium starch glycolate, and the like; suitable plasticizers include triacetin, triethyl citrate, dibutyl sebacate, polyethylene glycol, and the like.

Modified release solid oral dosage forms of the present invention may further comprise one or more pharmaceutically acceptable carriers or excipients.

Examples of pharmaceutically acceptable excipients are fillers, binders, glidants, plasticizers and lubricants.

Tablets in accordance with the present invention can be obtained by conventional methods of mixing, crushing and tabletting, which are well known in the manufacture of pharmaceutical compositions. A modified release tablet, for example, can be made by direct compression in molds and dies located on a rotary tablet press, extrusion or compression moulding, drying the wet granules, followed by compression or making a paste, and extruding the paste into a mold and cutting the extrudate into short pieces. Preferably, the process used to make tablets is direct compression of the mixture.

Pressing can be carried out using conventional equipment. Typically, a mixture of active ingredients, with or without auxiliary substances, is passed through a roller compression device. However, other means may be used to compress the API mixture, such as compressing into billets (or lumping).

To achieve the desired modified release rate, the modified release dosage form can be formulated as a polymer shell or matrix.

The USP #1 instrument (basket) is instrument 1 described in the United States Pharmacopeia, 29th edition, section 711. The instrument may be constructed as follows:

The layout consists of the following: a closed vessel consisting of glass or other inert transparent material; engine; metal bearing shaft; and a cylindrical basket. The vessel is partially immersed in a suitable water bath of any convenient size or placed in a heating mantle. The water bath or heating mantle maintains the temperature inside the vessel at 37 ± 0.5 during the test and keeps the bath liquid in constant, gentle motion. None of the assembly, including the environment in which the assembly is placed, contributes to significant movement, shaking or vibration when compared to those of a gently rotating agitating element. An instrument that allows the sample and stirring element to be observed during the test is preferred. The vessel is cylindrical, with a hemispherical bottom and with one of the following dimensions and capacities: for a nominal capacity of 1 l, the height is 160-210 mm and its internal diameter is between 98 and 106 mm; for a nominal capacity of 2L, the height is from 280 to 300mm and its inner diameter is from 98 to 106mm; and for a nominal capacity of 4L, the height is from 280 to 300mm and its inner diameter is from 145 to 155mm. Its sides are ribbed on top. A suitable lid may be used to prevent evaporation. The handle is positioned so that its axis is not more than 2 mm from any point on the vertical axis of the vessel and rotates smoothly and without significant oscillation. Use a speed control device that allows you to select the speed of rotation of the handle and maintain the speed set in a certain article within ± 4%. The stirrer handle and basket components are 316 stainless steel or equivalent.

Unless otherwise stated in a separate article, size 40 fabric is used. A basket having a 0.0001 inch (2.5 µm) thick gold plating may be used. The dosage form is placed in a dry basket at the beginning of each test. The distance between the inner bottom of the vessel and the basket is kept at 25+2 mm during the test.

pridopidin

Pridopidin is absorbed relatively quickly after oral administration with t _max 0.5-4 h (Lindskov 2012). Following absorption, pridopidine is eliminated partly via urinary excretion, partly via hepatic metabolism, and predominantly via N-depropylation via the CYP2D6 pathway to one major inactive metabolite, 4-(3-(methylsulfonyl)phenyl)piperidine, with a half-life after repeated doses of 10 -14 h. CYP2D6 polymorphisms can be classified according to one of four levels of activity: poor metabolizers (PM (PM)), intermediate metabolizers (IrM (IM)), fast metabolizers (BM (EM)) and ultra-rapid metabolizers (UM ( UM)). The BM phenotype is expressed in most of the population (about 90%). Approximately 5-10% Caucasian population of Europe and North America and 1% Chinese, Japanese and Koreans

- 13 040574 of the Russian population are PM. PMs inherit two deficient CYP2D6 alleles and, as a result, metabolize drugs at a much slower rate. The ultrarapid metabolizer (UR) phenotype is caused by duplication, multiduplication, or amplification of active CYP2D6 genes, including predominantly the CYP2D6*2 allele, but also including CYP2D6*1 and others. Individuals with the UM phenotype metabolize drugs at an ultrafast rate. Finally, individuals who are heterozygous for the defective CYP2D6 allele often exhibit a PM phenotype with a broad spectrum of metabolic activity that can vary from substantially better than the PM phenotype to activity that is close to that of the DM phenotype (Bernard 2006).

A phase 2, dose-identification, randomized, parallel-group, double-blind, placebo-controlled study is planned to evaluate the safety and efficacy of pridopidine 45, 67.5, 90, and 112.5 mg twice daily versus placebo for symptomatic treatment in patients with Huntington's disease (Clinicaltrials.gov Clinical Trial ID NCT02006472). Therefore, a dosage form comprising pridopidine at the indicated doses with a good safety profile is desirable. In addition, a dosage form administered less frequently than twice a day will increase adherence to treatment and be preferred by patients and staff.

The present study is illustrated by the following examples, which are not intended to limit the scope of the invention. It is understood that various modifications are in keeping with the trend and scope of the invention.

Examples

Example 1 Safety of Pridopidine Administration Following Administration of Immediate Release Dosage Forms

Multiple incremental dose (MAP) study

In a multiple incremental dose (MAD) study, thirty-six (36) healthy volunteers of both sexes (age 18-55 years) with the CYP2D6 BM genotype were randomized into 3 cohorts. In each cohort, 9 patients were randomized to 2 incremental doses of pridopidine twice daily in a fixed sequence (45-67.5, 67.5-90 and 90-112.5 mg) and 3 patients to matching placebo twice daily with both periods of treatment. Each period consisted of 9 consecutive days of double dosing (6.5 h between morning and afternoon dose) until steady state (Osterberg 2012). Pridopidine drug concentrations were monitored up to 24 hours after the first dose and single dose parameters (associated with the first 24 hour interval) were determined. Geometric mean plasma concentrations versus time over the course of the study are shown in FIG. 1.

Safety and tolerability were assessed by monitoring adverse events (AEs), assessment of vital signs, electrocardiogram (ECG), and clinical and laboratory parameters. The PK parameters of pridopidine were calculated using non-compartmental methods and summarized using descriptive statistics by treatment/dose level (Tables 1A and 1B for day 9 and day 1, respectively). The administration interval in the present study (tau) was defined as 24 hours.

Table 1A. Summary of pharmacokinetic parameters at steady state (mean ± SD)

N Dose and regimen Mean ± SD AUCtau, ss (h*ng/ml) C-max, ss (ng/ml) T (1/2) h Tmax, S3 (h) (range) 8 HB 45 mg 2 r / day 7178 ±1672 5253- 10458 499 ±97 382-664 10.5±3.05 1.5 (1.0- 2.5) 16 HB 67.5 mg 2 r / day 14185 ±3747 10228- 21065 906 ±207 639-1287 10.4±2.5 2.0 (1.04.0) 14 HB 90 mg 2 r / day 18065 ±3413 12670- 24151 1157 ±190 871-1568 10.2±2.1 2.0 (1.04.0)

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Table 1B. Summary of pharmacokinetic parameters after single dose administration (mean ± SD)

N Dose and regimen Mean ± SD Median AUC _tau , _ss (h * ng / ml) Stax, ss (ng/ml) T (1/2) (h) (range) Tmax,ss (H) (range) 8 HB 45 mg 2 r / day 5043 ±3276 2249- 12570 327 ±99, 3 244-545 6.41 (4.31- 15.4) 1.0 (1.002.50) 16 HB 67.5 mg 2 r / day 7897 +2811 3907- 14620 486 ±116 324-813 7.40 (4.39- 11.2) 1.5 (1.00- 2.50) 14 HB 90 mg 2 r / day 13594 ±3880 7934- 22138 718 ±144 493-1002 9.00 (6.6114.0) 1.75 (1.00- 2.50)

As shown in Table. 2, the incidence of adverse events such as gastrointestinal disturbances increased with increasing dose. Psychiatric disorders were mainly observed at a dose of 90 mg twice a day, with one case of psychiatric disorder at a dose of 45 mg 2 times a day.

A prolonged QT interval has been associated with an increased risk of torsades de pointes. Electrocardiogram (ECG) readings were obtained at baseline (before administration on day 1) and again on day 9 (together with PK samples). The high accuracy of the QT measurement technique was used. Primary endpoint for QTc analysis with placebo-adjusted change from baseline QTcF (QT adjusted by Fredericia correction;, ΔΔ QTcF). The relationship between plasma pridopidine concentrations and ΔΔQTcF was quantified using a mixed effects linear modeling approach.

The results show a concentration-dependent effect of pridopidine on ΔΔQTcF, suggesting that higher concentrations resulted in more significant QT prolongation. The estimated population cutoff and slope were 3.82 and 0.0185 ms per ng/mL (CI: 0.0139-0.0231), respectively (FIG. 2).

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Table 2. Summary of the most common adverse events (>10%) in selected organ system classes of particular interest

placebo N=14 4 5 mg pridopidine twice a day N=9 67.5 mg pridopidine twice daily N=17 pridopidine 90 mg twice daily N=18 N (%) E N (%) E N (%) E N (%) E Disorders of the nervous system 8 (57.1%) 17 6 (66.7%) 12 12 (70.6%) 33 14 (77.8%) 39 Headache 8 (57.1%) 14 4 (44.4%) 8 11 (64.7%) 24 7 (38, (%) 17 Dizziness 2 (14.3%) 2 1 (11.1%) 1 6 (35.3%) 7 9 (50.0%) eleven Perversion taste 1 (7.1%) 1 1 (11.1%) 1 1 (5.9%) 1 10 (55.6%) 10 Fainting 0 1 (11.1%) 1 1 (5.9%) 1 0 paresthesia 0 1 (11.1%) 1 0 0 Gastrointestinal Disorders 5 (35.7%) 7 1 (11.1%) 2 6 (35.3%) 14 10 (55.6%) 25 Nausea 3 (14.3%) 3 0 2 (11.8%) 5 4 (22.2%) 8 Vomit 2 (21.4%) 2 0 2 (11.8%) 2 3 (16.7%) 6 Dry mouth 1 (7.1%) 1 0 0 5 (27.8%) 5 Diarrhea 0 0 2 (11.8%) 5 3 (16.7%) 3 Constipation 0 1 (11.1%) 1 0 1 (5.6%) 1 Dyspepsia 0 0 2 (11.8%) 5 0 hard stool 0 1 (11.1%) 1 0 0 Psychiatric disorders 0 1 (11.1%) 1 0 7 (38.9%) 12 Insomnia 0 0 0 3 (16.7%) 3 Nightmares 0 0 0 2 (11.1%) 3 depressive mood 0 0 0 2 (11.1%) 2 Emotional disorders 0 1 (11.1%) 1 0 0

N: Number of patients, %: percentage of patients in the group of safety tests, E: Number of events

Summary of the results of example 1

The results, as presented in table. 1A showed that an average C _max , _ss such as about 1157 ng/ml (with a maximum value of 1568 ng/ml) can be safely administered to a human. The results presented in table. 1A also show that 45 mg NI administered twice daily resulted in a mean C _max , _{ss of} 499 ng/mL and a mean AUC _tau , _ss (tau was defined as a 24 hour interval spanning two doses) of 7178 h *ng/ml; such values are known to be of therapeutic benefit. The range of AUC _tau , _ss , resulting from the administration of 45-90 mg twice a day, was 525324151 h * ng / ml. Similarly, the results, as presented in table. 1B showed that the average C _max ,

- 16 040574 such as about 718 ng/ml on day 1 (with a maximum measured value of 1002 ng/ml) can be safely administered to a human. The results presented in table. 1B also show that administration of 45 mg HB twice daily resulted in a mean C _{max of} 327 ng/mL and a mean AUC ₀ _ _inf

5043 h * ng / ml. The range of AUC _0-in f obtained from the administration of 45-90 mg twice a day was

2249-22138 h*ng/ml.

In addition, the results presented in Fig. 2 show that a concentration such as 1400 ng/mL can be considered safe with respect to potential QT interval prolongation.

The results in the table. 1A, 1B, and 2 show that when certain doses of pridopidine are administered, there is a risk of an increase in the incidence of adverse events compared to the incidence of adverse events for previously tested safe dosages of pridopidine. Adverse events include, without limitation, QT interval prolongation, gastrointestinal disorders, and psychiatric disorders. A problem to be solved by the present invention is to provide new high dose pridopidine formulations that reduce the incidence of adverse events. By preventing _Cmax from reaching very high values, Applicants can limit adverse events such as those shown in Example 1. It was not known how it was possible to prevent peak _Cmax from pridopidine in order to minimize some or all of the adverse events associated with the dose of pridopidine. With an understanding of the problem, applicants have made the present invention, a dosage form of pridopidine modified release, which prevents the increase in C _max above previously tested safe doses.

Example 2. Dosage forms of pridopidine.

Dosage forms containing 90 mg of pridopidine were formulated and the in vitro dissolution rate was studied.

Dosage forms comprising 101.6 mg pridopidine HCl (equivalent to 90 mg pridopidine base) were formulated via a matrix mechanism using excipients in combination with several hydrophilic (water soluble) and/or hydrophobic (water insoluble) carriers.

The hydrophilic matrix, modified release system is a dynamic system including polymer wetting, polymer hydration, gel formation, polymer swelling and dissolution. The release rate of the drug is determined by diffusion (at solubility) through the gel and by the erosion rate of the tablet. At the same time, other soluble excipients or drugs also become wet, dissolve and diffuse out of the matrix, while insoluble materials are held in place until the surrounding polymer/adjuvant/drug complex breaks down or dissolves.

Preparation of Modified Release (MB) Pridopidine Dosage Forms

The matrix tablet was prepared using a wet granulation method. The granules were prepared for use in combination with a carrier or carriers and selected excipients to prepare modified release formulations.

Preparation of pridopidin granules

High shear granulation: All ingredients to be granulated were added to the granulator chamber and pre-comminuted (medium-high speed chopper; medium/low speed agitator) for sufficient time to ensure a homogeneous mixture and to break up any agglomerates. The granulating liquid was added and mixed (chopper high speed; stirrer medium speed). The amount of granulating liquid required is highly dependent on the composition. The granules were dried using a fluid bed dryer and milled with a Quadro Comill.

Granules of 90 mg and a high dose of pridopidine are presented in table. 3.1, tab. 3.2 and table. 3.3 respectively.

Table 3.1. Composition of granules R1-R3

batch number Application R1 R2 R3 Compound - mg/tab mg/tab mg/tab pridopidin HC1 medicinal substance 101.6 101.6 101.6

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Ethylcellulose (Ethocel™ 7 premium) Binder 20.4 20.4 50.8 Sanro ₄ Insoluble filler - 178.0 101.6 Peptized starch (Starch 1500®) Filler, disinfectant, binder - - 50.8 total weight - 122.0 300.0 304.8

Table 3.2. Composition of R4 granules based on the composition of HD HB capsules

Lot No. Application R4 Compound - mg/tab pridopidin HC1 medicinal substance 127.0 Microcrystalline cellulose (Avicel PH 102) Thinner/disintegrant 65.0 Hydro k ypro pilts el lyul oza (Klocel) Binder 100 total weight - 202.0

Table 3.3. Composition of R5 granules

Lot No. Application R5 Compound - mg/tab pridopidin HC1 medicinal substance 101.6 Silicified microcrystalline cellulose (Prosolv® SMCC 90) Filler 63.2

Study of the solubility of dosage forms

A typical dissolution of pridopidine tablets uses a USP #1 apparatus (basket) rotating at 100 rpm and 37°C in 500 ml HCl 0.1 N for 2 hours and then in phosphate buffer pH 6.8 for 12 hours Phosphate buffer was prepared by dissolving 6.805 g of KH2PO4 dibasic phosphate and 4.48 ml of 5M NaOH, diluted to 1000 ml with deionized water and mixed thoroughly. The sample was tested with a UV detector set at 268 nm and then returned to the dissolution vessel. The same dissolution results were obtained using a USP #2 instrument (paddle) at 75 rpm.

Example 3 Modified release (MB) pridopidine formulations of the invention.

Dosage forms were prepared with R5 granules and included in the invention.

Dosage forms included in the invention are presented in table. 4.

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Table 4. Dosage forms included in the present invention

Composition ingredients Composition (ng)/Prototype No. MV-1 MV-2 MV-3 pridopidin HC1 101.6 101.6 101.6 Silicified microcrystalline cellulose (Prosolv® SMCC 90) 63.2 63.2 63.2 Hydroxypropylmethylcellulose (Methocel™ K100M Premium CR) ** 150.0 150.0 Hydrogenated castor oil (HCO) 150.0 ** ** Lactose SD 70.0 70.0 70.0 Colloidal silicon dioxide (Aerosil®) 7.2 7.2 7.2 magnesium stearate 8.0 8.0 8.0 Ethylcellulose (Surelease®) * * * * 6.0-12.0 Total 400.0+5%* 400.0+5% 406.0- 412.0+5%

The results of dissolution in vitro are presented in table. 5 and FIG. 3.

Table 5. In vitro dissolution profile of MB-1, MB-2, and MB-3 dosage forms

Sample time (min) pH % dissolved MV-1 MV-2 MB-3 (8 mg ethylcellulose/tablet) 60 1.2 41 35 9 120 1.2 57 54 24 180 6, 8 68 67 37 240 6, 8 75 76 48 360 6, 8 86 88 64 480 6, 8 92 96 77 600 6, 8 97 101 86 720 6, 8 94

In addition to the dissolution profiles of the compositions determined immediately after formation (T0), the dissolution profiles of the compositions MB-1, MB-2 and MB-3 were also determined after 3 months (3M) and 4 months (4M), as presented in table. 5A. In addition, the dissolution profiles of the various batches were determined, and they are also presented in table. 5A. For each composition, batch 1 is the same batch presented in table. 5.

Table 5A. Dissolution profile of different batches of compositions MB-1, MB-2 and MB-3 MB-1

Time Time Party 1 The consignment 2 The consignment 3 The consignment 4 watch min THAT ZM 4M THAT THAT THAT 1 60 41 33 34 36 35 34 2 120 57 46 49 50 49 47

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3 180 68 60 65 60 58 56 4 240 75 67 72 68 65 63 6 360 86 77 82 79 75 73 8 480 92 84 89 87 83 81 10 600 97 89 95 92 89 87 12 720 100 92 99 96 93 92 14 840 102 95 101 99 96 96

MV-2

Time Time Party 1 The consignment 2 The consignment 3 The consignment 4 watch min THAT ZM 4M THAT THAT THAT 1 60 36 31 31 36 28 2 120 54 46 46 53 42 28 3 180 67 61 62 66 55 42 4 240 76 69 72 76 65 54 6 360 88 81 87 89 78 63 8 480 96 88 92 97 88 75 10 600 101 96 100 107 98 88 12 720 104 96 100 107 98 88 14 840 106 98 102 109 100 92

MV-3

Time Time Part I ¹ Party 2 ¹¹ Party Z ¹¹¹ watch min THAT THAT THAT ZM 1 60 9 5 6 16 2 120 24 15 18 thirty 3 180 37 26 31 45 4 240 48 35 42 55 6 360 64 50 58 71 8 480 77 63 72 - 10 600 87 73 - 90 12 720 94 82 90 97 14 840 100 89 - -

¹ 8 mg ethylcellulose/tablet ¹¹ 10 mg ethylcellulose/tablet ¹¹¹ 7 mg ethylcellulose/tablet

Example 4 Immediate Release (IR) Pridopidine Dosage Forms

When compared with pridopidine MB dosage forms, pridopidine IR dosage forms almost completely dissolved after about 20-30 minutes. Exemplary dissolution profiles of dosage forms of pridopidine HB are presented in table. 5.1. The composition of the dosage forms of HB in table. 5.1 is presented in table. 5.2:

Table 5.1. Dissolution process for pridopidine capsules - HB dosage forms

Force The consignment pH % dissolved (mg) 5 minutes 10 min 15 min 20 min thirty min 60 min 22.5 AA 1.2 62.1 97.5 99.4 99.4 99.9 99.6 22.5 AA 4.0 38.8 96.3 98.1 98.3 98.3 98.5 22.5 AA 6, 8 65, 3 94.1 96.1 96.7 96.9 97.0 45 DD 1.2 30.0 83.3 93.5 96.9 98.3 98.4 45 DD 4.0 30.3 82.3 94.0 97.4 97.7 97.8 45 DD 6, 8 23.4 67.4 94.0 96.5 96.8 96.6

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Table 5.2. Composition of HB dosage forms

batch number AA DD Composition Application Composition mg/capsule pridopidin HC1 medicinal substance 25, 4 50.8 Silicified microcrystalline cellulose (Prosolv® SMCC 90) Filler 43.2 86.4 magnesium stearate Lubricant 1.4 2.8

Additional compositions obtained in the development of the compositions of the present invention are presented in table. 5.3. As can be seen, composition A was formulated without a carrier. Some formulations, such as formulation B, C, and D, included rate control excipients (Table 5.3).

The dissolution profiles of compositions A, B, C and D are presented in table. 5.4. As shown in Table. 5.4, composition A provides an immediate release of the drug (1 hour).

The presence of up to 16% hydrophobic carrier hydrogenated castor oil (HCO) in matrix tablets with (composition B) or without (composition C) soluble carrier (lactose) did not result in delayed release of pridopidine, which was released after approximately 1 hour in both cases.

The dissolution results of composition D showed that 10% hydrophobic carrier (HCO) in composition D also provided 1 hour of release of pridopidine.

Table 5.3. Compositions with different carriers and quantities of carriers

Lot No. Application A IN With D Composition - mg/tablet mg/tablet mg/tablet mg/tablet Granules ¹ - R2 300.0 R3 304.8 R3 304.8 R4 202.0 Hydroxypropyl methylcellulose (Methocel™ K100M Premium CR) Hydrophilic carrier + + + + Hydrogenated castor oil (HCO) Hydrophobic carrier + 60.0 60.0 23.0 Lactose (anhydrous) Soluble filler + 75.2 + + Microcrystalline cellulose and glyceryl monostearate (Lubritose™ Blue) Soluble filler + + + + Colloidal silicon dioxide (Aerosil) Fluid agent or glidant 5.0 5.0 5.0 1.0 magnesium stearate Lubricant 5.0 5.0 5.2 2.5 total weight 310.0 450.0 375.0 228.5 Dissolution profile ² 1 hour release 1 hour release 1 hour release 1 hour release

¹ Granules R2, R3, and R4 are listed in Table 3.1, or 3.2.

² Solubility study was performed using USP,

The exemplary dosage forms shown in Example 3 (Table 5) exhibited an in vitro dissolution profile where about 41% (MB-1), about 36% (MB-2), and only about 9% (MB-3) were dissolved in first hour. After 4 hours, about 75% (MB-1), about 76% (MB-2) and about 48% (MB-3) of pridopidine were dissolved. Even after ten hours, not all of the pridopidin in the MB-1 dosage form was dissolved and only 86% of the pridopidin included in the MB-3 dosage form was dissolved compared to the pridopidine IR dosage forms shown in Example 4, where more than 20% of the pridopidin

- 21 040574 already dissolved after 5 minutes and almost completely dissolved after about 20-60 minutes. As shown in Example 4, some formulations containing rate control excipients did not act as modified release formulations.

Example 5 Development of a pharmacokinetic model applicable to the PK profile after pridopidine administration.

Plasma PK profiles resulting from administration of dosage forms were calculated using a simulation program. The PKPlus™ module, part of the Gastroplus™ simulation software available from Simulations Plus, Incorporated, was first used to determine the best type of ACAT (Advanced Compartmental Absorption and Transit) model for administering immediate release pridopidine.

The concentration data obtained after the administration of immediate release pridopidine (IR) was used as an approximation for IV. HB data were obtained from a study published by Hellden et al. (2012). Pridopidin was administered as capsules or 25.4 mg pridopidine HCl (22.5 mg pridopidin base) or 50.8 mg pridopidin (45 mg pridopidin base) IR to poor metabolizers (PM) and fast metabolizers (RB), respectively. FA samples were obtained within 50 h after administration. Mean plasma concentration versus time data for the PM group after a single dose were obtained using summary plots from the UN-SCAN-ITTM plot digitizing software available from Silk Scientific Inc. Plasma concentrations for the following time points were entered into the PK Plus module in hours: 0.0, 0.9, 2, 3, 4, 6, 9, 10.6, 1.7, 5 25, 33, and 50 hours. parts of the RK Plus module evaluated the mean pharmacokinetic parameters and performed calculations for the adequacy criterion and the Akaike information criterion for non-compartmental, single-chamber, two-chamber and three-chamber models. Based on the lowest value of the Akaike information criterion, the two-chamber model was chosen as having the highest adequacy. The model was validated by comparison with data from another pridopidin study (Linskov 2013, Hellden 2012) as shown in Fig. 4 and 5.

The model can simulate the concentration of pridopidine administered in a single dose, as well as in multiple doses (stable state) in the plasma of bad metabolizers (PM). Importantly, it has been shown that, during multiple doses, pridopidine can inhibit CYP2D6-mediated intrinsic metabolism in individuals with MD, meaning that upon repeated administration, PM and MB show comparable effects due to a decrease in CYP2D6-related metabolism in MD over time. (Lindskov 2012). In relation to the model presented, this means that while simulating plasma concentrations after single dose administration will only be important for PM, the results of PM steady state can be applied to PM steady state, and hence the general population, including both PM and PM. For the same reasons, the model is also expected to fit the WM and PM phenotypes.

Example 6 Predicted PK parameters after administration of oral dosage forms.

Using the dissolution profiles of the formulations described in Examples 2-4 and the pharmacokinetic model described in Example 5, the predicted plasma concentrations resulting from repeated dosing of the formulations of pridopidine MB were calculated. Pharmacokinetic parameters were calculated for twice-daily (2 r/d) administration of IR compositions containing various doses of pridopidine (with a 6.5-hour interval and a 7-hour interval between injections) and a once-daily administration of modified-release formulations of MB-1 , MB-2, and MB-3 containing various doses of pridopidine, both after single dose administration and at steady state. Data from the introduction of dosage forms of 45-157.5 mg HB twice a day or MB (90-315 mg) administered once a day are presented in table. 6 (day 1) and tab. 7 (stable state). The simulation calculated a PK value equivalent to the average C _max .

Table 6. Observed and simulated PK parameters of pridopidin on day 1 after a single dose of twice-daily HB formulations or once-daily MB formulations

Sample name AUC Day 1 0-38h* ng/ml*h Stakh* (ng/ml) AUC day 1 0-50h*ng/ml*h Observed NI 45 mg 2 once a day (6.5 hours between morning and afternoon dose) 9556 476 Simulated NI 45 mg twice daily (6.5 hours between morning and afternoon dose) 9178 417 10323

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Simulated NI 45 mg twice daily (7 hours between morning and afternoon dose) 9092 414 10301 Simulated NI 67.5 mg 2 times a day (7 hours between morning and afternoon dose) 611 15057 Simulated NI 90 mg twice daily (7 hours between morning and afternoon dose) 818 20166 Simulated NI 112.5 mg twice daily (7 hours between morning and afternoon dose) 1025 25280 Simulated NI 157.5 mg twice daily (6.5 hours between morning and afternoon dose) 1450 41635 MV-2 (1 time per day, 90 mg) 6780 258 7714 MV-3 (1 time per day, 90 mg) 4809 155 5647 MV-1 (1 time per day, 90 mg) 6890 269 7825 MV-2 (1 time per day, 125 mg) 352 10427

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MV-Z (1 time per day, 125 mg) 209 7587 MV-1 (1 time per day, 125 mg) 367 10583 MV-2 (1 time per day, 135 mg) 381 11276 MV-3 (1 time per day, 135 mg) 227 8207 MV-1 (1 time per day, 135 mg) 397 11445 MV-2 (1 time per day, 150 mg) 424 12551 MV-3 (1 time per day, 150 mg) 252 9138 MV-1 (1 time per day, 150 mg) 442 12737 MB-2 (1 time per day, 180 mg) 510 15101 MV-3 (1 time per day, 180 mg) 304 11001 MV-1 (1 time per day, 180 mg) 531 12325 MV-2 (1 time per day, 200 mg) 567 16802 MV-3 (1 time per day, 200 mg) 338 12244

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MV-1 (1 time per day, 200 mg) 591 17050 MV-2 (1 time per day, 225 mg) 639 18929 MV-1 (1 time per day, 225 mg) 381 13864 MB-3 (1 time per day, 225 mg) 666 19208 MV-2 (1 time per day, 250 mg) 711 21057 MV-3 (1 time per day, 250 mg) 424 15427 MB-1 (1 time per day, 250 mg) 740 21367 MB-2 (1 time per day, 315 mg) 897 26593 MB-3 (1 time per day, 315 mg) 536 19493 MB-1 (1 time per day, 315 mg) 934 26879

*AUC _0-38 and AUCo _-5 o can be regarded as a good estimate of AUC _inf

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Table 7. Pharmacokinetic (PK) parameters of pridopidine after multiple daily doses of pridopidine (HB formulation twice daily or MB formulation once daily), at steady state

Dose and regimen Average * AUCtau, ss (h * ng / ml) Stax,ss (ng/ml) Observed NI 45 mg twice daily (6.5 hours between morning and afternoon dose) 12547 807 Simulated NI 45 mg twice daily (6.5 hours between morning and afternoon dose) 12634 675 Simulated NI 45 mg twice daily (7 hours between morning and afternoon dose) 12641 670 Simulated NI 67.5 mg twice daily (6.5 hours between morning and afternoon dose) 18951 1013 Simulated NI 90 mg twice daily (6.5 hours between morning and afternoon dose) 25270 1351 Simulated NI 112.5 mg twice daily (6.5 hours between morning and afternoon dose) 31585 1689 Simulated NI 157.5 mg twice daily (6.5 hours between morning and afternoon dose) 43547 2336 MB-2 (1 time per day, 90 mg) 9479 495 MB-3 (1 time per day, 90 mg) 7236 340 MB-1 (1 time per day, 90 mg) 9591 508 MB-2 (1 time per day, 100 mg) 10532 550 MB-3 (1 time per day, 100 mg) 8052 378 MB-1 (1 time per day, 100 mg) 10657 564 MB-2 (1 time per day, 125 mg) 13165 688 MB-3 (1 time per day, 125 mg) 10051 472 MB-1 (1 time per day, 125 mg) 13322 706 MB-2 (1 time per day, 135 mg) 14218 743 MB-3 (1 time per day, 135 mg) 10855 510 MB-1 (1 time per day, 135 mg) 14387 762 MB-2 (1 time per day, 150 mg) 15798 826 MB-3 (1 time per day, 150 mg) 12061 567 MB-1 (1 time per day, 150 mg) 15986 847 MB-2 (1 time per day, 180 mg) 18957 991.1 MB-3 (1 time per day, 180 mg) 14474 680 MB-1 (1 time per day, 180 mg) 19183 1016 MB-2 (1 time per day, 225 mg) 23698 1239 MB-1 (1 time per day, 225 mg) 23981 1271 MB-2 (1 time per day, 315 mg) 32431 1712 MB-3 (1 time per day, 315 mg) 28068 1169 MB-1 (1 time per day, 315 mg) 32824 1757

* administration interval (tau)=24 h

The solubility data presented for the 90 mg dosage forms were experimentally tested as described in Examples 2-4. The solubility data reported for dosage forms greater than 90 mg are based on simulations using 90 mg sample profiles.

Results and discussion of examples 5-6

Safety concerns such as gastrointestinal disorders, psychiatric disorders, and cardiac adverse events are dose dependent. Especially for QT, these safety concerns are related to maximum drug concentrations (C _max ) rather than AUC. However, it is not known whether _Cmax or AUC is responsible for other adverse events, such as CNS-related and GI-related adverse events.

The formulations of the present invention have been shown to provide a maximum blood concentration (C _max ) comparable to twice daily administration of the same dose of drug per day while maintaining an AUC similar to that of previous studies (Huntington Study Group HART Investigators 2013, Yebenes 2011).

The calculated C _max obtained from administration of 90 mg pridopidine in the MB formulation of the present invention was lower when compared to the C _max obtained from administration of 45 mg IR twice daily (Table 7), demonstrating a better safety profile. In addition, the calculated AUC _tau , _ss for 90 mg MB administration was comparable to the AUC _tau , _ss found in patients administered 45 mg HB twice daily in the MAD study. Similarly, the calculated C _max obtained from administration of 135 mg pridopidine in the MB dosage form was lower when compared with the C _max obtained from administration of 67.5 mg HB twice daily; the calculated C _max obtained from the administration of 180 mg of pridopidine in the MB dosage form was lower when compared with the C _max obtained from the administration of 90 mg HB twice a day; the calculated C _max obtained from the administration of 225 mg of pridopidine in the MB dosage form was lower when compared with the C _max obtained from the administration of 112.5 mg HB twice a day, and the calculated C _max obtained from the administration of 315 pridopidine in dosage form MB, was lower when compared with C _max obtained by administering 157.5 mg HB twice a day (table. 7). The AUC _tau , _ss of these doses was higher than the AUC _tau , _ss associated with 45 mg HB twice daily. One skilled in the art will appreciate that the AUC _tau , _{ss of} the indicated doses is related to therapeutically effective amounts of the composition.

In addition, the calculated C _max , _ss obtained from the administration of MB dosage forms, including 100 and 125 mg of pridopidine, was lower than the C _max obtained from the administration of 45 mg HB twice a day (total dose 90 mg per day; see Table 7). For the 100 mg MB formulation, the calculated AUC _tau , _ss was about 80% of 45 mg IR twice daily and the AUC _tau , _ss calculated for 125 mg MB formulation was similar to 45 mg IR twice daily. Importantly, both were higher than the mean AUC _tau , _ss obtained from 45 mg HB twice daily in the MAD study. The results obtained showed that even for MB dosage forms comprising more than the same dose per day, administered twice a day, the safety profile was better, while clinical activity was maintained.

Example 7

Three dosage forms of pridopidine were prepared in accordance with examples 2 and 3, MB-1, MB-2 and MB-3. Periodic oral administration of MB-1, MB-2 or MB-3 to a person suffering from Huntington's disease showed that the incidence of adverse events was reduced compared to the incidence of adverse events in example 1.

Example 8

Three dosage forms of pridopidin were prepared according to examples 2-3, MB-1, MB-2 and MB-3, however, the amount of pridopidin was 100 mg (113 mg of pridopidine HCl) and the amount of each of the other components of MB-1, MB-2 and MB-3 increased proportionally. Periodic oral administration of dosage forms to a person suffering from Huntington's disease showed that Cmax was equal to or less than previously tested safe doses.

Example 9

Three dosage forms of pridopidin were prepared according to examples 2-3, MB-1, MB-2 and MB-3, however, the amount of pridopidin was 125 mg (141 mg of pridopidin) and the amount of each of the other components of MB-1, MB-2 and MV-3 increased proportionally. Periodic oral administration of dosage forms to a person suffering from Huntington's disease has shown that C _max is equal to or less than previously described safe doses.

Example 10

Three dosage forms of pridopidine were prepared according to examples 2-3, MB-1, MB-2 and MB-3, however, the amount of pidopinide was 135 mg (153 mg of pridopidine HCl) and the amount of each of the other components of MB-1, MB-2 and MB-3 increased proportionally. Periodic oral administration of dosage forms to a person suffering from Huntington's disease showed that Cmax was equal to or less than previously tested safe doses.

Example 11.

Three dosage forms of pridopidin were prepared according to examples 2-3, MB-1, MB-2 and MB-3, however, the amount of pridopidin was 150 mg (170 mg pridopidine HCl) and the amount of each of the components MB-1, MB-2 and MV-3 increased proportionally. Periodic oral administration of dosage forms to a person suffering from Huntington's disease has shown that C _max is equal to or less than previously tested safe doses.

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Example 12.

Three dosage forms of pridopidin were prepared according to examples 2-3, MB-1, MB-2 and MB-3, however, the amount of pridopidin was 180 mg (203 mg of pridopidine HCl) and the amount of each of the other components of MB-1, MB-2 and MB-3 increased proportionally. Periodic oral administration of dosage forms to a person suffering from Huntington's disease has shown that Cmax is equal to or less than previously tested safe doses.

Example 13

Three dosage forms of pridopidin were prepared according to examples 2-3, MB-1, MB-2 and MB-3, however, the amount of pridopidin was 225 mg (254 mg of pridopidine HCl) and the amount of each of the other components of MB-1, MB-2 and MB-3 increased proportionally. Periodic oral administration of dosage forms to a person suffering from Huntington's disease has shown that C _max is equal to or less than previously tested safe doses.

In summary, the inventors of the present invention were able to formulate therapeutically effective dosage forms with an improved safety profile when compared to administering the same dose twice daily or less.

In addition, the treatment of acute and chronic neurological and neuropsychiatric diseases, such as Huntington's disease, has a problem of adherence to treatment, since the patient or caregiver may forget to administer the drug. Accordingly, the oral dosage forms of the present invention provide advantages over previously known (twice daily) oral dosages. The oral dosage forms of the present invention are adapted for once-daily administration, providing a lower tablet burden for patients who are resistant to treatment, increasing convenience for patients and caregivers, and resulting in greater adherence to treatment and less burden on family members.

Example 14 PK study in beagle dogs after administration of a single dose of compositions MB-1, MB-2 and MB-3.

The pharmacokinetics of pridopidine in male beagle dogs was tested following oral administration of an immediate release (IR) formulation and three modified release (MB) formulations. The dogs were divided into 4 groups: Group 1 received one administration of MB-1 composition, Group 2 received one administration of MB-2 composition, and Group 3 received one administration of MB-3 composition. Each composition included 90 mg of pridopidine. Plasma concentration of pridopidine was assessed at several time points 0.5-36 hours after administration.

Group 4 received 45 mg of pridopidine in an IR formulation twice at 3 hour intervals. Plasma concentration of pridopidine was assessed at several time points 0.5-36 hours after the first injection.

The study was performed on an empty stomach, starting 12 hours before administration and continuing an additional 7 hours after the first injection.

The results are presented in table. 8.

Table 8

pridopidin Group No. pm average Tmax mean Stach average AUC _inf mean AUCq-24 average Frel_cmax Frel- AUCq-24 1 (n=4) MR-1 4.2 1.75 1135 6221.9 6336 0.56 0.70 02 (n=8) MR-2 3.7 2 1203 7153 7038 0.59 0.78 3 (n=7) MR-3 4.8 3.5 907 6846 6743 0.45 0.75

4 (n=6) 5.4 4.0 2031 9125 9004 1.00 1.00

Example 15 Additional Analysis of PK Parameters.

The concentration of pridopidin in the plasma samples in Example 14 was determined using liquid chromatography in tandem with LC-MS/MS mass spectrometry. In an additional assay, samples containing higher analyte concentrations than the upper limit of quantitation (ULOQ: 2000 ng/ml pridopidine) were reanalyzed after a 10-fold dilution.

Briefly, blood samples were centrifuged (within a maximum of 60 minutes after collection) at 2500 g at 5° C. for 15 minutes. Frozen plasma samples were stored in an ultra-freezer (-70±10°C). In plasma samples, the concentration of pridopidine was determined by liquid chromatography-tandem mass

- 28 040574 LC-MS/MS spectrometry. As described, samples containing a higher analyte concentration than the upper limit of quantitation (ULOQ: 2000 ng/ml pridopidine) were reanalyzed after 10-fold dilution.

For each composition, mean and S.D. values were calculated from individual data. for each time point, obtaining a plasma concentration versus time curve.

Pharmacokinetic analysis was performed using the approved Phoenix WinNonlin Version 5 6.3 software (Pharsight Corporation, USA). Individual and mean pharmacokinetic parameters were calculated using a non-compartmental method.

results

In FIG. 6 shows mean plasma levels (c S.D.) of pridopidine (6a-b) for formulations MB-1, MB-2, and MB-3. Two administrations of the immediate release (IR) formulation 3 hours later resulted in an initial peak followed by an initial decline, then a second peak followed by a terminal elimination phase. In comparison, the MB formulation had a prolonged absorption from the MB formulations resulting in a maximum concentration followed by a terminal elimination phase.

For all formulations, AUC( _0-inf ) and C _max values were normalized to a nominal pridopidine dose of 12 mg/kg. T _max , normalized to dose C _max , and total exposure (AUC( _0-inf ), _norm ) values) normalized to dose are summarized in Table 1. 9.

Table 9

Group 1 (MV-1) (S.D.) 2 (MV-2) (S.D.) 3 (MV-3) (S.D.) 4 (HB) (1st dose) (S.D.) 4 (HB) (2nd dose) (S.D.) Cmax,norm 1110 1170 803 1550 2030 (ng/ml) (200) (235) (228) (313) (538) Ttah 1.94 2.38 3, 63 1.16 3, 91 pridopidine (0.904) (1.03) (1.62) (0.351) (1.14) AUC(o-mf), norm (h*ng/ml) 6340 (1610) 7010 (3520) 6080 (2830) 9410 (3380)

As can be seen, the MB-1 and MB-2 formulations showed similar kinetic profiles, while the most delayed absorption was observed for the MB-3 formulation. The IR formulation resulted in the first pridopidin peak within the shortest period after administration: approximately 1 hour. For the MB formulations, pridopidin peaks appeared later: approximately 2 hours for the MB-1 formulation, 2.5 hours for the MB-2 and 3 formulations, 5 hours for composition MB-3.

Relative peak levels of the MB formulations compared to the higher, second peak level of the control NR formulation (F _rel C _max ) and relative total exposure (F _rel AUC _inf ) were calculated for the overall group means (Table 10).

Table 10

1 (MV-1) 2 (MV-2) 3 (MV-3) Frel_C _max 0.547 0.576 0.396 Mean Fr _e lAUCi _n f 0.721 0.746 0.625

The results show that the C _max obtained by administering pridopidine 90 mg once daily in formulations MB-1, MB-2 and MB-3 was 55%, 58% and 40%, respectively, of the C _max obtained by administering compositions 45 mg of pridopidine in the HB formulation twice a day. AUC _inf obtained as a result of a single administration once a day of 90 mg of pridipidine in the compositions MB-1, MB-2 and MB-3 was 72, 75 and 63%, respectively, AUC _inf obtained as a result of administration twice a day of 45 mg pridopidine in the HB composition.

Example 16

Tablet dosage forms of pridopidine were obtained with granules R1-R4 (Table 3.1 or 3.2) and are presented in Table. 11. The dissolution profile of such dosage forms is also presented in table. 11. Solubility study was performed using USP instrument I at 100 rpm in 900 ml of purified water at 37°C. Detailed dissolution profiles of dosage forms listed in table 11 are shown in table. 12.

Specialist in the field of technology understands that the dosage forms presented in table. 11 have a modified release dosage form dissolution profile.

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Table 11

No. Application MV-4 MV-5 MV-6 MV-7 MV-8 MV-9 MV-10 MV-11 Composition - mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab Granules - R1 122.0 R4 163.2 R3 304.8 R3 304.8 R1 122.0 R1 122.0 R2 300.0 R4 163.2 Dibasic calcium phosphate Insoluble filler + + + + 154.0 + + + Hydroxypropyl methylcellulose (HPMC) Methocel K100 PR CR hydrophilic carrier 122.0 + 90.0 90.0 120.0 120.0 90.0 150.0 Hydroxypropyl methylcellulose (HPMC) Methocel K15 CR Hydrophilic carrier + + + + + + + 25.0 Hydrogenated castor oil Hydrophobic carrier 30.0 175.0 + 60.0 + + + + Aerosil Fluidity agent + + 5.0 5.0 2.0 2.0 5.0 + Mg stearate Lubricating substance 2.0 1.8 5.2 5.2 2.0 2.0 5.0 1.8 LubriTose Blue Lubricant + 160.0 + + + + + + LubriTose Yellow Lubricating substance + + + + + + + 160.0 Anhydrous lectose Soluble filler + + 150.0 75.0 + 154.0 100 + total weight 276.0 500.0 555.0 540.0 400.0 400.0 500.0 500.0 Dissolution profile 12 h release 9-10 h release 9h release 9h release 9h release 9h release 9h release 9-12h release

1R1, R2, R3, and R4 pellets are listed in Table. 3.1, or 3.2.

² Lactose+(2%-10% glyceryl monostearate): yellow contains 10% GMS and blue contains 2% GMS. A dissolution study was performed using USP, instrument I at 100 rpm, in 900 ml of purified water at 37°C.

Table 12 Solubility Profiles of the Compositions in Table 12 eleven

Time/Batch 5 minutes 1 hour Zch 6h 9h 12h Release rate (%) MV-4 8 37 62 83 94 99 MV-5 12 40 65 83 94 101 MV-6 3 thirty 60 84 92 95 MV-7 5 36 67 88 97 100 MV-8 6 37 68 91 103 MV-9 3 32 68 94 105 MV-10 4 38 72 95 102 100 MV-11 5 32 60 82 93

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Claims (23)

Links: Clinicaltrials.gov Clinical Trial Identifier NCT02006472, A Phase 2, to Evaluating the Safety and Efficacy of Pridopidine Versus Placebo for Symptomatic Treatment in Patients With Huntington's Disease. de Yebenes JG, Landwehrmeyer B, Squitieri F, Reilmann R, Rosser A, Barker RA, Saft C, 5 Magnet MK, Sword A, Rembratt A, Tedroff J; MermaiHD study investigators, Pridopidine for the treatment of motor function in patients with Huntington's disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial, Lancet Neurol. 2011 Dec;10(12):1049- 57. doi: 10.1016/S1474-4422(11)70233-2 . Epub 2011 Nov 7. Huntington Study Group HART Investigators, A randomized, double-blind, placebo-10 controlled trial of pridopidine in Huntington's disease, Mov Disord. 2013 Sep;28(10):1407-15. doi: 10.1002/mds.25362. Epub 2013 Feb 28. Hellden A, Panagiotidis G, Johansson P, Waters N, Waters S, Tedroff J, Bertilsson L. The dopaminergic stabilizer pridopidine is to a major extent N-depropylated by CYP2D6 in humans Eur J Clin Pharmacol. 2012 Sep; 68(9): 1281-6. Epub 2012 Mar 8.15 Lindskov Krog P, Osterberg 0, Gundorf Drewes P, Rembratt A, Schultz A, Timmer W. Pharmacokinetic and tolerability profile of pridopidine in healthy-volunteer poor and extensive CYP2D6 metabolizers, following single and multiple dosing Eur J Drug Metab Pharmacokinet. March 2013; 38(1):43-51. Epub 2012 Sep 5. Osterberg, et al. A single center, randomized, placebocontrolled, double-blind study to 20 evaluate the safety, tolerability, and pharmacokinetics of multiple-ascending doses of pridopidine in healthy volunteers Poster presented at Sixth Annual Huntington Disease Clinical Research Symposium, Nov 2012, Seattle, Washington, USA. Neurotherapeutics CLAIM 1. A modified release solid oral dosage form comprising a therapeutically effective amount of pidopidine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable release rate controlling excipient, wherein the release rate controlling excipient is a hydrophilic or hydrophobic polymer selected from from the group consisting of hydrogenated castor oil, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and a combination of hydrogenated castor oil or hydroxypropyl methylcellulose (HPMC) with ethyl cellulose, wherein the total amount of release rate controlling agent is from about 30 to about 50 wt. % by weight of the dosage form, where the amount of pridopidine is from 45 to 300 mg. 2. The modified release solid oral dosage form of claim 1, wherein said dosage form contains a therapeutically effective amount of pridopidine or a pharmaceutically acceptable salt thereof, hydrogenated castor oil or hydroxypropyl methylcellulose (HPMC), or a combination of hydrogenated castor oil or hydroxypropyl methylcellulose (HPMC) with ethyl cellulose. 3. The modified release solid oral dosage form of claim 1, wherein said dosage form contains a therapeutically effective amount of pridopidine or a pharmaceutically acceptable salt thereof, hydrogenated castor oil, a mixture of silicified microcrystalline cellulose and lactose, colloidal silicon dioxide, and magnesium stearate. 4. The modified release solid oral dosage form of claim 1, wherein said dosage form contains a therapeutically effective amount of pridopidine or a pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose and ethylcellulose, a mixture of silicified microcrystalline cellulose and lactose, colloidal silicon dioxide, and magnesium stearate. - 31 040574 5. Solid oral dosage form modified release according to claim 3 or 4, where pidopidin is from 15 to 60 wt.% by weight of the dosage form; hydrogenated castor oil or hydroxypropyl methylcellulose (HPMC) or a combination of hydrogenated castor oil or hydroxypropyl methylcellulose (HPMC) with ethyl cellulose totals 30 to 50% by weight of the dosage form; a mixture of silicified microcrystalline cellulose and lactose, where silicified microcrystalline cellulose is 16 ± 0.8 wt.% by weight of the dosage form, and lactose is 17 ± 0.85 or 18 ± 0.9 wt.% by weight of the dosage form; colloidal silicon dioxide is from 0.2% ± 0.01 to 4% ± 0.2 wt.% of the mass of the dosage form and magnesium stearate is from 0.3% ± 0.015 to 4 ± 0.2 wt.% of the mass of the medicinal form forms. 6. The modified-release solid oral dosage form according to claim 3, wherein pridopidin is the hydrochloride salt of pridopidin and has a mass of 101.6 mg, hydrogenated castor oil has a mass of 150.0 mg, silicified microcrystalline cellulose has a mass of 63.2 mg, lactose has a mass of weight 70.0 mg, colloidal silicon dioxide has a weight of 7.2 mg and magnesium stearate has a weight of 8.0 mg, where the total weight of the composition is 400 mg ± 5%. 7. Modified release solid oral dosage form according to claim 4, wherein pridopidine is the hydrochloride salt of pidopidine and has a weight of 101.6 mg, hydroxypropyl methylcellulose (HPMC) has a weight of 150.0 mg, silicified microcrystalline cellulose has a weight of 63.2 mg, lactose has a mass of 70.0 mg, colloidal silicon dioxide has a mass of 7.2 mg and magnesium stearate has a mass of 8.0 mg, where the total mass of the composition is 400 mg ± 5%. 8. Solid oral dosage form modified release according to claim 4, where pridopidine is a salt of pridopidine hydrochloride and has a mass of 101.6 mg, hydroxypropyl methylcellulose (HPMC) has a mass of 150.0 mg, ethylcellulose has a mass of 6.0-12.0 mg , silicified microcrystalline cellulose has a mass of 63.2 mg, lactose has a mass of 70.0 mg, colloidal silicon dioxide has a mass of 7.2 mg and magnesium stearate has a mass of 8.0 mg, where the total mass of the composition is 406-412 mg ± 5% . 9. A modified release solid oral dosage form according to any one of claims 1 to 8, wherein the pharmaceutically acceptable salt of pridopidine is the hydrochloride salt. 10. Method for treating a subject suffering from Huntington's disease, Parkinson's disease, iatrogenic and non-iatrogenic parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinosis, schizophrenic disorders or schizophreniform disorders, mood and anxiety disorders, manic-depressive states, depression , obsessive-compulsive disorder, sleep disorder, autism spectrum disorder, ADHD, age-related cognitive impairment, alcohol and substance abuse, Alzheimer's disease or Rett syndrome, comprising administering a modified release oral dosage form according to any one of claims 1-9. 11. A method of treating a subject suffering from Huntington's disease, Parkinson's disease, iatrogenic and non-iatrogenic parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinosis, schizophrenic disorders or schizophreniform disorders, mood and anxiety disorders, manic-depressive states, depression , obsessive-compulsive disorder, sleep disorder, autism spectrum disorder, ADHD, age-related cognitive impairment, alcohol and substance abuse, Alzheimer's disease, or Rett syndrome, comprising administering to the subject a modified-release solid oral dosage form containing a therapeutically effective amount of pridopidine or a pharmaceutically effective amount thereof an acceptable salt and at least one pharmaceutically acceptable release agent, wherein the release agent is is a hydrophilic or hydrophobic polymer selected from the group consisting of hydrogenated castor oil, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), or a combination of hydrogenated castor oil or hydroxypropyl methyl cellulose (HPMC) with ethyl cellulose, wherein the total amount of release rate controlling agent is from about 30 to about 50 wt.% by weight of the dosage form; wherein the amount of pridopidine is from 45 to 300 mg, wherein the solid oral dosage form provides an in vivo plasma concentration profile of pridopidine having a C _max of about 244 to about 1568 ng/mL of the steady-state measured modified release solid oral dosage form. 12. A method of treating a subject suffering from Huntington's disease, Parkinson's disease, iatrogenic and non-iatrogenic parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinosis, schizophrenic disorders or schizophreniform disorders, mood and anxiety disorders, manic-depressive states, depression , obsessive-compulsive disorder, sleep disorder, autism spectrum disorder, ADHD, age-related cognitive impairment, alcohol and substance abuse - 32 040574 ki, Alzheimer's disease or Rett's syndrome, which includes administering to the subject a solid oral modified release dosage form containing a therapeutically effective amount of pridopidine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient that regulates the release rate, where the excipient that regulates release rate, is a hydrophilic or hydrophobic polymer selected from the group consisting of hydrogenated castor oil, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and a combination of hydrogenated castor oil or hydroxypropyl methylcellulose (HPMC) with ethyl cellulose, wherein the total amount of rate-regulating excipient is release, is from about 30 to about 50 wt.% by weight of the dosage form; wherein the amount of pridopidine is between 45 and 300 mg, wherein the solid oral dosage form provides an in vivo plasma pridopidin concentration profile having a mean _{Cmax of} 1400 ng/mL or less. 13. The method of claim 11 wherein the in vivo plasma concentration profile of pridopidine has a mean _{Cmax of} 1568 ng/mL measured at steady state. 14. The method according to any one of claims 11-13, wherein the release rate control agent is a combination of hydroxypropyl methylcellulose (HPMC) and hydrogenated castor oil. 15. The method according to any one of claims 11-14, wherein the solid oral dosage form provides an in vivo plasma concentration profile of pridopidin having an average C _max that is less than the average C _max , respectively, resulting from the administration of twice daily solid oral an immediate release dosage form that contains: a) half the amount of pridopidine, an immediate-release solid oral dosage form, or a pharmaceutically acceptable salt thereof, or b) 10 to 49% of an amount of pridopidine or a pharmaceutically acceptable salt thereof and a solid oral dosage form provides an in vivo plasma concentration profile of pridopidin having a mean AUC _tau that is 50 to 95% of the mean AUC _tau obtained from administering twice daily (bid) an immediate-release solid oral dosage form that contains half the amount of pridopidin of the immediate-release solid oral dosage form or a pharmaceutically acceptable salt thereof. 16. The method of any one of claims 11-15, wherein the twice daily administration of the immediate release solid oral dosage form has a time interval between doses of 5-10 hours, 6-8 hours, 6.5 hours, or 7 hours. 17. The method according to any one of claims 11-16, wherein the average time required to reach the maximum concentration of the drug in plasma, serum or blood, after administration of the drug, is more than 2 hours. 18. The method according to any one of claims 11-17, wherein the pharmaceutically acceptable salt of pridopidine is the hydrochloride salt. 19. The method of any one of claims 11-18, wherein pridopidine, or a pharmaceutically acceptable salt thereof, comprises from about 15% to about 60% by weight of the dosage form. 20. The method according to any one of claims 11-19, where the dosage form further comprises ethylcellulose and where the total amount of ethylcellulose is from about 0.5 to about 10% of the total weight of the dosage form, from about 0.5 to about 7.2% of the total by weight of the dosage form, from about 1.0 to about 5% of the total weight of the dosage form, from about 1.0 to about 3.0% of the total weight of the dosage form, from about 1.5 to about 3.0% of the total weight of the dosage form, from about 1.5 to about 2.4% of the total weight of the dosage form, about 1.5 wt.% of the solid oral dosage form, or about 2.4 or 2.9 wt.% of the solid oral dosage form. 21. The method according to any one of claims 11-20, wherein the weight ratio of pridopidine or a pharmaceutically acceptable salt thereof to the release rate regulating excipient is from about 0.2:1 to about 1:1, preferably from about 0.3: 1 to about 0.8:1, preferably from about 0.5:1 to about 0.7:1. 22. The method according to any one of claims 11-21, wherein the dosage form further comprises a mucoadhesive selected from the group consisting of water-soluble or water-insoluble hydrophilic polymers, polymers that have swellable networks, hydrogels, and polymers with groups that can crosslink other polymers. or mucosal, is preferably a mucoadhesive, and wherein pridopidine or a pharmaceutically acceptable salt thereof is about 15 to about 60%, about 25 to about 50%, or about 25% by weight of the dosage form. 23. The method according to any one of claims 11-22, wherein the dosage form further comprises one or more pharmaceutically acceptable carriers or excipients selected from the group consisting of a binder, a filler, a plasticizer, a glidant, a lubricant, and their -