Taste-masked pridopidine formulations, method of use thereof and process for preparation thereof

Abstract

This application provides a novel formulation of pridopidine drug in the form of particles designed to mask the intensely bitter taste of pridopidine while enabling rapid drug release. The formulation provides improved taste masking and dissolution characteristics, making it suitable for oral administration. The invention further relates to the process for preparation of the particles, methods of their administration, and to methods of using the formulation in the treatment of neurodegenerative or neurodevelopmental disease or disorder.

Description

P-636238-PCTASTE-MASKED PRIDOPIDINE FORMULATIONS, METHOD OF USE THEREOF AND PROCESS FOR PREPARATION THEREOFFIELD OF THE INVENTION

[0001] This application provides a novel formulation of pridopidine drug in the form of particles designed to mask the intensely bitter taste of pridopidine while enabling rapid drug release. The formulation provides improved taste masking and dissolution characteristics, making it suitable for oral administration. The invention further relates to the process for preparation of the particles, methods of their administration, and to methods of using the formulation in the treatment of neurodegenerative or neurodevelopmental disease or disorder.BACKGROUNDPridopidine

[0002] Pridopidine (formerly ACR16, Huntexil®) is a highly potent and highly selective sigma- 1 receptor (SIR) agonist in clinical development for neurodegenerative diseases including Huntington disease (HD) and amyotrophic lateral sclerosis (ALS). The chemical name of pridopidine is 4-(3-(Methylsulfonyl)phenyl)-l-propylpiperidine, and its Chemical Registry Number is CAS 346688-38-8 (CSID:7971505, 2016). The Chemical Registry number of pridopidine hydrochloride is 882737-42-0 (CSID:25948790 2016). Processes of synthesis of pridopidine and a pharmaceutically acceptable salt thereof are disclosed in U.S. Patent No. 7,923,459 and PCT Application Publication No. WO 2017 / 015609. U.S. Patent No. 6,903,120 claims pridopidine for the treatment of Parkinson's disease, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, mood and anxiety disorders, sleep disorder, autism spectrum disorder, ADHD, Huntington’s disease, age-related cognitive impairment, and disorders related to alcohol abuse and narcotic substance abuse.

[0003] The bitter taste of certain drugs presents a significant challenge in pharmaceutical formulations, often leading to poor patient compliance and reduced efficacy. This issue particularly affects oral dosage forms, where unpleasant taste can deter patient adherence to the prescribed medication regimen. Further, many patients have trouble swallowing tablets and capsules. This problem can lead to a variety of adverse events and patient noncompliance with treatment regimens.

[0004] Pridopidine is known to be bitter and produce trigeminal irritation. In addition, it is also highly water soluble which further increases the taste masking challenge, as bitterness is primarily sensed when a drug is in solution. However, the taste masking challenge for pridopidine has notP-636238-PC been quantified and hence the prospects for developing a palatable oral dosage form are unknown.

[0005] Various approaches have been employed to mask the bitter taste of pridopidine, including the use of flavoring agents, sweeteners, and encapsulation techniques. However, conventional taste-masking techniques often involve complex processes or prolonged release formulations, which may not be suitable for certain drug compounds, such as pridopidine, requiring immediate release. Further, these methods often pose limitations in terms of efficacy, stability, and manufacturing scalability.

[0006] Accordingly, there is a need for improved pharmaceutical compositions of pridopidine, or a pharmaceutically acceptable salt thereof (i.e., pridopidine hydrochloride), suitable for oral administration in the treatment of a neurodegenerative or neurodevelopmental disease or disorder, particularly formulations suitable for oral administration to patients that have trouble swallowing tablets and capsules, such as patients with dysphagia, or pediatric patients.

[0007] This application provides a novel formulation of pridopidine drug, utilizing bead coating technique to mask the bitter taste of pridopidine. The formulation comprises discrete particles containing pridopidine drug coated with taste-masking material, providing an effective solution for enhancing patient compliance and improving overall drug efficacy. This invention discloses a method for preparing such taste-masked pridopidine particles, ensuring uniformity and stability of the formulation.SUMMARY OF THE INVENTION

[0008] In some embodiments, the subject invention provides immediate release (IR) particles comprising pridopidine or pharmaceutically acceptable salt thereof, each of said particles comprises: a. beads substrate coated with a polymer seal coat; b. a drug layer comprising pridopidine or pharmaceutically acceptable salt thereof, coated over the seal coat, wherein the drug layer optionally comprises a binder and / or a glidant; c. a topcoat comprising an acrylate-based coating, further coated over the drug layer.

[0009] In some embodiments, the particles are configured such that, upon administration to the oral cavity of a subject, the taste of the pridopidine is substantially masked, and, upon subsequent exposure to the acidic environment of the subject’s stomach, the pridopidine is completely released, thereby producing an immediate-release pharmacokinetic profile. In some embodiments, the drug layer is characterized by a drug loading ranging between about 20% and 60% w / w relative to the weight of the coated beads of (a), preferably about 40% w / w. In some embodiments, the drugP-636238-PC loading is ranging between about 15% and 60% w / w with respect to the overall weight of the particle, preferably about 30% w / w. In some embodiments, the pridopidine or pharmaceutically acceptable salt thereof is pridopidine hydrochloride. In some embodiments, the beads substrate comprises microcrystalline cellulose (MCC) beads, sugar spheres or combination thereof. In some embodiments, the beads substrate has a particle size higher than about 100pm; preferably higher than 200 pm; more preferably lower than about 500 pm; most preferably about 350 pm. In some embodiments, the polymer amount in the seal coat layer ranges between 0.5% and 10% w / w; preferably 1-3% w / w; more preferably 1.3-1.9% w / w; most preferably 1.5% w / w; based on the total weight of the particle. In some embodiments, the binder amount in the drug layer ranges between 1 and 10% w / w ; preferably 1-5%; more preferably 3% w / w; based on the total weight of the particles. In some embodiments, the glidant is an anti-tacking agent. In some embodiments, the anti-tacking agent comprises: hydroxypropyl methylcellulose (HPMC), Magnesium Stearate, Calcium Stearate, Zinc Stearate, Sodium Stearyl Fumarate, Talc, Silicon Dioxide (Colloidal), , Hydrophobic Silica, Ethyl Cellulose, Carnauba Wax, or any combination thereof. In some embodiments, the glidant amount in the drug layer ranges between 0.5-5% w / w; preferably 0.5-3%; more preferably 1.5% w / w. In some embodiments, the topcoat is a seal coat, an outer taste masking coat, or combination thereof. In some embodiments, the topcoat comprises an acrylate based coating. In some embodiments, the topcoat comprises a methacrylate based coating. In some embodiments, the outer taste masking coat comprises: film coating, sugar coating, flavor masking, polymer coating or any combination thereof. In some embodiments, the film coating material comprises: hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyethylene glycol (PEG) or any combination thereof; the flavor masking agents comprise: sucrose, sorbitol, mannitol, aspartame, fruit flavors, artificial flavors or any combination thereof; and the polymer coating comprise: ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate (HPMCP), methacrylic acid copolymers (e.g., Eudragit® L, Eudragit ® EPO) or any combination thereof. In some embodiments, the topcoat amount ranges between about 1-50% w / w; preferably between about 10-30% w / w ; more preferably between about 19-20% w / w; with respect to the total weight of the final particle. In some embodiments, the polymer in the seal coat layer is Hypromellose; the binder in the drug layer is Hypromellose; the glidant in the drug layer is silicon dioxide, preferably colloidal silicon dioxide; the topcoat layer comprises acrylate-based coating, cellulose based coating or combination thereof; or any combination thereof. In some embodiments, the drug layer contains between about 15% and about 75% solids by weight; preferably higher than about 30%. In some embodiments, the weight ratio between the drug (e.g., pridopidine) and the binder (e.g., polymer) in the drug layer ranges between 100: 1 and 1 : 1 respectively, preferably greaterP-636238-PC than 10:1, more preferably between 15:1 and 20:1. In some embodiments, the particles are designed for administration by sprinkling on food or administered with liquids. In some embodiments, the food or liquid has a pH of between about 5 and about 8; preferably between about 6.0 and about 7.5; more preferably about 6.8.

[0010] In some embodiments, this invention further relates to an immediate release (IR) pharmaceutical dosage form comprising a plurality of particles, wherein each particle is as described hereinabove. In some embodiments, the dosage form is in the form of beads in a capsule, a compressed tablet, sprinkle beads in a sachet or sprinkle beads in a stick pack. In some embodiments, the dissolution profile of said dosage form exhibits at least 50% drug release in 30 minutes; preferably at least 60%; more preferably at least 75%; most preferably at least 85%. In some embodiments, upon oral administration, less than 35% of the drug is released from the dosage form within the initial 5 minutes; preferably less than 25%; more preferably less than 10%; most preferably less than 7%. In some embodiments, the dosage form comprises between about 10 mg and about 1000 mg of pridopidine or pharmaceutically acceptable salt thereof; preferably between about 22.5mg and 315 mg of pridopidine or pharmaceutically acceptable salt thereof; more preferably 22.5 mg or 45 mg.

[0011] In some embodiments, this invention further relates to a method of preparing the particles of the invention, comprising the steps of: a. coating a beads substrate with a polymer seal coat; b. coating the polymer seal coated beads with a drug layer comprising pridopidine or salt thereof, optionally comprising a binder and / or optionally comprising a glidant; and c. coating the drug layer with a topcoat.

[0012] In some embodiments, the particles are configured such that, upon administration to the oral cavity of a subject, the taste of the pridopidine is substantially masked, and, upon subsequent exposure to the acidic environment of the subject’s stomach, the pridopidine is completely released, thereby producing an immediate-release pharmacokinetic profile. In some embodiments, the glidant is an anti -tacking agent, the topcoat is an outer taste masking coat, or combination thereof. In some embodiments, the topcoat comprises an acrylate based coating. In some embodiments, the coating of the drug layer with a topcoat is carried out using aqueous solvent system, organic solvent system, or combination thereof. In some embodiments, the coating process of step (a), utilizes a polymer seal coat solution, which comprises between about 5%-30% of solid content; preferably about 10%. In some embodiments, the coating process of step (b), utilizes a drug coat solution, which comprises between about 15%-60% of solid content; preferably between about 20% and 50%; more preferably between about 25% and 45%; most preferably at least 30%. In some embodiments,P-636238-PC the coating process of step (c), utilizes a topcoat, which comprises between about 5%-25% of solid content; preferably between about 8% and 20%; more preferably between about 10% and 18%; most preferably about 16%. In some embodiments, the coating of the drug layer (step (b)) is maintained at a product temperature of below 70 °C; preferably below 50 °C or below 35 °C. In some embodiments, the beads substrate comprise microcrystalline cellulose (MCC) beads, sugar spheres or combination thereof. In some embodiments, the beads substrate has a particle size higher than about 100 pm; preferably higher than about 200 pm; more preferably lower than about 500 pm; most preferably about 350 pm; In some embodiments, the polymer amount in the seal coat layer ranges between about 0.5% and 10% w / w based on the total weight of the particle; preferably about 1-3%; more preferably about 1.3-1.9% w / w; most preferably about 1.5% w / w. In some embodiments, the polymer in the seal coat layer is Hypromellose. In some embodiments, the binder amount in the drug layer ranges between about 1% and 10% w / w based on the total weight of the particle; preferably about 1-5%; more preferably about 3% w / w. In some embodiments, the binder in the drug layer is Hypromellose. In some embodiments, the glidant amount in the drug layer ranges between 0.5-5% w / w; preferably 0.5-3%; more preferably 1.5% w / w. In some embodiments, the glidant in the drug layer is silicon dioxide, more preferably colloidal silicon dioxide. In some embodiments, the topcoat amount ranges between about 1-50% w / w with respect to the weight of the final particle; preferably between about 10-30% w / w; more preferably between about 19-20% w / w. In some embodiments, the topcoat is a seal coat, taste masking coat or combination thereof. In some embodiments, the topcoat comprises an acrylate based coating. In some embodiments, the topcoat comprises a methacrylate based coating. In some embodiments, the drug layer contains between 15% to 75% solids by weight, preferably higher than 30%. In some embodiments, the weight ratio between the pridopidine and the polymer in the drug layer ranges between 100: 1 and 1 : 1 respectively, more preferably between 20: 1 and 15:1, most preferably greater than 10: 1. In some embodiments, step (a) is carried out at a temperature range of between 25°C and 75°C; preferably at about 45°C. In some embodiments, step (a) is carried out at a spray rate of between 1 and 2 g / min; preferably between 4.7 and 8.4 g / min.

[0013] In some embodiments, this invention further relates to immediate release (IR) particles comprising pridopidine or pharmaceutically acceptable salt thereof, prepared according to the methods as described hereinabove. In some embodiments, the particles are configured such that, upon administration to the oral cavity of a subject, the taste of the pridopidine is substantially masked, and, upon subsequent exposure to the acidic environment of the subject’s stomach, the pridopidine is completely released, thereby producing an immediate-release pharmacokinetic profile.P-636238-PC

[0014] In some embodiments, this invention further relates to a method of treating, slowing the progression, lessening the decline, delaying onset of symptoms, or slowing the progression of symptoms of a neurodegenerative or neurodevel opmental disease or disorder in a subject, comprising administering to the subject the dosage form as described hereinabove.

[0015] In some embodiments, the neurodegenerative disease or disorder is selected from the group consisting from Huntington Disease, prodromal / premanifest Huntington disease, Juvenile onset Huntington Disease, Amyotrophic Lateral Sclerosis (ALS), Parkinson’s Disease, Parkinson’s Disease associated with glucocerebrosidase (GBA) deficiency, dystonia, cognitive disorder, dyskinesia, medication-induced dyskinesia, tardive dyskinesia, levodopa-induced dyskinesia (LID), mild cognitive impairment (MCI), Alzheimer’s Disease, age related memory loss, major depressive disorder, depression, anxiety, bacterial infections-induced depression, optic neuropathies including glaucoma, age-related macular degeneration (AMD), geographic atrophy, Leber’s Hereditary Optic Neuropathy (LHON) and retinitis pigmentosa, and wherein the neurodevelopmental disease or disorder is Rett syndrome (RTT) or Fragile X Syndrome (FXS). In some embodiments, this invention further relates to a method of treating, slowing the progression, lessening the decline, delaying onset of symptoms, or slowing the progression of symptoms of a mitochondrial disease or dysfunction (i.e. Lysosomal storage disease (LSD), leukodystrophies, vanishing white matter (VWM) disease), Wolfram disease or viral infection (i.e. COVID-19) in a subject, comprising administering to the subject the dosage form as described hereinabove.

[0016] In some embodiments, this invention further relates to a pharmaceutical dosage form comprising a plurality of particles according to this invention for use in the treatment of a patient in need thereof by: a. sprinkling the plurality of particles on soft food; and b. administering the soft food orally.

[0017] In some embodiments, the particles are configured such that, upon administration to the oral cavity of a subject, the taste of the pridopidine is substantially masked, and, upon subsequent exposure to the acidic environment of the subject’s stomach, the pridopidine is completely released, thereby producing an immediate-release pharmacokinetic profile.

[0018] In some embodiments, this invention further relates to a pharmaceutical dosage form comprising a plurality of particles according to this invention, for use in the treatment of a patient in need thereof by: a. administering the particles orally; and b. subsequent administration of a liquid.

[0019] In some embodiments, the particles are configured such that, upon administration to theP-636238-PC oral cavity of a subject, the taste of the pridopidine is substantially masked, and, upon subsequent exposure to the acidic environment of the subject’s stomach, the pridopidine is completely released, thereby producing an immediate-release pharmacokinetic profile.BRIEF DESCRIPTION OF THE FIGURES

[0020] Figure 1: Time-intensity curves for bitter taste intensity of pridopidine solutions of various concentrations. The solutions had strength-dependent bitterness profiles spanning the Flavor Profile supra-threshold intensity range. Based on bitterness alone, solution strengths within the range 2.5mg to 9mg / ml represent a particularly difficult taste masking challenge

[0021] Figure 2: Time-intensity curves for solvent aromatic intensity of various pridopidine samples. Pridopidine also has a solvent-like aromatic off-note that fades rapidly in the aftertaste. This aromatic is above a patient-perceptible intensity (>1) only at the clinical strengths (9, 5 and 2.5mg / mL).

[0022] Figure 3: Time-intensity curves for numbing mouthfeel intensity of various pridopidine samples. Pridopidine has a slight numbing mouthfeel but all concentrations were below a patient- perceptible intensity (<1).

[0023] Figure 4: Time-intensity curves for bitter taste intensity of various pridopidine capsule strengths . compared with equivalent solution strengths. Pridopidine capsule contents dispersed in a sweetened commercial vehicle, SyrSpend® (dashed lines) have lower bitterness than their equivalent solution concentrations (solid lines). The dosing vehicle provided some reduction in bitterness intensity but was insufficient for acceptable palatability.

[0024] Figure 5A-5C: bitterness, sweetness, sourness and solvent aromatic attributes intensity vs. time for 9 mg / mL (Figure 5A), 5 mg / mL (Figure 5B) and 2.5 mg / mL (Figure 5C) pridopidine capsules content suspension in SyrSpend®. All capsule content suspensions failed in this respect, showing poor bitterness “coverage”. Therefore, dispersing existing capsule contents into SyrSpend® does not represent a practical dosing option

[0025] Figure 6: Manufacturing Process of pridopidine hydrochloride Immediate Release Capsules, 45 mg containing coated beads PROTOTYPES - 1-4.

[0026] Figure 7: Dissolution profiles at pH-6.8 of pridopidine hydrochloride Immediate release capsules containing coated beads (Prototype 1 & 2) to mimic oral pH.

[0027] Figure 8: Dissolution profile (pH-6.8) of pridopidine hydrochloride Immediate Release capsules containing coated beads (Prototype 3) to mimic oral pH.

[0028] Figure 9: Dissolution profile of pridopidine hydrochloride Immediate Release Beads (pH 6.8 Media - Prototype 4) to mimic oral pH.P-636238-PC

[0029] Figure 10: Dissolution profile of pridopidine hydrochloride Immediate Release Beads (pH 1.2 Media - Prototype 4) to mimic gastric pH.

[0030] Figure 11: Dissolution profile of pridopidine hydrochloride Immediate Release Beads (pH 4.5 Media - Prototype 4) to mimic pH in the presence of acidic foods.DETAILED DESCRIPTION OF THE INVENTIONImmediate release (IR) particles comprising pridopidine drug

[0031] In some embodiments, this invention provides immediate release (IR) particles comprising pridopidine or pharmaceutically acceptable salt thereof, each of said particles comprises: a. beads substrate; b. a drug layer comprising pridopidine or pharmaceutically acceptable salt thereof, coated over the beads substrate; and c. a topcoat further coated over the drug layer.

[0032] In some embodiments, the beads substrate is further coated with a polymer seal coat. In some embodiments, the drug layer further comprises a binder. In some embodiments, the drug layer further comprises a glidant. In some embodiments, the drug layer further comprises a binder and a glidant. In some embodiments, the topcoat comprises an acrylate-based coating. In some embodiments, the topcoat consists of an acrylate-based coating.

[0033] In some embodiments, the particles are configured such that, upon administration to the oral cavity of a subject, the taste of the pridopidine is substantially masked, and, upon subsequent exposure to the acidic environment of the subject’s stomach, the pridopidine is completely released, thereby producing an immediate-release pharmacokinetic profile.

[0034] In some embodiments, this invention provides immediate release (IR) particles comprising pridopidine or pharmaceutically acceptable salt thereof, each of said particles comprises: a. beads substrate, optionally coated with a polymer seal coat; b. a drug layer comprising pridopidine or pharmaceutically acceptable salt thereof, coated over the beads substrate or the polymer seal coat, wherein the drug layer optionally comprises a binder and / or a glidant; and c. a topcoat further coated over the drug layer.

[0035] In some embodiments, the particles are configured such that, upon administration to the oral cavity of a subject, the taste of the pridopidine is substantially masked, and, upon subsequentP-636238-PC exposure to the acidic environment of the subject’s stomach, the pridopidine is completely released, thereby producing an immediate-release pharmacokinetic profile.

[0036] In some embodiments, the beads substrate is coated with a polymer seal coat. In some embodiments, the drug layer comprises a binder. In some embodiments, the drug layer comprises a glidant. In some embodiments, the drug layer comprises a binder and a glidant. In some embodiments, the topcoat comprises an acrylate-based coating. In some embodiments, the topcoat consists based coating. In some embodiments, the topcoat comprises a methacrylate-based coating. In some embodiments, the topcoat consists of a methacrylate -based coating.

[0037] In some embodiments, this invention provides immediate release (IR) particles comprising pridopidine or pharmaceutically acceptable salt thereof, each of said particles comprises: a. beads substrate, coated with a polymer seal coat; b. a drug layer comprising pridopidine or pharmaceutically acceptable salt thereof, coated over the polymer seal coat; and c. a topcoat further coated over the drug layer.

[0038] In some embodiments, the particles are configured such that, upon administration to the oral cavity of a subject, the taste of the pridopidine is substantially masked, and, upon subsequent exposure to the acidic environment of the subject’s stomach, the pridopidine is completely released, thereby producing an immediate-release pharmacokinetic profile.

[0039] In some embodiments, the drug layer further comprises a binder. In some embodiments, the drug layer further comprises a glidant. In some embodiments, the drug layer further comprises a binder and a glidant. In some embodiments, the topcoat comprises an acrylate-based coating. In some embodiments, the topcoat consists of an acrylate-based coating. In some embodiments, the topcoat comprises a methacrylate-based coating. In some embodiments, the topcoat consists of a methacrylate-based coating.

[0040] In some embodiments, this invention provides immediate release (IR) particles comprising pridopidine or pharmaceutically acceptable salt thereof, each of said particles comprises: a. beads substrate, coated with a polymer seal coat; b. a drug layer comprising pridopidine or pharmaceutically acceptable salt thereof, coated over the beads substrate or the polymer seal coat, wherein the drug layer comprises a binder and / or a glidant; and c. a topcoat, further coated over the drug layer.P-636238-PC

[0041] In some embodiments, the particles are configured such that, upon administration to the oral cavity of a subject, the taste of the pridopidine is substantially masked, and, upon subsequent exposure to the acidic environment of the subject’s stomach, the pridopidine is completely released, thereby producing an immediate-release pharmacokinetic profile.

[0042] In some embodiments, the drug layer comprises a binder. In some embodiments, the drug layer comprises a glidant. In some embodiments, the drug layer comprises a binder and a glidant. In some embodiments, the topcoat comprises an acrylate-based coating. In some embodiments, the topcoat consists of an acrylate-based coating. In some embodiments, the topcoat comprises a methacrylate-based coating. In some embodiments, the topcoat consists of a methacrylate-based coating.

[0043] In some embodiments, this invention provides immediate release (IR) particles comprising pridopidine or pharmaceutically acceptable salt thereof, each of said particles comprises: a. beads substrate, optionally coated with a polymer seal coat; b. a drug layer comprising pridopidine or pharmaceutically acceptable salt thereof, coated over the beads substrate or the polymer seal coat, wherein the drug layer optionally comprises a binder; and c. a topcoat further coated over the drug layer.

[0044] In some embodiments, the particles are configured such that, upon administration to the oral cavity of a subject, the taste of the pridopidine is substantially masked, and, upon subsequent exposure to the acidic environment of the subject’s stomach, the pridopidine is completely released, thereby producing an immediate-release pharmacokinetic profile.

[0045] In some embodiments, the beads substrate is coated with a polymer seal coat. In some embodiments, the drug layer comprises a binder. In some embodiments, the drug layer further comprises a glidant. In some embodiments, the topcoat comprises an acrylate-based coating. In some embodiments, the topcoat consists of an acrylate-based coating. In some embodiments, the topcoat comprises a methacrylate-based coating. In some embodiments, the topcoat consists of a methacrylate-based coating.

[0046] In some embodiments, this invention provides immediate release (IR) particles comprising pridopidine or pharmaceutically acceptable salt thereof, each of said particles comprises: a. beads substrate, coated with a polymer seal coat; b. a drug layer comprising pridopidine or pharmaceutically acceptable salt thereof, coated over the beads substrate or the polymer seal coat, wherein the drug layerP-636238-PC comprises a binder; and c. a topcoat comprising an acrylate-based coating, further coated over the drug layer.

[0047] In some embodiments, the particles are configured such that, upon administration to the oral cavity of a subject, the taste of the pridopidine is substantially masked, and, upon subsequent exposure to the acidic environment of the subject’s stomach, the pridopidine is completely released, thereby producing an immediate-release pharmacokinetic profile.

[0048] In some embodiments, the drug layer further comprises a glidant.

[0049] As used herein, the term "particles" encompasses a variety of particulate forms, including granules, beads, pellets, microspheres, microparticles, and other similar formulations used in pharmaceuticals; each represents a separate embodiment according to this invention. In some embodiments, the particles according to this invention are granules. In some embodiments, the particles according to this invention are beads. In some embodiments, the particles according to this invention are pellets. In some embodiments, the particles according to this invention are microspheres. In some embodiments, the particles according to this invention are microparticles.

[0050] In some embodiments, the pridopidine or pharmaceutically acceptable salt thereof is pridopidine hydrochloride.

[0051] In some embodiments, the immediate release (IR) particles of the invention comprise beads substrate. Non limited examples of various beads substrates include: Microcrystalline Cellulose Beads (MCC), Sugar Spheres (Sucrose or Mannitol), Starch Beads, Gelatin Beads, Polymeric Beads (e.g., Polyethylene Glycol), Alginate Beads, Calcium Carbonate Beads, Chitosan Beads, Lipid Beads, Magnetic Beads, and Silica Beads. In some embodiments, the beads substrate comprises microcrystalline cellulose (MCC) beads. In some embodiments, the beads substrate comprises sugar spheres.

[0052] In some embodiments, the beads substrate comprises particles of various diameter sizes. In some embodiments, the beads have a diameter ranging from 10pm to 1000pm. In some embodiments, the beads diameter is between about 100 pm and 1000 pm; between about 150 pm and 800pm; between about 250pm and 600pm; between about 300pm and 550pm; between about 350pm and 500pm; between about 300pm and 400pm; between about 450pm and 550pm; 350 pm; or 500 pm; each represents a separate embodiment according to this invention. In some embodiments, the MCC beads diameter is at least 100pm; 150pm; 200pm; 250pm; 300pm; 350pm; 400pm; 450pm; 500pm; 550pm; 600pm; 650pm; 700pm; or 800pm; each represents a separate embodiment according to this invention. In some embodiments, the MCC beads diameter is lower than 100pm; 150pm; 200pm; 250pm; 300pm; 350pm; 400pm; 450pm; 500pm; 550pm;P-636238-PC600pm; 650pm; 700pm; or 800pm; each represents a separate embodiment according to this invention. In some embodiments, the MCC beads diameter is about 100pm; 150pm; 200pm; 250pm; 300pm; 350pm; 400pm; 450pm; 500pm; 550pm; 600pm; 650pm; 700pm; or 800pm; each represents a separate embodiment according to this invention. In some embodiments, the bead content with respect to the particle weight ranges between approximately 30% and 85% w / w; between about 35% and 80%; between about 40% and 75%; between about 40% and 85%; between about 25% and 75%; about 30% w / w; 40% w / w; 45% w / w; 50% w / w; 60% w / w; 70% w / w; 75% w / w; 80% w / w; 85% w / w; or 90% w / w; based on the weight of the particle; each represents a separate embodiment according to this invention.

[0053] According to some embodiments of this invention, polymer-based seal coat is required for preventing bead agglomeration during pridopidine layer application - a unique challenge encountered specifically in pridopidine bead-based dosage forms.

[0054] The polymer-based seal coat prevents premature wetting of the microcrystalline cellulose (MCC) core during application of the drug layer solution, which accordingly enables drug coating at lower temperatures, which may lead to an improvement in drug stability.

[0055] The requirement for applying a seal coat underneath the pridopidine-containing layer is a specific and essential adaptation developed uniquely for the preparation of a bead-based dosage form comprising pridopidine. This necessity arises from the exceptionally high solubility of pridopidine in aqueous solutions ( >600mg / ml) at pH 6.8, which leads to significant challenges during its formulation. In particular, when pridopidine is sprayed directly onto the beads without an intervening seal coat, the high water solubility causes substantial agglomeration of the beads. This agglomeration interferes with uniform drug coating and ultimately prevents the formation of a consistent, stable, and pharmaceutically acceptable bead-based dosage form. This issue became evident during the course of multiple formulation experiments conducted prior to the successful development of the present dosage form containing pridopidine. Importantly, the agglomeration problem could not be resolved through conventional means (e.g., increasing concentrations of binder in the drug layer solution) and was only overcome by the application of a polymer -based seal coat directly on the bead substrate — prior to pridopidine layering. This intermediate seal coat proved essential in stabilizing the substrate surface, thereby enabling uniform drug deposition and avoiding agglomeration. As such, according to some embodiments of this invention, the application of this seal coat layer directly onto the beads is an essential precursor to the successful application of the drug layer on to the beads and successful manufacture of the product.

[0056] In some embodiments, the beads substrate is coated with a seal coat. In some embodiments, the beads substrate is not coated with a seal coat. Non limiting examples of sealP-636238-PC coats include: Polyvinyl Alcohol (PVA), Polyvinylpyrrolidone (PVP), Shellac, Cellulose derivatives such as hydroxypropyl methylcellulose (HPMC, Hypromellose), Methylcellulose (MC), Hydroxyethyl Cellulose (HEC), Sodium Carboxymethyl Cellulose (NaCMC), and ethyl cellulose, Polyethylene Glycol (PEG), Acrylic Polymers such as Eudragit®, Poly(lactic-co- glycolic acid) (PLGA), Gelatin, Chitosan, Sodium Alginate, Polyethylene Oxide (PEO), and Poly(acrylic acid) (PAA). In some embodiments, the seal coat is a hydrophilic seal coat. In some embodiments, the seal coat is a polymer seal coat. In some embodiments, the seal coat is a hydrophilic polymer seal coat. In some embodiments, the seal coat is a hydrophilic polymer-based seal coat. In some embodiments, the polymer is Hypromellose. In some embodiments, the seal coat is applied to the beads directly. In some embodiments, the seal coat is positioned beneath the drug layer.

[0057] In some embodiments, the polymer content within the seal coat layer may vary, typically falling within the range of 1% to 100% w / w relative to the total weight of the particle. In some embodiments, the polymer content within the seal coat layer fall within the range of about 0.5% to 50% w / w; 0.5% to 20% w / w; 0.5% to 10% w / w; 1% to 10% w / w; 1% to 4% w / w; 2% to 4% w / w; 1% to 5% w / w; 1% to 3% w / w; 1% to 2% w / w; 1.3% to 1.9% w / w; relative to the total weight of the particle; each represents a separate embodiment according to this invention. In some embodiments, the polymer content within the seal coat layer is about 0.5%; 0.7%; 0.9%; 1%; 1.2%; 1.5%; 1.7%; 1.9%; 2%; 2.5%; or 3% w / w relative to the total weight of the particle; each represents a separate embodiment according to this invention.

[0058] In some embodiments, the beads substrate is coated with a drug layer comprising pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the beads substrate is coated with a seal coat prior to coating with the drug layer. In some embodiments, the seal coat is applied to the beads directly. In some embodiments, the seal coat is positioned beneath the drug layer. In some embodiments, the seal coat is hydrophilic seal coat. In some embodiments, the seal coat is polymeric seal coat. In some embodiments, the polymer seal coat, coated over the beads substrate, is coated with a drug layer comprising pridopidine or pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the drug layer of the particles of the invention further comprises at least one of Compounds 1-8 or pharmaceutically acceptable salt thereof:P-636238-PC

[0060] In some embodiments, the drug layer further comprises a binder. In some embodiments, the drug layer does not comprise a binder. In some embodiments, the drug layer further comprises a glidant. In some embodiments, the drug layer does not comprise a glidant. In some embodiments, the drug layer further comprises both a binder and a glidant.

[0061] As used herein, the term “binder” refers to a compound that can cause a composition to hold together. Non limiting examples of binders include: Hydroxypropyl Methylcellulose (HPMC, Hypromellose), Methyl Cellulose (MC), microcrystalline cellulose, Ethylcellulose (EC), Carboxymethyl Cellulose (CMC), Hydroxyethyl Cellulose (HEC), Polyvinylpyrrolidone (PVP), Polyvinyl Alcohol (PVA), Acrylic Polymers such as Eudragit®, Sodium Alginate, Gelatin, Starches such as corn starch or pregelatinized starch, natural gums (eg., acacia gum, gum Arabic), and sucrose. In some embodiments, the binder in the drug layer is Hypromellose. In some embodiments, the binder is hydroxypropyl methylcellulose.

[0062] In some embodiments, the binder content within the drug layer may vary, typically falling within the range of 1% to 100% w / w relative to the total weight of the particle. In someP-636238-PC embodiments, the binder content within the drug layer falls within the range of about 0.5% to 50% w / w; 0.5% to 20% w / w; 1% to 10% w / w; 1% to 5% w / w; 1.5% to 5% w / w; 1% to 3% w / w; 2% to 3% w / w; 1.9% to 3% w / w;; relative to the total weight of the particle; each represents a separate embodiment according to this invention. In some embodiments, the binder content within the drug layer is about 0.5%; 0.7%; 0.9%; 1%; 1.2%; 1.5%; 1.7%; 1.9%; 2%; 2.5%; 3%; 3.5%; 4%; 4.5%; 5%; w / w relative to the total weight of the particle; each represents a separate embodiment according to this invention.

[0063] In some embodiments, each particle comprises about 0.5 wt% to about 10 wt% of binder. In some embodiments, each particle comprises about 2 wt% to about 8 wt% of binder. In some embodiments, each particle comprises about 3 wt% to about 7 wt% of binder. In some embodiments, each particle comprises about 4 wt% to about 6 wt% of binder. In some embodiments, each particle comprises about 4.5 wt% to about 5.5 wt% of binder. In some embodiments, each particle comprises about 5 wt% of binder. In some embodiments, each particle comprises about 0.5 wt% to about 10 wt%, about 0.5 wt% to about 7.5 wt%, about 2.5 wt% to about 10 wt%, or about 2.5 wt% to about 7.5 wt% of binder (e.g., Hypromellose, hydroxypropyl methylcellulose). In some embodiments, each particle comprises about 1.5 wt%, about 2.5 wt%, about 4 wt%, about 5 wt%, about 6 wt%, or about 7.5 wt% of binder (e.g., Hypromellose, hydroxypropyl methylcellulose).

[0064] In some embodiments, the pharmaceutical dosage form comprises about 0.5 wt% to about 10 wt%, about 0.5 wt% to about 7.5 wt%, about 2.5 wt% to about 10 wt%, or about 2.5 wt% to about 7.5 wt% of binder (e.g., Hypromellose, hydroxypropyl methylcellulose). In some embodiments, the pharmaceutical dosage form comprises about 1.5 wt%, about 2.5 wt%, about 4 wt%, about 5 wt%, about 6 wt%, or about 7.5 wt% of binder (e.g., Hypromellose, hydroxypropyl methylcellulose).

[0065] In some embodiments, the weight ratio between the pridopidine amount in the drug layer, and the binder (and / or glidant amount) ranges between 100: 1 and 1 : 1; 50: 1 and 5:l; 30: 1 and 10: 1; 20: 1 and 15: 1; each represents a separate embodiment according to this invention. In some embodiments, the weight ratio between the pridopidine or salt thereof amount and the binder and / or glidant amount in the drug layer is greater than 1: 1; 5: 1; 8:1; 10:1; 12: 1; 15: 1; 20:1; 25: 1; 30:1; 40: 1; 50: 1; or 60:1; each represents a separate embodiment according to this invention.

[0066] In some embodiments, the drug layer further comprises a glidant. Non limiting examples of glidants include: Colloidal Silicon Dioxide (Silica), Talc, Magnesium Stearate, Stearic Acid, Sodium Lauryl Sulfate (SLS), Polyethylene Glycol (PEG), Microcrystalline Cellulose (MCC), and Crosslinked Polyvinylpyrrolidone (PVP). In some embodiments, the glidant in the drug layer is Colloidal silicon dioxide.

[0067] In some embodiments, the glidant content within the drug layer may vary, typicallyP-636238-PC falling within the range of 0.1% to 20% w / w relative to the total weight of the particle. In some embodiments, the glidant content within the drug layer falls within the range of about 0.1% to 10% w / w; 0.5% to 10% w / w; 0.5% to 5% w / w; 0.5% to 3% w / w; 0.5% to 5% w / w; 1% to 5% w / w; 0.5% to 3% w / w; relative to the total weight of the particle; each represents a separate embodiment according to this invention. In some embodiments, the glidant content within the drug layer is about 0.5%; 0.7%; 0.9%; 1%; 1.2%; 1.5%; 1.7%; 1.9%; 2%; 2.5%; 3%; 3.5%; 4%; 4.5%; 5%; w / w relative to the total weight of the particle; each represents a separate embodiment according to this invention.

[0068] In some embodiments, the glidant is an anti-tacking agent. "Anti-tacking agents", also known as "anti -adherent agents" or "anti-sticking agents", are normally used in pharmaceutical manufacturing of beads formulations to prevent the beads from sticking together or adhering to processing equipment. Overall, anti-tacking agents play a vital role in ensuring the manufacturability, quality, and performance of bead formulations by preventing agglomeration, improving flow properties, enhancing coating uniformity, and minimizing equipment fouling. Common anti-tacking agents used in bead formulations include magnesium stearate, talc, colloidal silicon dioxide, and hydroxypropyl methylcellulose (HPMC). More examples of anti-tacking agents include: Calcium Stearate, Zinc Stearate, Sodium Stearyl Fumarate, Hydrophobic Silica, Ethyl Cellulose, and Carnauba Wax. In some embodiments, the anti-tacking agent comprises: hydroxypropyl methylcellulose (HPMC), Magnesium Stearate, Calcium Stearate, Zinc Stearate, Sodium Stearyl Fumarate, Talc, Silicon Dioxide (Colloidal), Hydrophobic Silica, Ethyl Cellulose, and / or Carnauba Wax; each represents a separate embodiment according to this invention. In some embodiments, the anti-tacking agent comprises colloidal silicon dioxide.

[0069] In some embodiments, the drug layer is coated with a topcoat. Non limiting examples of topcoats include: Polymer Topcoats such as Ethylcellulose, Acrylic Polymers (e.g., Eudragit®) and Polyvinyl Alcohol (PVA); Shellac topcoats; Wax topcoats such as Carnauba Wax, and Beeswax; Cellulose Derivative Topcoats such as Methylcellulose and Hydroxypropyl Methylcellulose (HPMC), Protein Topcoats such as Gelatin, and Surfactant Topcoats such as polysorbates (e.g., Polysorbate 80), sugar-based coatings such as sucrose or glucose syrup, flavoring and sweeteners, Opadry, and Surelease. In some embodiments, the topcoat is Opadry®, Surelease®, and / or Eudragit® E PO ReadyMix. In some embodiments, the topcoat is Eudragit® E PO ReadyMix. In some embodiments, the topcoat is Eudragit® RL. In some embodiments, the topcoat is Eudragit® L. In some embodiments, the topcoat is Eudragit® E. In some embodiments, the topcoat is a taste masking topcoat. In some embodiments, the topcoat is an outer taste masking coat. In some embodiments, the topcoat is a seal coat. In some embodiments, the topcoat is aP-636238-PC combination of a taste masking coat and a seal coat. In some embodiments, the topcoat is a cellulose based coating, an acrylate-based coating or combination thereof. In some embodiments, the topcoat layer comprises acrylate-based coating. Non limiting examples for acrylate based coatings include: Eudragit E (Poly(methacrylate) copolymers, such as EudragitE 100, orEudragit E PO); Eudragit RS and RL (Methacrylate Copolymers such as: Eudragit RS 30 D or Eudragit RL 30 D); Eudragit NE 30 D; Eudragit® L. In some embodiments, the topcoat comprises a methacrylate based coating. In some embodiments, the topcoat layer comprises cellulose based coating. Non limiting examples of cellulose based coating include: Ethylcellulose (EC) (such as Surelease or Ethocel (Ethylcellulose)); Hydroxypropyl Methylcellulose (HPMC) (such as Opadry® or Pharmacoat®); Hydroxypropyl Cellulose (HPC) (such as Klucel®); Cellulose Acetate; Cellulose Acetate Phthalate (CAP); and Methylcellulose (MC) (such as Methocel).

[0070] In some embodiments, the topcoat is an outer taste masking coat. In some embodiments, the outer taste masking coat comprises: enteric coating, film coating, sugar coating, and / or flavor masking; each represents a separate embodiment according to this invention. In some embodiments, the enteric coating material comprises: cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), and / or methacrylic acid copolymers (e.g., Eudragit® L, Eudragit ® EPO); each represents a separate embodiment according to this invention. In some embodiments, the outer taste masking coat comprises an acrylate based coating. In some embodiments, the outer taste masking coat comprises a methacrylate based coating. In some embodiments, the outer taste masking coat does not comprise enteric coating. In some embodiments, the outer taste masking coat comprises: film coating, sugar coating, and / or flavor masking; each represents a separate embodiment according to this invention. In some embodiments, the film coating material comprises: hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), and / or polyethylene glycol (PEG); each represents a separate embodiment according to this invention. In some embodiments, the flavor masking agents comprise sweeteners. In some embodiments, the flavor masking agents comprise fruit flavors, artificial flavors, sweeteners and / or intense sweeteners. In some embodiments, the sweeteners comprise: sucrose, fructose, glucose, sorbitol, mannitol, xylitol, maltitol, isomalt, glycerol (glycerin); each represents a separate embodiment according to this invention. In some embodiments, the intense sweeteners comprise: aspartame, sucralose, steviol glycosides (Stevia), saccharin, acesulfame potassium (Ace-K), neotame, advantame, cyclamate, thaumatin, and / or monk fruit extract (Luo Han Guo); each represents a separate embodiment according to this invention. In some embodiments, the fruit flavors comprise: strawberry, cherry, orange, lemon, lime, raspberry, grape, apple, pineapple, peach, banana, blueberry, blackberry, blackcurrant, mango, watermelon, citrus mix and / or berry mix; eachP-636238-PC represents a separate embodiment according to this invention. In some embodiments, the artificial flavors comprise: bubblegum flavor and Vanillin; each represents a separate embodiment according to this invention. In some embodiments, the flavor masking agents comprise: sucrose, sucralose, sorbitol, mannitol, aspartame, artificial flavors and / or fruit flavors; each represents a separate embodiment according to this invention. In some embodiments, the polymer coating comprise: ethyl cellulose, hydroxypropyl cellulose, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), and / or methacrylic acid copolymers (e.g., Eudragit® L, Eudragit ® EPO); each represents a separate embodiment according to this invention.

[0071] In some embodiments, the topcoat amount may vary, typically falling within the range of 1% to 100% w / w relative to the total weight of the particle. In some embodiments, the topcoat falls within the range of about 0.5% to 50% w / w; 1% to 30% w / w; 1% to 50% w / w; 1% to 25% w / w; 15% to 25% w / w; 15% to 20% w / w; 10% to 30% w / w; 19% to 20% w / w; relative to the total weight of the particle; each represents a separate embodiment according to this invention.

[0072] In some embodiments, the polymer in the seal coat layer is Hypromellose and the binder in the drug layer is Hypromellose. In some embodiments, the polymer in the seal coat layer is Hypromellose and the glidant in the drug layer is colloidal silicon dioxide. In some embodiments, the binder in the drug layer is Hypromellose and the glidant in the drug layer is colloidal silicon dioxide. In some embodiments, the polymer in the seal coat layer is Hypromellose, the binder in the drug layer is Hypromellose and the glidant in the drug layer is colloidal silicon dioxide.

[0073] In some embodiments, the drug layer is characterized by a drug loading ranging between about 10% and 80% w / w; 15% and 85% w / w; 20% and 75% w / w; 25% and 75% w / w; 20% and 60% w / w; 25% and 65% w / w; 30% and 80% w / w; 35% and 55% w / w; 35% and 45% w / w; relative to the weight of the seal coated beads, before loading of the drug; each represents a separate embodiment according to this invention. In some embodiments, the drug layer is characterized by a drug loading of about 20% w / w; 25% w / w; 30% w / w; 35% w / w; 40% w / w; 45% w / w; 50% w / w; 55% w / w; 60% w / w; 70% w / w; 80% w / w; relative to the weight of the seal coated beads, before loading of the drug; each represents a separate embodiment according to this invention.

[0074] In some embodiments, the drug layer is characterized by a drug loading ranging between about 10% and 80% w / w; 15% and 85% w / w; 15% and 60% w / w; 15% and 75% w / w; 20% and 75% w / w; 20% and 60% w / w; 25% and 65% w / w; 25% and 80% w / w; 25% and 50% w / w; 20% and 45% w / w; relative to the total weight of the particle; each represents a separate embodiment according to this invention. In some embodiments, the drug layer is characterized by a drug loading of about 20% w / w; 25% w / w; 30% w / w; 35% w / w; 40% w / w; 45% w / w; 50% w / w; 55% w / w; 60% w / w; 70% w / w; 80% w / w; relative to the total weight of the particle; each represents a separateP-636238-PC embodiment according to this invention.

[0075] In some embodiments, the particles have an average particle size of at least about 250 pm; 300 pm; 350 pm; 400 pm; 450 pm; 500 pm; 550 pm; 600 pm; 650 pm; 700 pm; 750 pm; 800 pm; 850 pm; 850 pm; 900 pm; 950 pm; 1000 pm; each represents a separate embodiment according to this invention. In some embodiments, the particles have an average particle size of between about 100 pm and about 1300 pm; between about 250 pm and about 1200 pm; between about 300 pm and about 1000 pm; between about 100 pm and about 600 pm; between about 150 pm and about 900 pm; between about 600 pm and about 1200 pm; between about 700 pm and about 1200 pm; between about 750 pm and about 1200 pm; between about 600 pm and about 1200 pm; each represents a separate embodiment according to this invention. In some embodiments, the particles are combination of particles of various sizes. In some embodiments, the particles have a particle size between about 100pm and about 1mm. In some embodiments, the particles have a particle size between about 100pm and about 500pm. In some embodiments, the particles have a particle size between about 100pm and about 350pm. In some embodiments, the particles have a particle size between about 350pm and about 500pm.

[0076] In some embodiments, the particles have a D90 of at least about 250 pm; 300 pm; 350 pm; 400 pm; 450 pm; 500 pm; 550 pm; 600 pm; 650 pm; 700 pm; 750 pm; 800 pm; 850 pm; 850 pm; 900 pm; 950 pm; 1000 pm; 1100 pm; 1200 pm; each represents a separate embodiment according to this invention. In some embodiments, the particles have a D50 of at least about 500 pm; 550 pm; 600 pm; 650 pm; 700 pm; 750 pm; 800 pm; 850 pm; 850 pm; 900 pm; 950 pm; 1000 pm; 1100 pm; 1200 pm; each represents a separate embodiment according to this invention. In some embodiments, the particles have a Dio of at least about 500 pm; 550 pm; 600 pm; 650 pm; 700 pm; 750 pm; 800 pm; 850 pm; 850 pm; 900 pm; 950 pm; 1000 pm; each represents a separate embodiment according to this invention.

[0077] In some embodiments, the particles have a D90 of between about 300 pm and about 1000 pm; about 350 pm and about 900 pm; about 400 pm and about 1000 pm; about 450 pm and about 950 pm; about 500 pm and about 950 pm; about 520 pm and about 940 pm; about 800 pm and about 1200 pm; about 750 pm and about 1150 pm; each represents a separate embodiment according to this invention. In some embodiments, the particles have a D50 of between about 300 pm and about 1000 pm; about 350 pm and about 900 pm; about 400 pm and about 950 pm; about 400 pm and about 900 pm; about 450 pm and about 850 pm; about 450 pm and about 900 pm; about 650 pm and about 1050 pm; about 700 pm and about 1000 pm; each represents a separate embodiment according to this invention. In some embodiments, the particles have a Dio of between about 300 pm and about 1000 pm; about 300 pm and about 900 pm; aboutP-636238-PC300 pm and about 800 pm; about 350 pm and about 750 pm; about 350 pm and about 700 pm; about 400 pm and about 700 pm; about 600 pm and about 800 pm; about 550 pm and about 850 pm; each represents a separate embodiment according to this invention.

[0078] In some embodiments, each particle has an average diameter of about 0.5 mm to about 5 mm. In some embodiments, each granule has an average diameter of about 1.5 mm to about 5 mm. In some embodiments, each particle has an average diameter of about 0.5 mm to about 1.5 mm. In some embodiments, each particle has an average diameter of about 0.8 mm to about 1.5 mm. In some embodiments, each particle has an average diameter of about 2 mm to about 3 mm. In some embodiments, each particle has an average diameter of about 2.15 mm to about 2.25 mm. In some embodiments, each particle has an average diameter of about 2.18 mm to about 2.23 mm. In some embodiments, each particle has an average diameter of about 2.19 mm to about 2.21 mm. In some embodiments, each particle has an average diameter of about 2.2 mm. In some embodiments, each particle has an average diameter of about 2 mm. In some embodiments, each particle has an average diameter of about 1 mm to about 5 mm. In some embodiments, each particle has an average diameter of about 1 mm to about 4 mm. In some embodiments, each particle has an average diameter of about 1 mm to about 3.5 mm. In some embodiments, each particle has an average diameter of about 1.2 mm to about 5 mm. In some embodiments, each particle has an average diameter of about 1.2 mm to about 4 mm. In some embodiments, each particle has an average diameter of about 1.2 mm, about 1.4 mm, about 1.6 mm, about 1.8 mm, about 1.9 mm, about 2 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.8 mm, or about 3 mm.

[0079] In some embodiments, each particle has a diameter variation of no more than 20% from the average diameter. In some embodiments, each particle has a diameter variation of no more than 15%, no more than 10%, no more than 7.5%, or no more than 5% from the average diameter. In some embodiments, each particle has a d99 particle diameter distribution of at most about 2.8 mm. In some embodiments, each particle has a d99 particle diameter distribution of at most about 2.5 mm. In some embodiments, each particle has a d99 particle diameter distribution of about 1.2 to about 2.8 mm, about 1.2 mm to about 2.5 mm, about 1.6 mm to about 2.8 mm, about 1.6 mm to about 2.5 mm, about 1.8 mm to about 2.8 mm, or about 1.8 mm to about 2.5 mm.

[0080] As used herein, the diameter of a particle described herein refers to the largest dimension thereof (e.g., a diameter of a spherical particle, a length of an ovoid particle, the greater of the height and diameter of a cylindrical particle, etc.). As used herein, a d99 particle diameter distribution refers to the value of the particle diameter (e g., the diameter of a particle) at which about 99% of the particles in a sample have a value that is lower than the d99 value, and about 1%P-636238-PC of the particles in the sample have a value that is higher than the d99 value. The average diameter and particle diameter distribution of particles described herein can be measured using conventional particle size analysis techniques (e.g., sieve analysis, laser diffraction analysis, or microscope counting).

[0081] As used herein, the term “diameter variation” indicates the maximum amount that the diameter of a particle in a distribution varies from the average diameter of the distribution. For example, for a sample of particles having a diameter variation of no more than 20%, the diameter of each particle in the sample is no less than 20% and no more than 20% of the indicated average diameter of the particles.

[0082] In some embodiments, each particle has an average density of at least about 0.5 g / cm3. In some embodiments, each particle has an average density of at least about 0.3 g / cm3. In some embodiments, each particle has an average density of at least about 0.8 g / cm3. In some embodiments, each particle has an average density of at least about 0.75 g / cm3, at least about 1 g / cm3, at least about 1.25 g / cm3, or at least about 1.5 g / cm3. In some embodiments, each particle has an average density of about 0.5 g / cm3to about 2.5 g / cm3. In some embodiments, each particle has an average density of about 0.3 g / cm3to about 2 g / cm3, In some embodiments, each particle has an average density of about 0.5 g / cm3to about 2 g / cm3, about 0.75 g / cm3to about 2.5 g / cm3, about 0.75 g / cm3to about 2 g / cm3, about 1 g / cm3to about 2.5 g / cm3, or about 1 g / cm3to about 2 g / cm3. In some embodiments, each particle has an average density of about 1 g / cm3, about 1.25 g / cm3, about 1.5 g / cm3, about 1.75 g / cm3, about 2 g / cm3, or about 2.25 g / cm3, or about 2.5 g / cm3.

[0083] In some embodiments, each particle has an average hardness of about 0.5 kp to about 4 kp. In some embodiments, each particle has an average hardness of about 0.5 kp to about 3 kp. In some embodiments, each particle has an average hardness of about 0.8 kp to about 2.6 kp. In some embodiments, each particle has an average hardness of about 1 kp to about 2.4 kp. In some embodiments, each particle has an average hardness of about 1.2 kp to about 2 kp. In some embodiments, each particle has an average hardness of about 1.4 kp to about 1.8 kp. In some embodiments, each particle has an average hardness of about 1.5 kp to about 1.7 kp. In some embodiments, each particle has an average hardness of about 1.6 kp. In some embodiments, each particle has an average hardness of about 1 kp to about 2.5 kp. In some embodiments, each particle has an average hardness of about 1 kp to about 2 kp, about 1.2 kp to about 2.5 kp, or about 1.2 kp to about 2 kp. In some embodiments, each particle has an average hardness of about 1 kp, about 1.1 kp, about 1.2 kp, about 1.3 kp, about 1.4 kp, about 1.5 kp, about 1.6 kp, about 1.7 kp, about 1.8 kp, about 1.9 kp, or about 2 kp.

[0084] In some embodiments, each particle has an average weight of about 8 mg to about 11P-636238-PC mg. In some embodiments, each particle has an average weight of about 8 mg to about 12 mg. In some embodiments, each particle has an average weight of about 8 mg to about 10.2 mg. In some embodiments, each particle has an average weight of about 8 mg to about 10 mg. In some embodiments, each particle has an average weight of about 8.2 mg to about 10.1 mg. In some embodiments, each particle has an average weight of about 8.3 mg to about 9.9 mg. In some embodiments, each particle has an average weight of about 8.5 mg to about 9.7 mg. In some embodiments, each particle has an average weight of about 8.7 mg to about 9.5 mg. In some embodiments, each particle has an average weight of about 8.9 mg to about 9.3 mg. In some embodiments, each particle has an average weight of about 9 mg to about 9.2 mg. In some embodiments, each particle has an average weight of about 9. 1 mg.

[0085] In some embodiments, the weight ratio between the drug and the binder in the drug layer ranges between 100:1 and 1: 1; 50:1 and 10: 1; 30:1 and 10: 1; or 20: 1 and 15:1 respectively; each represents a separate embodiment according to this invention. In some embodiments, the weight ratio between the drug and the binder in the drug layer is greater than 1: 1; greater than 5 : 1 ; or greater than 10: 1 respectively; each represents a separate embodiment according to this invention.

[0086] In some embodiments, the particles are designed for administration by sprinkling on food. In some embodiments, the particles are designed for administration with liquids. In some embodiments, the food has a pH of between about 5 and about 8; between about 5.5 and about 7.5; between about 6.0 and about 7.0; between about 6.0 and about 7.5; between about 6.5 and about7.5; each represents a separate embodiment according to this invention. In some embodiments, the food has a pH of about 0.5; 0.7; 0.9; 1.0; 1.1; 1.2; 1.4; 1.5; 1.7; 1.8; 2; 2.5; 3; 3.5; 4; 4.5; 5.0; 5.5; 6.0; 6.5; 6.7; 6.8; 6.9; 7.0; 7.5; 8.0; 8.5; or 9; each represents a separate embodiment according to this invention.

[0087] In some embodiments, the drug layer comprises between about 15% and about 75% solids by weight. In some embodiments, the drug layer comprises between about 5% and 80% w / w; 10% and 80% w / w; 15% and 90% w / w; 20% and 75% w / w; 30% and 60% w / w; 35% and 80% w / w; 15% and 55% w / w; 25% and 55% w / w; 25% and 60% w / w; solids by weight; each represents a separate embodiment according to this invention. In some embodiments, the drug layer comprises higher than about 15% w / w; 20% w / w; 25% w / w; 30% w / w; 35% w / w; 40% w / w; 45% w / w; 55% w / w; 60% w / w; 65% w / w; 70% w / w; 75% w / w; 80% w / w; solids by weight; each represents a separate embodiment according to this invention.P-636238-PCAn immediate release (IR) solid dosage forms comprising a plurality of particles according to this invention

[0088] This invention further provides an immediate release (IR) pharmaceutical dosage form comprising a plurality of particles according to this invention as described hereinabove.

[0089] This invention further provides an immediate release (IR) pharmaceutical

[0090] composition comprising a plurality of particles according to this invention as described hereinabove.

[0091] The composition provides effective taste masking while enabling rapid drug release during dissolution. The composition provides improved taste masking and dissolution characteristics, making it suitable for oral administration, specifically a composition which is suitable for sprinkling onto food.

[0092] This invention further provides an immediate release (IR) pharmaceutical dosage form comprising a plurality of particles comprising pridopidine or pharmaceutically acceptable salt thereof, wherein the particles comprise: a. beads substrate; b. a drug layer comprising pridopidine or pharmaceutically acceptable salt thereof, coated over the beads substrate; and c. a topcoat further coated over the drug layer.

[0093] In some embodiments, the beads substrate is further coated with a polymer seal coat. In some embodiments, the drug layer further comprises a binder and / or a glidant. In some embodiments, the drug layer further comprises a binder. In some embodiments, the drug layer further comprises a glidant. In some embodiments, the drug layer further comprises a binder and glidant. In some embodiments, the topcoat comprises an acrylate-based coating. In some embodiments, the topcoat consists of acrylate-based coating. In some embodiments, the topcoat comprises a methacrylate-based coating. In some embodiments, the topcoat consists of a methacrylate-based coating.

[0094] In some embodiments, the dosage form is in the form of a capsule. In some embodiments, the dosage form is in the form of a tablet. In some embodiments, the dosage form is in the form of a compressed tablet. In some embodiments, the dosage form is in the form of sprinkled beads in a sachet. In some embodiments, the dosage form is in the form of sprinkled beads in a stick pack. In some embodiments, the dosage form is in the form of a coated tablet. In some embodiments, the dosage form is in the form of suspension. In some embodiments, the dosage form is in the form ofP-636238-PC an emulsion. In some embodiments, the dosage form further comprises talc.

[0095] In some embodiments, the composition as described herein above comprises a unit dose of between 1 mg to 1000 mg of pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the composition as described herein above comprises a unit dose of between 1 mg to 20 mg of pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the composition as described herein above comprises a unit dose of between lOmg to 1000 mg of pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the composition as described herein above comprises a unit dose of between 22.5mg to 315 mg of pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the composition as described herein above comprises a unit dose of 22.5 mg; 45 mg; 90 mg; 135 mg; 180 mg; 200 mg; 250 mg; 300 mg; or 315 mg of pridopidine or pharmaceutically acceptable salt thereof; each represents a separate embodiment according to this invention. In some embodiments, the composition comprises a unit dose of 45 mg of pridopidine or pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the dosage form comprises between 1 mg to 1000 mg of pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises between 1 mg to 10 mg of pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises between lOmg to 1000 mg of pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises between 22.5mg to 315 mg of pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises 1 mg, 5 mg, 10 mg, 15 mg, 22.5 mg; 45 mg; 90 mg; 135 mg; 180 mg; 200 mg; 250 mg; 300 mg; or 315 mg of pridopidine or pharmaceutically acceptable salt thereof; each represents a separate embodiment according to this invention. In some embodiments, the dosage form comprises 1 mg of pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises 5 mg of pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises 10 mg of pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises 22.5 mg of pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises 45 mg of pridopidine or pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the composition or the dosage form according to the invention further comprises excipients that may be useful for improving flow properties. In some embodiments, the composition further comprises additional excipients, including but not limited to: talc, Magnesium Stearate, Calcium Carbonate, Microcrystalline Cellulose (MCC), Silicon Dioxide (Silica), Sodium Lauryl Sulfate (SLS), Croscarmellose Sodium, Polyvinylpyrrolidone (PVP), Polyethylene Glycol (PEG), Corn Starch, Gelatin. In some embodiments, the composition furtherP-636238-PC comprises talc.

[0098] In some embodiments, upon oral administration, the composition or the dosage form described hereinabove demonstrates a minimum of 5%; 10%; 15%; 20%; 25%; 30%; 35%; 40%; 45%; 50%; 55%; 60%; 65%; 70%; 75%; 80%; 85%; or 90% drug release within the initial 30 minutes, as discerned from its dissolution profile; each represents a separate embodiment according to this invention. In some embodiments, the composition or the dosage form described hereinabove demonstrates a minimum of 15% drug release within the initial 30 minutes, as discerned from its dissolution profile. In some embodiments, the composition or the dosage form described hereinabove demonstrates a minimum of 25% drug release within the initial 30 minutes, as discerned from its dissolution profile. In some embodiments, the composition or the dosage form described hereinabove demonstrates a minimum of 50% drug release within the initial 30 minutes, as discerned from its dissolution profile. In some embodiments, the composition or the dosage form described hereinabove demonstrates a minimum of 60% drug release within the initial 30 minutes, as discerned from its dissolution profile. In some embodiments, the composition or the dosage form described hereinabove demonstrates a minimum of 70% drug release within the initial 30 minutes, as discerned from its dissolution profile. In some embodiments, the composition or the dosage form described hereinabove demonstrates a minimum of 75% drug release within the initial 30 minutes, as discerned from its dissolution profile. In some embodiments, the composition or the dosage form described hereinabove demonstrates a minimum of 85% drug release within the initial 30 minutes, as discerned from its dissolution profile. In some embodiments, the composition or the dosage form described hereinabove demonstrates a minimum of 90% drug release within the initial 30 minutes, as discerned from its dissolution profile. This enhanced embodiment signifies a formulation engineered for rapid and efficient drug delivery, ensuring prompt therapeutic action and efficacy.

[0099] In some embodiments, upon oral administration, the composition or the dosage form described hereinabove demonstrates a maximum of 1%, 3%; 4%; 5%; 6%; 7% 8%; 9%; 10%; 15%; 20%; 25%; 30%; 35%; 40%; 45%; 50%; 55%; 60%; 65%; 70%; 75%; 80%; 85%; or 90% drug release within the initial 5 minutes, as discerned from its dissolution profile; each represents a separate embodiment according to this invention. In some embodiments, the composition or the dosage form described hereinabove demonstrates a maximum of 35% drug release within the initial 5 minutes, as discerned from its dissolution profile. In some embodiments, the composition or the dosage form described hereinabove demonstrates a maximum of 25% drug release within the initial 5 minutes, as discerned from its dissolution profile. In some embodiments, the composition or the dosage form described hereinabove demonstrates a maximum of 10% drug release within the initialP-636238-PC5 minutes, as discerned from its dissolution profile. In some embodiments, the composition or the dosage form described hereinabove demonstrates a maximum of 7% drug release within the initial 5 minutes, as discerned from its dissolution profile. This enhanced embodiment signifies a formulation engineered for rapid and efficient drug delivery, ensuring prompt therapeutic action and efficacy.Methods for particles preparation

[0100] In some embodiments, this invention further relates to a method of preparing particles according to this invention, the method comprises the steps of: a. coating beads substrate with a drug layer comprising pridopidine or salt thereof; and b. coating the drug layer with a topcoat.

[0101] In some embodiments, this invention further relates to a method of preparing particles according to this invention, the method comprises the steps of: a. coating beads substrate with a drug layer comprising pridopidine or salt thereof, optionally comprising a binder and / or optionally comprising a glidant; and b. coating the drug layer with a topcoat.

[0102] In some embodiments, this invention further relates to a method of preparing particles according to this invention, the method comprises the steps of: a. coating beads substrate with a drug layer comprising pridopidine or salt thereof, and further comprising a binder and / or a glidant; and b. coating the drug layer with a topcoat.

[0103] In some embodiments, this invention further relates to a method of preparing particles according to this invention, the method comprises the steps of: a. coating beads substrate with a polymer seal coat; b. coating the polymer seal coated beads with a drug layer comprising pridopidine or salt thereof; and c. coating the drug layer with a topcoat.

[0104] In some embodiments, this invention further relates to a method of preparing particles according to this invention, the method comprises the steps of: a. coating beads substrate with a polymer seal coat; b. coating the polymer seal coated beads with a drug layer comprising pridopidine or salt thereof, and further comprising a binder and / or a glidant; and c. coating the drug layer with a topcoat.

[0105] In some embodiments, this invention further relates to a method of preparing particlesP-636238-PC according to this invention, the method comprises the steps of: a. coating beads substrate with a polymer seal coat; b. coating the polymer seal coated beads with a drug layer comprising pridopidine or salt thereof, optionally comprising a binder and / or optionally comprising a glidant; and c. coating the drug layer with a topcoat.

[0106] In some embodiments, the glidant is an anti -tacking agent as described hereinabove. In some embodiments, the topcoat is an outer taste masking coat. In some embodiments, the topcoat is an outer seal coat. In some embodiments, the topcoat comprises an acrylate-based coating. In some embodiments, the topcoat consists of an acrylate-based coating. In some embodiments, the topcoat comprises a methacrylate-based coating. In some embodiments, the topcoat consists of a methacrylate-based coating.

[0107] In some embodiments, a method according to this invention comprises a step of coating a beads substrate with a polymer seal coat. In some embodiments, the polymer seal coat solution used in the coating process comprises between about 1-75%, 3-50%; 5%-30%; 5%-25%; 3%-20%; 5%- 15%; 7%-13%; 5%-10% of solid content; each represents a separate embodiment according to this invention. In some embodiments, the polymer seal coat solution used in the coating process comprises between about 5%-30% of solid content. In some embodiments, the polymer seal coat solution used in the coating process comprises about 3%; 5%; 7%; 9%; 10%; 13%; 15%; 20%; 25%; 30%; 35%; 40%; 45%; 50%; 60%; 65%; 70%; 75% of solid content; each represents a separate embodiment according to this invention. In some embodiments, the polymer seal coat solution used in the coating process comprises at least about 3%; 5%; 7%; 9%; 10%; 13%; 15%; 20%; 25%; 30%; 35%; 40%; 45%; 50%; 60%; 65%; 70%; 75% of solid content; each represents a separate embodiment according to this invention. In some embodiments, the polymer seal coat solution used in the coating process comprises Hypromellose.

[0108] In some embodiments, a method according to this invention comprises a step of coating the beads, or the polymer seal coated beads with a drug layer comprising pridopidine or salt thereof. In some embodiments, the drug coat solution used in the coating process comprises between about l%-75%; 3-70%; 5%-65%; 10%-75%; 15%-60%; 20%-50%; 25%-45%; 20%-40%; 25%-35% of solid content; each represents a separate embodiment according to this invention. In some embodiments, the drug coat solution used in the coating process comprises between about 15%-60% of solid content. In some embodiments, the drug coat solution used in the coating process comprises between about 20%-50% of solid content. In some embodiments, the drug coat solution used in the coating process comprises between about 25%-45% of solid content. In some embodiments, the drug coat solution used in the coating process comprises about 3%; 5%; 7%; 9%; 10%; 13%; 15%;P-636238-PC20%; 25%; 30%; 35%; 40%; 45%; 50%; 60%; 65%; 70%; 75% of solid content; each represents a separate embodiment according to this invention. In some embodiments, the drug coat solution used in the coating process comprises at least about 3%; 5%; 7%; 9%; 10%; 13%; 15%; 20%; 25%; 30%; 35%; 40%; 45%; 50%; 60%; 65%; 70%; 75% of solid content; each represents a separate embodiment according to this invention. In some embodiments, the drug coat solution used in the coating process further comprises a binder. In some embodiments, the binder is as described herein above. In some embodiments, the binder comprises Hypromellose. In some embodiments, the drug coat solution used in the coating process further comprises a glidant. In some embodiments, the glidant is as described herein above. In some embodiments, the glidant comprises colloidal silicon dioxide.

[0109] In some embodiments, a method according to this invention comprises a step of coating the drug layer with a topcoat. In some embodiments, the topcoat solution used in the coating process comprises between about l%-75%; 3-70%; 5%-65%; 5%-50%; 5%-35%; 5%-25%; 8%-20%; 10%- 18%; 10%-75%; 15%-60%; 20%-50%; 25%-45%; 20%-40%; 25%-35% of solid content; each represents a separate embodiment according to this invention. In some embodiments, the topcoat solution used in the coating process comprises between about 5%-25% of solid content. In some embodiments, the topcoat solution used in the coating process comprises between about 8%-20% of solid content. In some embodiments, the topcoat solution used in the coating process comprises between about 10%-18% of solid content. In some embodiments, the topcoat solution used in the coating process comprises about 3%; 5%; 7%; 9%; 10%; 12%; 13%; 14%; 15%; 16%; 17%; 18%; 19%; 20%; 25%; 30%; 35%; 40%; 45%; 50%; 60%; 65%; 70%; 75% of solid content; each represents a separate embodiment according to this invention. In some embodiments, the topcoat solution used in the coating process comprises at least about 3%; 5%; 7%; 9%; 10%; 12%; 13%; 14%; 15%; 16%; 17%; 18%; 19%; 20%; 25%; 30%; 35%; 40%; 45%; 50%; 60%; 65%; 70%; 75% of solid content; each represents a separate embodiment according to this invention. In some embodiments, the topcoat solution used in the coating process comprises acrylate based coating. In some embodiments, the topcoat solution used in the coating process comprises cellulose based coating. In some embodiments, the topcoat is as described herein above.

[0110] In some embodiments, the drug layer coating step is maintained at a product temperature of below 80 °C; below 75 °C; below 70 °C; below 65 °C; below 60 °C; below 65 °C; below 60 °C; below 55 °C; below 50 °C; below 45 °C; below 40 °C; below 35 °C; or below 30 °C; each represents a separate embodiment according to this invention.

[0111] In some embodiments, the seal coat layer coating step is maintained at a temperature range of between 25 °C and 75 °C; between 30 °C and 70 °C; between 35 °C and 65 °C; between 40 °C andP-636238-PC60 °C; between 35 °C and 55 °C; between 40 °C and 50 °C; each represents a separate embodiment according to this invention. In some embodiments, the seal coat layer coating step is maintained at a temperature of about 70 °C; 65 °C; 60 °C; 65 °C; 60 °C; 55 °C; 50 °C; 45 °C; 40 °C; 35 °C; or 30 °C; each represents a separate embodiment according to this invention.

[0112] In some embodiments, the seal coat layer coating step is carried out at a spray rate of between 1 and 2 g / min; between 1 and 20 g / min; between 3 and 10 g / min; or between 4.7 and 8.4 g / min; each represents a separate embodiment according to this invention.

[0113] In some embodiments, this invention further relates to immediate release (IR) particles comprising pridopidine or pharmaceutically acceptable salt thereof, prepared according to the methods of this invention as described hereinabove.Biological Activity

[0114] This invention further provides a method of treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms of a neurodegenerative or neurodevelopmental disease or disorder in a subject; wherein the method comprises administering to the subject a composition or a dosage form comprising the particles according to this invention, as described herein.

[0115] In some embodiments, the neurodegenerative disease or disorder is selected from the group consisting of Huntington Disease (HD), prodromal / premanifest Huntington disease, Juvenile onset Huntington Disease, Amyotrophic Lateral Sclerosis (ALS), Parkinson’s Disease, Parkinson’s Disease associated with glucocerebrosidase (GBA) deficiency, dystonia, cognitive disorder, dyskinesia, medication-induced dyskinesia, tardive dyskinesia, levodopa-induced dyskinesia (LID), mild cognitive impairment (MCI), Alzheimer’s Disease, age related memory loss, major depressive disorder, depression, anxiety, bacterial infections-induced depression, neurodegenerative eye disease, optic neuropathies including glaucoma, age-related macular degeneration (AMD), geographic atrophy, Leber’s Hereditary Optic Neuropathy (LHON), and retinitis pigmentosa, Microphthalmia, syndromic 12 (MCOPS12) ; and wherein the neurodevelopmental disease or disorder is Rett syndrome or Fragile X Syndrome.

[0116] This invention further provides a method of treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms of a mitochondrial disease or dysfunction (i.e. Lysosomal storage disease (LSD), leukodystrophies, vanishing white matter (VWM) disease), Wolfram disease or viral infection (i.e. COVID-19) in a subject; wherein the method comprises administering to the subject a composition or a dosage form comprising the particles according to this invention, as described herein.P-636238-PC

[0117] In some embodiments, the neurodegenerative disease or disorder is a neurodegenerative eye disease. In some embodiments, the neurodegenerative eye disease is selected from the group consisting of glaucoma, Age-related Macular Degeneration (AMD), geographic atrophy (GA), optic neuropathy, Microphthalmia, syndromic 12 (MCOPS12), and retinitis pigmentosa. In another embodiment, the neurodegenerative eye disease refers to any disease affecting retinal ganglion cells, photoreceptors, other retinal neurons, and corneal nerves. In one embodiment, the neurodegenerative eye disease is glaucoma. In another embodiment, the neurodegenerative eye disease is Wet Age-related Macular Degeneration (“Wet AMD”), Dry Age-related Macular Degeneration (“Dry AMD”) or geographic atrophy (GA). In a further embodiment, the neurodegenerative eye disease is Leber hereditary optic neuropathy (LHON).

[0118] In some embodiments, this invention further provides a method of treating, reducing or inhibiting a neurodegenerative eye disease or a symptom thereof in a subject; wherein the method comprises administering to the subject a composition or a dosage form comprising the particles according to this invention, as described hereinabove.

[0119] In some embodiments, the symptom is retinal ganglion cell (RGC) damage. In other embodiments, the symptom is retinal ganglion cell (RGC) loss. In other embodiments, the symptom is an optic nerve axon loss or damage. In other embodiments, the symptom is macular degeneration. In other embodiments, the symptom is a retinal ganglion cell (RGC) loss or damage / death. In other embodiments, the symptom is a retinal pigment epithelium cell (RPE) loss or death. In other embodiments, the symptom is photoreceptor loss or death. In other embodiments, the composition is effective to reduce or prevent optic nerve axon loss or damage in a subject. In other embodiments, the composition or a dosage form is effective to reduce or prevent a retinal ganglion cell (RGC) loss or death in a subject. In other embodiments, the composition or a dosage form is effective to reduce or prevent a retinal pigment epithelium (RPE) cell loss or death in a subject. In other embodiments, the composition or a dosage form is effective to reduce or prevent an optic nerve head astrocyte (ONHA) loss or damage. In other embodiments, the composition or a dosage form is effective to reduce or prevent photoreceptor loss or death in a subject.

[0120] In other embodiments, the composition comprising the particles of pridopidine or a pharmaceutically acceptable salt thereof according to this invention for use in the methods of this invention is administered in a daily dose comprising between 0.5 - 315 mg pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the composition is an oral dosage form administered in a daily dose comprising 0.5 - 315 mg pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the oral dosage unit form is administered in a daily dose comprising 1 - 1000 mg ; 1-10 mg ; 10 - 1000 mg ; 10 - 22.5 mg ; 22.5 - 315 mg ; 10 - 315P-636238-PC mg ; 0.5 - 50 mg ; 22.5 - 90 mg ; 22.5 - 50 mg ; 45 - 90 mg ; 45 - 250 mg ; 45 - 135 mg or 90 - 315 mg pridopidine or a pharmaceutically acceptable salt thereof; each represents a separate embodiment according to this invention.

[0121] In other embodiments, the dosage form comprising the particles of pridopidine or a pharmaceutically acceptable salt thereof according to this invention for use in the methods of this invention comprises between 0.5 - 315 mg pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises 0.5 - 315 mg pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the daily dose of the dosage form comprises 1 - 1000 mg ; 1-10 mg ; 10 - 1000 mg ; 10 - 22.5 mg ; 22.5 - 315 mg ; 10 - 315 mg ; 0.5 - 50 mg ; 22.5 - 90 mg ; 22.5 - 50 mg ; 45 - 90 mg ; 45 - 250 mg ; 45 - 135 mg or 90 - 315 mg pridopidine or a pharmaceutically acceptable salt thereof; each represents a separate embodiment according to this invention.

[0122] In another embodiment the method of this invention is directed to delaying the onset of symptoms in prodromal / premanifest Huntington disease individuals which have >36 CAG repeats in the huntingtin gene, comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention.

[0123] In other embodiments, the methods of this invention are directed to treating or slowing the progression of symptoms of prodromal / premanifest Huntington disease.

[0124] In other embodiments, the methods of this invention provide maintaining, reducing, or lessening the increase of Neurofilament light protein (NfL) in biofluids (i.e. cerebrospinal fluid, blood and plasma). In other embodiments, the method of this invention provides maintaining, reducing, or lessening the increase of Neurofilament light protein (NfL) in biofluids (i.e. cerebrospinal fluid, blood and plasma) in a neurodegenerative disease including Huntington disease, ALS and Parkinson’s disease patients.

[0125] In other embodiments, the methods of this invention are directed to treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms of Parkinson’s disease comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention.

[0126] In other embodiments, the methods of this invention are directed to treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms of Parkinson’s disease associated with glucocerebrosidase (GBA) deficiency comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention.

[0127] In other embodiments, the methods of this invention are directed to treating, slowing theP-636238-PC progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms of Parkinson’s disease, a disease associated with parkinsonism, or Parkinson’s disease associate with glucocerebrosidase (GBA) deficiency comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention. In other embodiments the symptoms comprise a functional decline, cognitive decline. In certain embodiments, the functional decline of the subject is presented as a symptom selected from the group consisting of tremor, bradykinesia, rigidity, postural instability, a decline according to the Unified Parkinson’s Disease Rating Scale part II (UPDRS part II), including Activities of Daily living, and a decline according to the Modified Hoehn and Yahr Staging of PD. In certain embodiments, the functional decline of the subject is presented as a decline according to the Unified Parkinson’s Disease Rating Scale part II (UPDRS part II), including Activities of Daily living. In certain embodiments, the functional decline of the subject is presented as a decline according to the Modified Hoehn and Yahr Staging of PD.

[0128] In certain embodiments, the cognitive decline of the subject is presented as a symptom selected from the group consisting of intellectual impairment, thought disorder, depression, decreased motivation, decreased initiative, impaired speech, increased salivation, impaired swallowing, impaired handwriting, and increased pain sensation.

[0129] In other embodiments, the methods of this invention are directed to treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms dystonia comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention. In another embodiment, the dystonia is severe dystonia. In other embodiments the symptoms of dystonia comprise involuntary limb movement or muscle contractions, twisted posture of the limbs or trunk, abnormal fixed posture of the limbs or trunk, talipes equinovarus, turning in of the leg, turning in of the arm, tremor of the hand, head, trunk or arms, dragging of the leg, torticollis, writer’s cramp, or dystonia of trunk and / or extremities. In another embodiment, the dystonia is a severe dystonia.

[0130] “Severe dystonia” may be determined by Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) having Rating Scale > 4 for at least one body part. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) evaluates nine body parts (eyes, mouth, speech, swallowing, neck, trunk, right arm, right leg, left arm, and left leg) by rating the severity factor and provoking factors for each part on a 5-point scale of 0 (no dystonia) to 4 (indicating the presence of dystonia at rest). The dystonia scores of the eyes, mouth and neck are assigned a weighting factor of 0.5, while the other 6 parts are assigned a weighting factor of 1.0. The score of each part is obtained by multiplying the provoking factor by the severity factor and the weighting factor, and then summingP-636238-PC the scores of each part. The maximum score possible is 120.

[0131] Severe dystonia may be also determined by the Unified Dystonia Rating Scale (UDRS) Rating Scale having Rating Scale > 4 for at least one body part. UDRS evaluates 14 body parts (eyes and upper face, lower face,jaw and tongue, larynx, neck, trunk, right shoulder / proximal arm, left shoulder / proximal arm, right distal arm / hand, left distal arm / hand, right proximal leg, left proximal leg, right distal leg / foot, and left distal leg / foot) by rating the severity and duration factors for each part. The severity factor for each part is rated using a 5 -point scale, ranging from 0 (no dystonia) to 4 (severe dystonia). The duration factor is rating on a 5-point scale ranging from 0 (at rest / action) to 4 (submaximal / maximal). The total score is the sum of each domain (part), with the maximum being 112.

[0132] In other embodiments, the methods of this invention are directed to treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms of a cognitive disorder comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention.

[0133] In certain embodiments the cognitive disorder is mild cognitive impairment. In certain embodiments, the cognitive disorder comprises memory loss. In certain embodiments, the cognitive disorder comprises age related memory loss.

[0134] Cognitive disorder refers to impairment of cognitive function which is selected from the group consisting of global cognitive functioning, sustained cognition, memory, language, executive functioning, and attention. In another embodiment, the cognitive function is memory. In an embodiment, memory is short term memory. In another embodiment, memory is long term memory. In another embodiment, memory is working memory. In an embodiment, the subject is afflicted with a cognitive deficit. In another embodiment, the subject is prone to or predisposed to have a cognitive deficit. In an embodiment, the cognitive deficit is a memory deficit. In an embodiment, the memory deficit is a short-term memory deficit. In another embodiment, the memory deficit is memory loss. In an embodiment, memory loss is caused by one or more of age- related changes in memory, mild cognitive impairment, dementia or depression. In an embodiment, the cognitive deficit is caused by or associated with a disease or disorder. In another embodiment, the disease or disorder is schizophrenia or autism. In another embodiment, the disease or disorder is epilepsy or an anxiety disorder. In another embodiment, the disease or disorder is amyotrophic lateral sclerosis (ALS). In another embodiment, the disease or disorder is frontotemporal dementia (FTD). In another embodiment, the disease or disorder is mild cognitive impairment (MCI). In another embodiment, the disease or disorder is bipolar disorder. In another embodiment, the disease or disorder is Huntington disease. In another embodiment, the disease orP-636238-PC disorder is selected from the group consisting of major depressive disorder (MDD), Parkinson's disease, Alzheimer's disease, tardive dyskinesia, depression, sickle cell anemia, stroke, chronic pain syndrome, and addiction. In another embodiment, the disease or disorder is selected from the group consisting of mild cognitive impairment, memory loss, memory deficit, a memory deficit related to brain injury or a post-stroke event, a learning deficiency, and behavioral and cognitive problems associated with brain tumors. In another embodiment, the disease or disorder is selected from the group consisting of dementia, dementia associated with Lewy Bodies, age-related cognitive decline, psychosis, attention deficit disorder (ADHD), bipolar disorder, brain injury, mood and affective disorders, Tourette's syndrome, mental retardation, progressive supranuclear palsy, Creutzfeldt-Jacob disease, corticobasal Degeneration, vascular dementia, and Pick's disease. In another embodiment, the disease or disorder is selected from the group consisting of generalized anxiety disorder (GAD), social anxiety disorder (SAD), tardive dyskinesia, depression, sickle cell anemia, chronic pain syndrome, addiction, nicotine addiction, internet addiction, cocaine addiction, Tourette's syndrome, mental retardation, corticobasal degeneration, vascular dementia, Pick's disease, posttraumatic stress disorder (PTSD), obsessive compulsive disorder, panic disorder (PD), trigeminal pain, trigeminal musculoskeletal pain, phantom limb pain, irritable bowel syndrome, blepharospasm, complex regional pain syndrome, chronic low back pain, autism spectrum disorder (ASD), infantile spasm (IS).

[0135] In other embodiments, the methods of this invention are directed to treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms of dyskinesia comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention.

[0136] Dyskinesias are abnormal, involuntary movements which may appear as jerking, twisting or writhing of parts of the body. There are several different types of dyskinesias, which can be categorized as chorea, dystonia, myoclonus, tremor and paroxysmal tardive (late-onset type). These movement disorders include, without limitation, parkinsonism, tardive dyskinesia, chorea, dystonia, tremor, akathisia, athetosis, myoclonus or tics. In some embodiments, the dyskinesia is L-DOPA Induced Dyskinesia (LID). In some embodiments, the dyskinesia is Parkinson’s disease (PD)-LID.

[0137] In other embodiments, the methods of this invention are directed to treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms lessening the decline of Alzheimer’s Disease comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention.P-636238-PC

[0138] In other embodiments, the methods of this invention are directed to treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms age related memory loss comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention.

[0139] In other embodiments, the methods of this invention are directed to treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms of neurodegenerative eye disease, optic neuropathies including glaucoma, age-related macular degeneration (AMD), Leber’s Hereditary Optic Neuropathy (LHON) geographic atrophy (GA), and retinitis pigmentosa, and related symptoms comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention.

[0140] In other embodiments, the methods of this invention are directed to treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms of Wolfram Disease comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention. In other embodiments Wolfram Disease symptoms comprise urinary tract abnormalities, ataxia, loss of sense of smell, loss of gag reflex, myoclonus, peripheral neuropathy, seizures, depression, impulsive and / or aggressive behavior, psychosis, gastrointestinal problems, intellectual disability, irregular breathing, central apnea, central respiratory failure, hypogonadism in males, stomach and / or intestinal ulcers, and a tendency to bleed excessively from wounds.

[0141] In other embodiments, the methods of this invention are directed to treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms of bacterial infection-induced depression comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention.

[0142] In other embodiments, the methods of this invention are directed to treating, slowing the progression, lessening the decline, delaying onset of symptoms or slowing the progression of symptoms of Microphthalmia, syndromic 12 (MCOPS12), comprising administering a composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention.

[0143] In other embodiment, the composition or a dosage form comprises a pridopidine base. In other embodiment, the composition or a dosage form comprises a pridopidine salt.

[0144] The subject invention further provides a method of treating a subject afflicted with a neurodegenerative eye disease comprising administering to the subject a pharmaceuticalP-636238-PC composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof according to this invention.

[0145] The subject invention further provides a method of treating, reducing, or inhibiting a symptom of neurodegenerative eye disease in a subject afflicted with a neurodegenerative eye disease comprising administering to the subject a composition or a dosage form comprising pridopidine or pharmaceutically acceptable salt thereof according to this invention.

[0146] In one embodiment, the administration of a composition or a dosage form comprising pridopidine or pharmaceutically acceptable salt thereof according to this invention is effective to reduce or inhibit a symptom of the neurodegenerative eye disease in the subject.

[0147] In an embodiment, the neurodegenerative eye disease is selected from the group consisting of glaucoma, Age-related Macular Degeneration (AMD), geographic atrophy (GA), optic neuropathy, Microphthalmia, syndromic 12 (MCOPS12) and retinitis pigmentosa. In another embodiment, the neurodegenerative eye disease refers to any disease affecting retinal ganglion cells, photoreceptors, other retinal neurons, and corneal nerves.Methods of administering

[0148] For the methods and use disclosed herein, the route of administration can be, e.g., oral.

[0149] In other embodiments, the composition described herein is administered orally.

[0150] In one embodiment, the pharmaceutical composition or a dosage form comprising pridopidine or a pharmaceutically acceptable salt thereof is administered via systemic administration. In some embodiments, the pharmaceutical composition or a dosage form is administered via oral administration. In another embodiment, the pharmaceutical composition or a dosage form is administered in the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a cream, a solid, a capsule or a tablet.

[0151] In some embodiments, this invention further relates to a method of administering pridopidine or pharmaceutically acceptable salt thereof, to a patient in need thereof, comprising: a. providing the pharmaceutical dosage form according to the invention as described hereinabove; b. sprinkling the plurality of particles on soft food; and c. administering the soft food orally.

[0152] In some embodiments, this invention further relates to a pharmaceutical dosage form comprising a plurality of particles according to this invention for use in the treatment of a patient in need thereof by: a. sprinkling the plurality of particles on soft food; andP-636238-PC b. administering the soft food orally.

[0153] In some embodiments, this invention further relates to a method of administering pridopidine or pharmaceutically acceptable salt thereof, to a patient in need thereof, comprising: a. providing the pharmaceutical dosage form according to the invention as described hereinabove; b. mixing the plurality of particles with liquid; and c. administering the liquid orally.

[0154] In some embodiments, this invention further relates to a method of administering pridopidine or pharmaceutically acceptable salt thereof, to a patient in need thereof, comprising: a. providing the pharmaceutical dosage form according to the invention as described hereinabove; b. mixing the plurality of particles with liquid; and c. administering the particles orally followed by a liquid.

[0155] In some embodiments, this invention further relates to a method of administering pridopidine or pharmaceutically acceptable salt thereof, to a patient in need thereof, comprising: a. providing the pharmaceutical dosage form according to the invention as described hereinabove; b. administering the particles orally; and c. followed by liquid administration.

[0156] In some embodiments, this invention further relates to a pharmaceutical dosage form comprising a plurality of particles according to this invention, for use in the treatment of a patient in need thereof by: a. administering the particles orally; and b. subsequent administration of a liquid.

[0157] In some embodiments, the food has a pH of between about 1 and about 9. In some embodiments, the food has a pH of between about 1.2 and about 8; about 1.5 and about 7.5; about 5.5 and about 7.8; about 6 and about 7.5; about 6.5 and about 7; about 0.8 and about 2; about 1 and about 1.5; about 6.6 and about 7; about 6.7 and about 6.9; each represents a separate embodiment according to this invention. In some embodiments, the pH of the food is at least about 0.8; 1; 1.2; 1.5; 2; 2.5; 3; 3.5; 4; 4.5; 5; 5.5; 6; 6.2; 6.5; 6.8; 7; 7.2; 7.5; 7.8; 8; 8.5; or 9; each represents a separate embodiment according to this invention. In some embodiments, the pH of the food is about 0.8; 1; 1.2; 1.5; 2; 2.5; 3; 3.5; 4; 4.5; 5; 5.5; 6; 6.2; 6.5; 6.8; 7; 7.2; 7.5; 7.8; 8; 8.5; or 9; each represents a separate embodiment according to this invention. In some embodiments, the pH of the food is about 6.8.P-636238-PC

[0158] In some embodiments, the liquid has a pH of between about 1 and about 9. In some embodiments, the liquid has a pH of between about 1.2 and about 8; about 1.5 and about 7.5; about 5.5 and about 7.8; about 6 and about 7.5; about 6.5 and about 7; about 0.8 and about 2; about 1 and about 1.5; about 6.6 and about 7; about 6.7 and about 6.9; each represents a separate embodiment according to this invention. In some embodiments, the pH of the liquid is at least about 0.8; 1; 1.2; 1.5; 2; 2.5; 3; 3.5; 4; 4.5; 5; 5.5; 6; 6.2; 6.5; 6.8; 7; 7.2; 7.5; 7.8; 8; 8.5; or 9; each represents a separate embodiment according to this invention. In some embodiments, the pH of the liquid is at least about 3. In some embodiments, the pH of the liquid is about 0.8; 1; 1.2; 1.5; 2; 2.5; 3; 3.5; 4; 4.5; 5; 5.5; 6; 6.2; 6.5; 6.8; 7; 7.2; 7.5; 7.8; 8; 8.5; or 9; each represents a separate embodiment according to this invention. In some embodiments, the pH of the liquid is about 6.8.

[0159] In one embodiment, the amount of pridopidine administered is 22.5 mg / day-315 mg / day, 90 mg / day-315 mg / day, 90-250 mg / day, or 90-180 mg / day. In another embodiment, the amount of pridopidine administered is about 22.5 mg / day, about 45 mg / day, about 67.5 mg / day, about 90 mg / day, about 100 mg / day, about 112.5 mg / day, about 125 mg / day, about 135 mg / day, about 150 mg / day, about 180 mg / day, about 200 mg / day, about 225 mg / day, about 250 mg / day, or about 315 mg / day. In other embodiments, the composition or the dosage form comprising pridopidine or pharmaceutically acceptable salt thereof is administered in a daily dose comprising an amount of pridopidine between 22.5 mg / day-315 mg / day.

[0160] In one embodiment the pharmaceutical composition or a dosage form described herein is administered periodically.

[0161] In one embodiment, the pharmaceutical composition or a dosage form described herein is administered daily.

[0162] In another embodiment, the pharmaceutical composition or a dosage form described herein is administered more often than once daily or less often than once daily. In one embodiment, the pharmaceutical composition or a dosage form described herein is administered more often than once daily, for example twice or thrice daily. In another embodiment, the pharmaceutical composition or a dosage form described herein is administered less often than once daily, for example, every other day or weekly.

[0163] In one embodiment, the periodic administration of the pharmaceutical composition or a dosage form described herein continues for at least 3 days, more than 30 days, more than 42 days, 8 weeks or more, at least 12 weeks, at least 24 weeks, at least 26 weeks, at least 52 weeks, at least 78 weeks, more than 78 weeks, or 24 months or more. In some embodiments, for example, in the treatment of a subject with glaucoma, the treatment is a chronic treatment, with periodic administration of the pharmaceutical composition or a dosage form described herein for more thanP-636238-PC12 months, more than 18 months, more than 24 months.

[0164] In one embodiment, the subject is a human patient.

[0165] In one embodiment, the method further comprises the administration of a second agent for the treatment of the neurodegenerative or neurodevelopmental disease. In some embodiments, the second agent is an agent treating Huntington's Disease (HD), including but not limited to: Tetrabenazine (Xenazine), Deutetrabenazine (Austedo), Valbenazine, Antipsychotic medications (e.g., Haloperidol, Olanzapine). In some embodiments, the second agent is an agent treating Alzheimer's Disease (HD), including but not limited to: Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne), Memantine (Namenda), Aducanumab (Aduhelm), Lecanemab (Leqembi). In some embodiments, the second agent is an agent treating Parkinson's Disease, including but not limited to: Levodopa / Carbidopa (Sinemet), Pramipexole (Mirapex), Ropinirole (Requip), Rotigotine (Neupro), Rasagiline (Azilect), Selegiline (Eldepryl, Zelapar), Entacapone (Comtan), Tolcapone (Tasmar), Amantadine (Symmetrel, Gocovri). In some embodiments, the second agent is an agent treating Amyotrophic Lateral Sclerosis (ALS), including but not limited to: Riluzole (Rilutek), Edaravone (Radicava). In some embodiments, the second agent is an agent treating Multiple Sclerosis (MS), including but not limited to: Interferon beta-la (Avonex, Rebif), Interferon beta-lb (Betaseron, Extavia), Glatiramer acetate (Copaxone), Natalizumab (Tysabri), Fingolimod (Gilenya), Dimethyl fumarate (Tecfidera), Teriflunomide (Aubagio), Ocrelizumab (Ocrevus), and / or Siponimod (Mayzent).

[0166] In one embodiment, the subject is administered a fixed-dose combination comprising the pharmaceutical composition or a dosage form described herein and the second agent.

[0167] In one embodiment, the package further comprises a second pharmaceutical composition comprising an amount of a second agent for the treatment of a neurodegenerative or neurodevelopmental disease, wherein the instructions provide for use of the first and second pharmaceutical compositions together to treat a subject afflicted with a neurodegenerative or neurodevelopmental disease.

[0168] In one embodiment, the amount of pridopidine and the amount of the second agent are prepared to be administered simultaneously, contemporaneously or concomitantly.

[0169] The subject invention also provides a pharmaceutical composition or a dosage form comprising pridopidine or a pharmaceutical acceptable salt thereof according to this invention for treating a subject afflicted with a neurodegenerative or neurodevelopmental disease.

[0170] In one embodiment, the pharmaceutical composition or a dosage form further comprises an amount of a second agent for the treatment of a neurodegenerative or neurodevelopmental disease.P-636238-PC

[0171] In one embodiment, the pharmaceutical composition or a dosage form comprising pridopidine or pharmaceutically acceptable salt thereof according to this invention and the second agent are prepared to be administered simultaneously, contemporaneously or concomitantly.

[0172] The subject invention also provides a pharmaceutical composition or a dosage form comprising an amount of pridopidine or pharmaceutically acceptable salt thereof for use in treating a subject afflicted with a neurodegenerative or neurodevel opmental disease as an add-on therapy or in combination with a second agent for the treatment of a neurodegenerative or neurodevelopmental disease.

[0173] The subject invention also provides a pharmaceutical composition or a dosage form comprising pridopidine or pharmaceutically acceptable salt thereof according to this invention, for use in a combination therapy together with a pharmaceutical composition comprising a second agent for the treatment of a neurodegenerative or neurodevelopmental disease.

[0174] In one embodiment, the amount of pridopidine in the pharmaceutical composition is about 22.5 mg, about 45 mg, about 67.5, mg, about 90 mg, about 100 mg, about 112.5 mg, about 125 mg, about 135 mg, about 150 mg, about 180 mg, about 200 mg, about 250 mg, or about 315 mg.

[0175] In one embodiment, the amount of pridopidine in the pharmaceutical composition is 0.1 mg to 50 mg, or 0.2 mg to 20 mg.

[0176] In one embodiment, the dose of pridopidine in the pharmaceutical composition is measured as amount of pridopidine per weight of the subject. In another embodiment, the dose is between 1-100 mg / kg. In another embodiment, the dose is between 1-10, 20-50 or 50-100 mg / kg. In another embodiment, the dose is 3, 10, 30, 45, 60 or 90 mg / kg. The subject invention also provides a pharmaceutical composition in a unit dosage form, useful in treating a subject afflicted with a neurodegenerative or neurodevelopmental disease, which comprises an amount of pridopidine or pharmaceutically acceptable salt thereof, wherein the amount of said pridopidine in said composition is effective, upon administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.Terms

[0177] As used herein, and unless stated otherwise, each of the following terms shall have the definition set forth below.

[0178] As used herein, “pridopidine” means pridopidine base or a pharmaceutically acceptable salt thereof, as well as derivatives, for example deuterium -enriched version of pridopidine and salts. In some embodiments, pridopidine means pridopidine hydrochloride. In some embodiments,P-636238-PC pridopidine further includes pridopidine or a pharmaceutically acceptable salt thereof, as well as pridopidine analogs such as compounds 1-8 as described hereinabove.

[0179] A “salt thereof is a salt of the instant compounds which have been modified by making acid or base salts of the compounds. The term “pharmaceutically acceptable salt” in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. For example, one means of preparing such a salt is by treating a compound of the present invention with an inorganic base.

[0180] As used herein, an “amount” or “dose” of pridopidine as measured in milligrams refers to the milligrams of pridopidine (4-[3-(methylsulfonyl)phenyl]-l-propyl-piperidine) present in a preparation, regardless of the form of the preparation. For example, a unit dose containing “90 mg pridopidine” means the amount of pridopidine in a preparation is 90 mg (i.e., free base), regardless of the form of the preparation. Thus, when in the form of a salt, e.g. pridopidine hydrochloride, the weight of the salt form necessary to provide a dose of 90 mg pridopidine would he greater than 90 mg due to the presence of the salt.

[0181] As used herein, a “unit dose”, “unit doses” and “unit dosage form(s)” mean a single drug administration entity / entities.

[0182] As used herein, “about” in the context of a numerical value or range means ±10% of the numerical value or range recited or claimed.

[0183] As used herein, “effective” when referring to an amount of pridopidine refers to the quantity of pridopidine that is sufficient to yield a desired therapeutic response.

[0184] “Administering to the subject” or “administering to the (human) patient” means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject / patient to relieve, cure, or reduce the symptoms associated with a condition, e.g., a pathological condition. The administration can be periodic administration. As used herein, “periodic administration” means repeated / recurrent administration separated by a period of time. The period of time between administrations is preferably consistent from time to time. Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times weekly and so on, etc.Pharmaceutically Acceptable Salts

[0185] The active compounds for use according to the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the compound of the invention. Examples of pharmaceutically acceptable salts include, without limitation, the non-toxic inorganicP-636238-PC and organic acid addition salts such as the hydrochloride, the hydrobromide, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzenesulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulphonate, the naphthalene-2-sulphonate, the phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate, the toluene-p-sulphonate, and the like. Such salts may be formed by procedures well known and described in the art.Pharmaceutical Composition or a dosage form for use in the methods of this invention:

[0186] In some embodiments the methods of this invention make use of a pharmaceutical composition or a dosage form comprising pridopidine or pharmaceutically acceptable salt thereof according to this invention. In some embodiments the methods of this invention make use of a pharmaceutical composition or a dosage form comprising pridopidine or pharmaceutically acceptable salt thereof and at least one of compounds 1-8:P-636238-PC or pharmaceutically acceptable salt thereof.

[0187] In other embodiments the methods of this invention make use of a pharmaceutical composition comprising pridopidine salt, wherein the salt is hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methane-sulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p-sulphonate salt.

[0188] While the compounds for use according to the invention may be administered in the form of the raw compound, it is preferred to introduce the active ingredients, optionally in the form of physiologically acceptable salts, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries. In an embodiment, the invention provides pharmaceutical compositions comprising the active compounds or pharmaceutically acceptable salts or derivatives thereof, together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and / or prophylactic ingredients know and used in the art. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[0189] The pharmaceutical composition of the invention may be administered by any convenient route, which suits the desired therapy. Preferred routes of administration include oral administration, in particular in tablet, in capsule, in beads, in particles, in multiparticulates, in powder, suspension, emulsion, or in liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular, or intravenous injection.

[0190] The pharmaceutical composition for use in the methods of this invention is an oral dosage unit formulated as a tablet, a capsule, beads, multiparticulates, a pill, liquid emulsion or as a liquid suspension.

[0191] While the compounds for use according to the invention may be administered in the form of the raw compound, it is preferred to introduce the active ingredients, optionally in the form of physiologically acceptable salts, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0192] In an embodiment, the invention provides pharmaceutical compositions comprising the active compounds or pharmaceutically acceptable salts or derivatives thereof, together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and / or prophylactic ingredients know and used in the art. The carrier(s) must be “acceptable” in the senseP-636238-PC of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[0193] General techniques and compositions for making dosage forms useful in the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). These references in their entireties are hereby incorporated by reference into this application.

[0194] “Treating” as used herein encompasses, e.g., inducing inhibition, regression, or stasis of a disease or disorder, e.g., glaucoma, or alleviating, lessening, suppressing, inhibiting, reducing the severity of, eliminating or substantially eliminating, or ameliorating a symptom of the disease or disorder. Treatment further comprises providing neuroprotection to an ocular cell, for example a retinal ganglion cell or optic nerve axon in a subject. The "neuroprotective" activity of pridopidine is disclosed herein. Neuroprotection comprises protection of neurons, for example RGC or optic nerve axon, from injury or death or b) improvement of neuronal function for example of RGC, RPE, photoreceptor, optic nerve head astrocyte (ONHA) or optic nerve axon. As used herein, "neuroprotection" refers to reducing, preventing, attenuating and / or reversing progression of neurodegeneration. As used herein, "neurodegeneration" refers to the progressive loss of neurons, for example RGC or optic nerve axon loss, by injury or death.

[0195] “Inhibition” of disease progression or disease complication in a subject means preventing or reducing the disease progression and / or disease complication in the subject.

[0196] A “symptom” associated with glaucoma includes any clinical or laboratory manifestation associated with glaucoma and is not limited to what the subject can feel or observe.

[0197] As used herein, a subject "afflicted" with glaucoma means the subject has been diagnosed with glaucoma.P-636238-PC

[0198] As used herein, a subject at “baseline” is as subject prior to administration of pridopidine in a therapy as described herein.

[0199] A “pharmaceutically acceptable carrier” refers to a carrier or excipient that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio. It can be a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the subject.

[0200] It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example, “0.1 mg - 40.0 mg” includes 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, etc. up to 40.0 mg.

[0201] As used herein, a “fixed-dose combination” or “fixed-dosage combination” refers to a medicament which comprises two active agents. Typically, the two agents are very difficult to separate by means readily available to patients. Non-limiting examples include tablets, pills, or solutions comprising two agents.

[0202] In this application, when a comparative term is used, such as “the retinal ganglion cell (or optic nerve axon, or retinal pigment epithelium cell, or photoreceptor cell or optic nerve head astrocytes) loss is reduced by at least 10% in a subject” the comparison is relative to a subject afflicted with an analogous disease for example the control subject in a prior relevant clinical study, and not to a healthy subject. For example, the retinal ganglion cell (or optic nerve axon, or retinal pigment epithelium cell, or photoreceptor cell or optic nerve head astrocytes) loss may be compared to the average retinal ganglion cell (or optic nerve axon, or retinal pigment epithelium cell, or photoreceptor cell or optic nerve head astrocytes) loss in similarly diseased subjects without treatment with pridopidine. Thus, the comparison value may be obtained by reference to the placebo group of a clinical study.

[0203] The combination of the invention may be formulated for its simultaneous, separate or sequential administration, with at least a pharmaceutically acceptable earner, additive, adjuvant or vehicle as described herein. Thus, the combination of the two active compounds may be administered:• as a combination that is part of the same medicament formulation, the two active compounds are then administered simultaneously, or• as a combination of two units, each with one of the active substances giving rise to the possibility of simultaneous, sequential or separate administration.As used herein, “concomitant administration” or administering “concomitantly” means the administration of two agents given in close enough temporal proximately to allow the individualP-636238-PC therapeutic effects of each agent to overlap.

[0204] As used herein, “add-on” or “add-on therapy” means an assemblage of reagents for use in therapy, wherein the subject receiving the therapy begins a first treatment regimen of one or more reagents prior to beginning a second treatment regimen of one or more different reagents in addition to the first treatment regimen, so that not all the reagents used in the therapy are started at the same time. For example, adding pridopidine therapy to a glaucoma patient already receiving therapy with Intraocular Pressure (IOP) reducing eye drops.

[0205] For the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. For instance, the elements recited in the method embodiments can be used in the pharmaceutical composition, package, and use embodiments described herein and vice versa.

[0206] This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.EXAMPLESExample 1: An Open-Label Taste Assessment of Pridopidine in Healthy Panelists

[0207] An oral dosage form of pridopidine, indicated for neurodegenerative brain diseases, (e.g., Huntington Disease (HD), ALS), was developed. Pridopidine is known to be bitter and produce trigeminal irritation. However, the taste masking challenge for pridopidine has not been quantified and hence the prospects for developing a palatable oral dosage form are to be assessed. Accordingly, sensory dose / response analysis of pridopidine was conducted to quantify the taste masking challenge and inform the formulation development approach.

[0208] The objective was to assess the critical sensory attributes of pridopidine as a function of strength. This was an open-label study to evaluate the taste properties of pridopidine.

[0209] Ten experienced pharmaceutical sensory panelists were screened and enrolled in the study. The Principal Investigator conducted the on-site screening assessment to qualify the sensory panelists for inclusion in the study.

[0210] The qualified sensory panelists reviewed and executed the informed consent form.

[0211] The panelists were assigned unique code numbers, which were used to track the individual panelist’s results as well as their drug exposures.

[0212] Pridopidine solutions in water were prepared at a range of concentrations to assess the taste masking challenge and establish the highest free-API concentration that would be consideredP-636238-PC palatable, i.e., guide taste masking strategy. In addition, 45mg pridopidine capsule contents were evaluated in SyrSpend® SF (liquid commercial dosing vehicle) at three strengths.• Pridopidine aqueous Solutions a. Pridopidine Clinical Strengths: 9mg / mL, 5mg / mL, 2.5mg / mL b. Lower Pridopidine Strengths (factor of three dilution): Img / mL, 0.33mg / mL, 0.1 Img / mL, 0.04mg / mL• Pridopidine capsule contents in SyrSpend® SF - 9mg / mL, 5mg / mL and 2.5mg / mL

[0213] The sensory panelists evaluated the samples using the Flavor Profile Method of sensory analysis (Keane, P. "The Flavor Profile Method". In C. Hootman (Ed.), Manual on Descriptive Analysis Testing for Sensory Evaluation ASTM Manual Series: MNL 13. Baltimore, MD. (1992)). Flavor Profile was used to identify, characterize and quantify the sensory attributes of products, e.g., basic tastes, aroma, texture and mouthfeel.

[0214] Character Notes'. Aromatics, basic tastes (sweet, sour, salty, bitter, umami), and feeling factors (listed in order of appearance along with a measurement of strength).

[0215] Intensity Scale. 0-1 None; 1-2 Slight; 2-3 Moderate; 3 Strong

[0216] Aftertaste'. Measurement of all sensation remaining at selected time intervalsSample Evaluation Protocol

[0217] The pridopidine oral liquids were evaluated as follows:1. Bulk pridopidine liquids were agitated and each panelist was provided with a 5mL aliquot in a one-ounce cup.2. Starting at the same time, the panelists poured the contents of the cup directly into the mouth, swished contents around the oral cavity for 10 seconds and expectorated.3. During this time, the panelists independently evaluated and recorded the initial flavor characteristics.4. The panelists then independently evaluated and recorded the aftertaste characteristics at periodic intervals up to 30 minutes.5. The panelists recited their individual results, and a final Flavor Profile was generated for the sample.

[0218] The Flavor Leadership Criteria (L.B. Sjostrom, S.E. Cairncross. (1953) “ What Makes Flavor Leadership?" Food Technology, (7) 2: 56-58) are used to interpret sensory results and guide the development of products that can be differentiated on the basis of perceived flavor quality. The applicable Flavor Leadership Criteria were used to evaluate the Flavor Profile resultsP-636238-PC for the formulations.

[0219] The objective for pharmaceuticals is patient compliance. For many APIs, the aftertaste is more critical as many flavor systems provide adequate coverage in the early aftertaste, but these beneficial effects quickly decrease, exposing the API. As a general rule it is easier to mask a strongly bitter API that “fades” quickly (steep decay curve) versus a moderately bitter API initially that lingers well into the aftertaste (flat decay curve). The challenge for the formulator is to mask the taste of the active throughout the duration of the aftertaste, be it 30 seconds or 15 minutes.

[0220] The resulting Flavor Profile for the study samples are summarized on the pages that follow in tabular and graphical formats.

[0221] Per the Flavor Profile methodology, attributes are listed in order they were perceived, so early impact of negative attributes is more deleterious to flavor quality than those with a delayed perception. The challenge for many oral pharmaceuticals is to mask a drug product’s aversive sensory characteristics, e.g., bitterness, aromatic off-notes, trigeminal irritation in the initial flavor and throughout the aftertaste. Based on experience, sensory characteristics above a slight intensity (>1) are clearly perceptible to patients (shaded area in the graphs contained herein). Accordingly, negative or aversive attributes should be below a slight intensity.Pridopidine Solution Dose / Response ResultsTable 1. Flavor Profile for pridopidine 9mg / mL Oral Solution.*: Off-Notes**: Mouthfeel

[0222] Pridopidine 9mg / mL oral solution was characterized by the panelists as having a strong intensity lingering bitterness, moderate intensity sourness, slight intensity mouthfeels (numbing and tongue sting), and solvent and metallic aromatic off-notes (Table 1)P-636238-PC

[0223] The flavor of pridopidine oral solution at 5mg / mL is similar to the 9mg / mL strength, retaining a strong bitterness and underlying secondary aromatic and mouthfeel attributes.

[0224] At a 2.5mg / mL solution concentration, pridopidine bitterness is still strong in initial intensity, but aftertaste intensity begins to decrease for all attributes.

[0225] The Img / mL pridopidine oral solution has a moderate intensity bitterness and commensurately lower aftertaste intensity.Table 2. Flavor Profile for pridopidine 0.33mg / mL Oral Solution.*: Off-Notes**: Mouthfeel

[0226] Bitterness was the only attribute above a patient-perceptible intensity (>1 intensity) in the 0.33mg / mL pridopidine solution.

[0227] At 0.1 Img / mL, bitterness was just above a patient-perceptible intensity (>1).

[0228] At 0.04mg / mL, no attributes are above a patient-perceptible intensity (>1 intensity).

[0229] Figures 1-5 show the time intensity curves for selected sensory attributes of the pridopidine samples. Attributes: Bitter basic taste (primary challenge), Solvent -like aromatic off- note, Numbing mouthfeel. For the Bitterness Profile, color-coded (greyscale) decision boundaries are shown: a. Low Taste Masking Challenge (lower left): Bitterness is easily masked b. Moderate Taste Masking Challenge (middle): A palatable formulation can be readily developed. c. Difficult Taste Masking Challenge (upper right): May require alternative technologies.

[0230] For the other attributes, the area above a slight intensity (>1) has been shaded. In Senopsys’ experience, aversive sensory characteristics above this intensity are clearly perceptible to consumers / patients and are often found to be unacceptable.

[0231] Figure 1 shows that pridopidine solutions had strength-dependent bitterness profiles spanning the Flavor Profile supra-threshold intensity range. Based on bitterness alone, clinical strengths of pridopidine (9, 5, and 2.5mg / mL) represent a difficult taste masking challenge.P-636238-PC

[0232] Figure 2 shows that pridopidine also has a solvent-like aromatic off-note that fades rapidly in the aftertaste. This aromatic is above a patient-perceptible intensity (>1) only at the clinical strengths (9, 5 and 2.5mg / mL).

[0233] Figure 3 shows that pridopidine has a slight numbing mouthfeel but all concentrations were below a patient-perceptible intensity (<1).

[0234] In conclusion - pridopidine oral liquids are characterized by several aversive sensory attributes that are primary and secondary taste masking challenges, specifically: the predominant aversive attribute of pridopidine is a bitter basic taste that ranged in intensity from strong intensity (3) at the highest concentration to below the threshold of patient perception (<1) at the lowest. Pridopidine solutions are also characterized by solvent-like and metallic aromatic off notes that were less intense than bitterness. Underlying mouthfeels (primarily numbing) lingered in the aftertaste below the threshold of patient-perception (<1 intensity).Pridopidine 45mg Capsules contents dispersed in Dosing VehiclesTable 3. Flavor Profile of neat SyrSpend® Vehicle.*: Off-Notes**: Mouthfeel***: Amplitude****: Aromatic Intensity

[0235] To serve as a baseline for pridopidine capsule preparations, the SyrSpend® suspension vehicle was evaluated alone. The dosing vehicle was characterized as having moderate flavor impact, with slight-to moderate intensity sweet and sour basic tastes, starchy aromatic and starchy mouthfeel (Table 3)P-636238-PCTable 4. Flavor Profile for pridopidine Capsules in SyrSpend® Suspension 9 mg / mL equating to a 5ml dosing volume for a 45mg pridopidine dose*: Off-Notes**: Mouthfeel

[0236] Pridopidine 9mg / mL capsule contents suspended in SyrSpend® have a strong intensity bitter basic taste with slight intensity solvent-like aromatics and numbing mouthfeel. Otherwise, it is largely similar to the neat suspending vehicle (Table 4) Table 5. Flavor Profile for pridopidine Capsules in SyrSpend® Suspension 5 mg / mL.*: Off-Notes**: MouthfeelP-636238-PC

[0237] 5mg / mL pridopidine capsule contents in SyrSpend® had a moderate-to strong bitterness intensity, but the suspension otherwise had the same flavor profile as the 9mg / mL suspension(Table 5)Table 6. Flavor Profile for pridopidine Capsules in SyrSpend® Suspension 2.5 mg / mL.*: Off-Notes**: Mouthfeel

[0238] 2.5mg / mL pridopidine capsule contents in SyrSpend® had a moderate intensity bitterness, but the suspension otherwise had the same flavor profile as the other capsule suspensions (Table 6).

[0239] Figure 4 shows that pridopidine capsule contents in SyrSpend® (dashed lines) have lower bitterness than their equivalent solution concentrations (solid lines). Thus, the dosing vehicle provided some, but insufficient bitterness reduction for palatability.

[0240] A properly balanced flavor system is one which has positive flavor attributes (e.g., sweet and sourness) higher in intensity than its negative attributes (e.g., bitterness) throughout the flavor profile. Figure 5A-5C show that all capsule content suspensions failed in this respect, showing poor bitterness “coverage”.

[0241] In summary, the bitterness and other aversive attributes of pridopidine capsule contents are only somewhat mitigated when dosed in SyrSpend®. The predominant aversive attribute of pridopidine capsule contents remains a lingering bitter basic taste from the pridopidine which ranged in intensity from strong (3) at 9mg / mL to a moderate intensity at 2.5mg / mL. The other aversive attributes (solvent aromatic, and mouthfeels) fared better, and were reduced to the threshold of patient perception (<1 intensity).

[0242] In conclusion, pridopidine represents a difficult taste masking challenge due to strongP-636238-PC and lingering aversive bitterness and secondary aromatics and mouthfeels.

[0243] Dosing pridopidine in SyrSpend® SF suspension vehicle produced a measurable reduction of bitterness, which was inadequate for acceptable palatability, i.e., target of less than a slight intensity (<1).A pridopidine liquid formulation will require further taste masking to yield a palatable drug product. Due to the somewhat improved palatability of pridopidine in the SyrSpend® suspension vehicle, a traditional excipient approach to taste masking (i.e., sweeteners, buffers, taste modifiers and flavors) reduced bitterness intensity but still presented palatability challenges at clinical pridopidine strengths. Encapsulation of the active through hot melt extrusion or particle coating may also effectively reduce aversive sensory characteristics. The addition of (low intensity) identifying flavoring aromatics (e.g., cherry, grape, or orange) would reduce the residual solvent aromatics, thereby improving flavor quality / palatability; however, this may not be a critical product attribute for this patient population.Conclusions - Palatability Guidance

[0244] SyrSpend® has a moderate sweetness intensity and no identifying aromatics (e.g., cherry, grape, orange). Other vehicle options with a more “robust” flavor system could be evaluated (e.g., Humco, Paddock) to determine if they provide greater bitterness coverage.Example 2: Pridopidine Particles, a Multi-Particulate Immediate Release (IR) Drug ProductObjective

[0245] This study summarizes the outcome of four (4) batches manufactured of pridopidine hydrochloride Immediate Release (IR) beads with Prototypes 1,2 and 3 encapsulated each containing a 45 mg dose. The scope of work is to develop an IR capsule of pridopidine HC1, suitable for sprinkling on food, that ensures minimal drug release in the first 5-10 minutes, masks the drug’s intense bitterness, and maintains a rapid dissolution profile despite bead coating.Manufacturing Details

[0246] Batch number of beads and capsule batches outlined in this report are shown in Table 7.P-636238-PCTable 7: Manufacturing Batches OverviewNote: Prototype Formulation 4 was not encapsulatedFormulation Composition

[0247] Formulation composition of pridopidine hydrochloride Immediate release beads for all four bead compositions and three formulations encapsulated to deliver Immediate release capsules, 45 mg are shown in Table 8 and Table 10 respectively. The major differences between pridopidine hydrochloride Immediate release bead prototypes are shown in Table 9. Table 8: Composition of pridopidine hydrochloride Immediate Release BeadsP-636238-PCTable 9: Composition Interpretation of pridopidine hydrochloride Immediate Release Beads.P-636238-PCTable 10: Composition of pridopidine hydrochloride Immediate Release Capsules*Theo. = Theoretical; **Act. = Actual Manufacturing process - general outline *

[0248] Seal Coat:• Seal coat solution of Hypromellose in purified water mixed.• MCC spheres were loaded in fluid bed (Wurster set-up).• Seal coat solution sprayed on to MCC spheres • Drug Coat:• Drug coat solution in purified water• Seal coated beads were loaded in fluid bed (Wurster set-up)• Spray drug coat solution on seal coated beads

[0249] Topcoat: • Top-coat solution in purified water was prepared• Drug coated beads were loaded in a fluid bed coater• Top-coat was spayed on to drug coated beadsP-636238-PC

[0250] Encapsulation:

[0251] Encapsulation was performed for Prototype beads 1,2 and 3 into capsule size 2. *Note: Prototypes formulation or process equipment changes are shown in manufacturing process flow chart (Figure 6).

[0252] Figure 6 depicts the Manufacturing Process of pridopidine hydrochloride ImmediateRelease Capsules, 45 mg, Prototypes - 1-4.Table 11: Process Parameters for pridopidine hydrochloride Immediate Release BeadsP-636238-PCTable 12: Process Parameters for pridopidine hydrochloride IR Beads - Prototype 4

[0253] As shown in Table 11, during spraying product temperature was maintained close to 45.0 °C during seal coating with Inlet air temperature in range of 57 - 68 °C and spray rate of 4.7- 8.4 g / min.

[0254] In absence of seal coating in batch 01 (beads for protype 1), challenges were encountered with fluidization of substrate due to wetting of MCC spheres when spraying of drug layering solution was initiated. The same was encountered for batch 05 (beads for prototype 3), for which wetting of MCC was partially reduced by the inclusion of 10.0 g of Hypromellose in the drug layering solution. During drug layer coating, a higher product temperature was required in the absence of seal coat in batch 01 and 05 to prevent wetting of substrate and promote ease of fluidization.

[0255] Binder concentration in batch 07 was increased in lieu of seal coat but it did not produceP-636238-PC the desired results, with the spray solution becoming sticky and leading to bead agglomeration. In efforts to rectify, a seal coat was applied, and the drug containing solution modified by adding colloidal silicon dioxide and overall spray rate reduced. There were no issues with the coating process using Eudragit E PO ready -mix. As mentioned in

[0256] Table 8, Opadry® clear was used as topcoat in batch 01 and 02 while for batch 05, Surelease® dispersion with pore former (Hypromellose) was used. This resulted in the process parameters changing for batch 05 compared to the previous two batches. Eudragit® E PO was used batch 07 as topcoat requiring process parameter changes for coating.ResultsIn-Process test result

[0257] During encapsulation, individual fill weights and gross capsule weights were measured, and results reported in Table 13, which shows individual weight variation for batches 04, 03 and 06 respectively. As shown the individual weights of all encapsulated batches are within minimum and maximum individual weight range. The data indicates good weight control during the encapsulation process.Table 13: In-Process testing of pridopidine hydrochloride Immediate Release Capsules

[0258] Table 13 depicts the in-process weight variation of encapsulation batches 04, 03 and 06 of prototypes 1, 2 and 3 respectively. Data demonstrates that the individual tablets weight and average tablets weight are within the specification limits of the individual weight and gross weight respectively. It indicates that there was good weight uniformity during the encapsulation run.P-636238-PC

[0259] Particle size distribution and percent moisture content of pridopidine hydrochloride Immediate release beads are shown in Tables 14 & 15 below. In all batches, moisture content was below 1.0 % after drug layering and top coating, which reflected effective water removal during the manufacturing process. Particle size distribution was measured on Camsizer for the final top coated beads of all batches. Highest value of Dw, D50 and D90 was observed in batch 07 resulting from a higher amount of drug layer and topcoat being applied as compared to remaining batches.Table 14: Particle size distribution for pridopidine hydrochloride Immediate Release BeadsNote: % Total weight gain calculated based on total amount of solid applied on MCC spheres Table 15: Particle size distribution for pridopidine hydrochloride Immediate Release BeadsNote: % Total weight Gain = 100 * (Theoretical solids applied @ X% or at end of process / Theoretical Weight of starting MCC sphere or substrate).Analytical test result

[0260] Analytical test results are presented in Table 16. Table 16 shows assay for drug coated beads and Topcoat (Seal or Taste Masking coat) coated beads. Both batches 03 and 06 have close to 100 % Assay and content uniformity for the finished product (prototype 2 (batch 3) and prototype 3 (batch 6) is close to 100% which indicates that no drug loss occurred during fluid bedP-636238-PC processing at process parameters used.Table 16: Assay result of pridopidine hydrochloride Immediate release beads and finished productDissolution test results

[0261] Based on the floating nature of capsules and beads and in order to determine the type of apparatus that is suitable for the dissolution, two dissolution experiments (n=3) using baskets and paddles with sinkers were performed. However, based on the dissolution data there were no differences observed in the dissolution results with different apparatus. Data in Table 19 for Prototypes 1 and 2 does confirm this.

[0262] Tables 17 & 18 present the dissolution testing conditions used for assessment of dissolution profiles of the different prototype formulations.Table 17: Dissolution Testing Condition (Prototype 1 - 3)P-636238-PCTime point 5, 10, 15, 20, 30 and 45 minutesTable 18: Dissolution Testing Conditions (Prototype 4 beads)Table 19: Dissolution data in pH 6.8 media of pridopidine hydrochloride Immediate Release beads or beads in capsules (Prototype 1 - 3)P-636238-PCTable 20: Dissolution data of pridopidine hydrochloride Immediate Release Beads (Prototype 4)

[0263] Dissolution profiles for the different prototype (bead and capsule) formulations are shown in Figures 7 - 11 and dissolution data are presented in Table 19 - 20 for different dissolution conditions and coating levels as mentioned above. As shown in Table 19, batch 05P-636238-PC(Beads) and 06 (Capsules) exhibited less than 25% drug release in initial 5 min with all remaining batches showing more than 80 % drug release in 5 min. All batches showed at least 85% drug released in 30 minutes which fulfilled criteria of immediate release drug products. As pridopidine is a highly water soluble and intensely bitter tasting drug, taste masking was a primary requirement, particularly with the pediatric population in mind, where the capsules could be opened, and the beads sprinkled onto soft food or liquids before administration. Based on these criteria, minimal to no drug release from beads was targeted in the initial 5 minutes which was evaluated in prototype 3 & 4 batches using different taste masking polymers. Table 20 shows that beads from the Prototype 4 formulation provide the best drug release protection at pH 6.8 with drug release of 1% in the first 5 minutes and 5% in 10 minutes at a 50% top coating level.SummaryManufacturing and Process Findings

[0264] MCC beads without a polymeric seal coat exhibit agglomeration during application of the drug layer, which cannot be fully resolved by increasing binder concentration in the drug layer solution.

[0265] Application of a seal coat to MCC beads, in combination with a small proportion of binder in the aqueous drug solution, reduces bead wetting, improves processability, and facilitates control of product temperature during manufacture.

[0266] Pridopidine hydrochloride can be dissolved in an aqueous solution and uniformly sprayed onto seal-coated MCC bead substrates to produce a multiparticulate formulation.Drug spray solution (DS):

[0267] Solids content demonstrated up to 40%.

[0268] Drug solution: polymer ratio preferably greater than 10: 1 to reduce agglomeration.

[0269] Addition of silicon dioxide improves fluidization and mitigates agglomeration.Eudragit E PO coating:

[0270] 25% weight gain delays drug release at pH 6.8 for up to 5 minutes.

[0271] 50% weight gain delays drug release at pH 6.8 for approximately 10-15 minutes.

[0272] Minimal further delay observed at 75% weight gain.

[0273] The multiparticulate formulation enables encapsulation of a 45 mg dose of pridopidineP-636238-PC hydrochloride in a small size 2 capsule.

[0274] Content uniformity and weight variation testing indicate low segregation propensity of beads at small-scale encapsulation.

Claims

P-636238-PCCLAIMSWhat is claimed is:

1. Immediate release (IR) particles comprising pridopidine or pharmaceutically acceptable salt thereof, each of said particles comprises: a. beads substrate coated with a polymer seal coat. b. a drug layer comprising pridopidine or pharmaceutically acceptable salt thereof, coated over the seal coat, wherein the drug layer optionally comprises a binder and / or a glidant; c. a topcoat comprising an acrylate-based coating, further coated over the drug layer.

2. The particles of claim 1, configured such that upon administration of the particles to the oral cavity of a subject, the taste of the pridopidine is substantially masked, and, upon subsequent exposure to the acidic environment of the subject’s stomach, the pridopidine is completely released, thereby producing an immediate-release (IR) pharmacokinetic profile for said particles.

3. The particles of claim 1 or 2, wherein the drug layer is characterized by a drug loading ranging between about 20% and 60% w / w relative to the weight of the coated beads of (a), preferably about 40% w / w.

4. The particles of any one of claims 1 -3, wherein the drug loading is ranging between about 15% and 60% w / w with respect to the overall weight of the particle, preferably about 30% w / w.

5. The particles of any one of claims 1 -4, wherein the pridopidine or pharmaceutically acceptable salt thereof is pridopidine hydrochloride.

6. The particles of any one of claims 1 to 5, wherein the beads substrate comprises microcrystalline cellulose (MCC) beads, sugar spheres or combination thereof.

7. The particles of any one of claims 1 to 6, wherein the bead content with respect to the particle weight ranges between about 30% and 85% w / w; preferably between about 35% and 80%; most preferably between about 40% and 75%.

8. The particles of any one of claims 1-7, wherein the beads substrate has a particle size higherP-636238-PC than about 100 pm; preferably lower than about 500 pm; more preferably about 350 pm .

9. The particles of any one of claims 1-8, wherein the polymer amount in the seal coat layer ranges between 0.5% and 10% w / w; preferably 1-4% w / w; more preferably 1.3 -1.9% w / w; most preferably 1.5% w / w; relative to the total weight of the particle.

10. The particles of any one of claims 1-9, wherein the binder amount in the drug layer ranges between 1 and 10% w / w ; preferably 1-5%; more preferably 3% w / w; based on the total weight of the particles.

11. The particles of any one of claims 1-10, wherein the glidant is an anti -tacking agent.

12. The particles of claim 11, wherein the anti-tacking agent comprises: hydroxypropyl methylcellulose (HPMC), Magnesium Stearate, Calcium Stearate, Zinc Stearate, Sodium Stearyl Fumarate, Talc, Silicon Dioxide (Colloidal), , Hydrophobic Silica, Ethyl Cellulose, Carnauba Wax, or any combination thereof.

13. The particles of any one of claims 1 to 12, wherein the glidant amount in the drug layer ranges between 0.5-5% w / w; preferably 0.5-3%; more preferably 1.5% w / w.

14. The particles of any one of claims 1 to 13, wherein the topcoat is a seal coat, an outer taste masking coat, or combination thereof.

15. The particles of claim 14, wherein the outer taste masking coat comprises: film coating, sugar coating, flavor , polymer coating or any combination thereof.

16. The particles of claim 15, wherein the film coating material comprises: hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyethylene glycol (PEG) or any combination thereof;P-636238-PC the flavor masking agents comprise: sucrose, sorbitol, mannitol, aspartame, fruit flavors, artificial flavors or any combination thereof; and / or the polymer coating comprise: ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate (HPMCP), methacrylic acid copolymers (e.g., Eudragit® L, Eudragit ® EPO) or any combination thereof.

17. The particles of any one of claims 1 to 16, wherein the topcoat amount ranges between about 1-50% w / w; preferably between about 10-30% w / w ; more preferably between about 19-20% w / w; with respect to the total weight of the final particle.

18. The particles of any one of claims 1-17, wherein the polymer in the seal coat layer comprises Hypromellose; wherein the binder in the drug layer comprises Hypromellose; wherein the glidant in the drug layer comprises silicon dioxide, preferably colloidal silicon dioxide; wherein the acrylate based coating of said topcoat layer is methacrylate based coating; or any combination thereof.

19. The particles of any one of claims 1-18, wherein the drug layer contains between about 15% and about 75% solids by weight; preferably higher than about 30%.

20. The particles of any one of claims 1 to 19, wherein the weight ratio between the pridopidine and the binder (e.g., polymer) in the drug layer ranges between 100: 1 and 1 : 1 respectively, preferably between 20:1 and 15:

1. more preferably greater than 10:

121. The particles of any one of claims 1-20, wherein the particles are designed for administration by sprinkling on food or administered with liquids.

22. The particles of claim 21, wherein said food or liquid has a pH of between about 5.0 and about 8.0; preferably between about 6.0 and about 7.5; more preferably about 6.8.P-636238-PC23. An immediate release (IR) pharmaceutical dosage form comprising a plurality of particles, according to any one of claims 1-21.

24. The dosage form of claim 23, in the form of a capsule, a compressed tablet, sprinkle beads in a sachet or sprinkle beads in a stick pack.

25. The dosage form of any one of claims 23-24, wherein the dissolution profile of said dosage form exhibits at least 50% drug release in 30 minutes; preferably at least 85%.

26. The dosage form of any one of claims 23-25, wherein upon oral administration, less than 35% of the drug is released from the dosage form within the initial 5 minutes; preferably less than 25%; more preferably less than 10%; most preferably less than 7%.

27. The dosage form of any one of claims 23-26 wherein the dosage form comprises between about 10 mg and about 1000 mg of pridopidine or pharmaceutically acceptable salt thereof; preferably between about 22.5mg and 315 mg of pridopidine or pharmaceutically acceptable salt thereof; more preferably 22.5 mg or 45 mg.

28. A method of preparing the particles of any one of claims 1 to 21, comprising the steps of: a. coating a beads substrate with a polymer seal coat; b. coating the polymer seal coated beads with a drug layer comprising pridopidine or salt thereof, optionally comprising a binder and / or optionally comprising a glidant; and c. coating the drug layer with a topcoat comprising an acrylate-based coating.

29. The method of claim 28, wherein the glidant is an anti-tacking agent, the topcoat is an outer taste masking coat, or combination thereof.

30. The method of claims 28, wherein the coating of the drug layer with a topcoat is carried out using aqueous solvent system, organic solvent system, or combination thereof.P-636238-PC31. The method of claim 28, wherein the coating process of step (a), utilizes a polymer seal coat solution, which comprises between about 5%-30% of solid content; preferably about 10%; wherein the coating process of step (b), utilizes a drug coat solution, which comprises between about 15%-60% of solid content; preferably between about 20% and 50%; more preferably between about 25% and 45%; most preferably at least 30%; wherein the coating process of step (c), utilizes a topcoat, which comprises between about 5%-25% of solid content; preferably between about 8% and 20%; more preferably between about 10% and 18%; most preferably about 16%; wherein the coating of the drug layer (step (b)) is maintained at a product temperature of below 70 °C; preferably below 50 °C or below 35 °C; or any combination thereof.

32. The method of claim 31, wherein the beads substrate comprises microcrystalline cellulose (MCC) beads, sugar spheres or combination thereof; wherein the beads substrate has a particle size higher than about 100 pm; preferably lower than about 500 pm; more preferably about 350 pm; wherein the polymer amount in the seal coat layer ranges between about 0.5% and 10% w / w based on the total weight of the particle; preferably about 1-3%; more preferably about 1.3 -1.9% w / w; most preferably about 1.5% w / w; preferably wherein the polymer in the seal coat layer is Hypromellose; wherein the binder amount in the drug layer ranges between about 1% and 10% w / w based on the total weight of the particle; preferably about 1-5%; more preferably about 3% w / w; preferably wherein the binder in the drug layer is Hypromellose; wherein the glidant amount in the drug layer ranges between 0.5-5% w / w; preferably 0.5-3%; more preferably 1.5% w / w; preferably wherein the glidant in the drug layer is silicon dioxide,P-636238-PC more preferably colloidal silicon dioxide; wherein the topcoat amount ranges between about 1 -50% w / w with respect to the weight of the final particle; preferably between about 10-30% w / w; more preferably between about 19-20% w / w; preferably wherein the topcoat is a seal coat, taste masking coat or combination thereof; more preferably wherein the acrylate based coating of said topcoat layer is methacrylate based coating; wherein the drug layer contains between 15% to 75% solids by weight, preferably higher than 30%; and / or wherein the weight ratio between the pridopidine and the polymer in the drug layer ranges between 100: 1 and 1 :1 respectively, preferably between 20:1 and 15: 1 and more preferably greater than 10: 1.

33. Immediate release (IR) particles comprising pridopidine or pharmaceutically acceptable salt thereof, prepared according to the method of any one of claims 28-32.

34. The dosage forms according to anyone of claims 23-27 for use in treating, slowing the progression, lessening the decline, delaying onset of symptoms, or slowing the progression of symptoms of a neurodegenerative or neurodevelopmental disease or disorder in a subject.

35. The dosage form for use of claim 34, wherein the neurodegenerative disease or disorder is selected from the group consisting from Huntington Disease, prodromal / premanifest Huntington disease, Amyotrophic Lateral Sclerosis (ALS), Parkinson’s Disease, Parkinson’s Disease associate with glucocerebrosidase (GBA) deficiency, dystonia, cognitive disorder, dyskinesia, medication-induced dyskinesia, tardive dyskinesia, levodopa-induced dyskinesia (LID), mild cognitive impairment (MCI), Alzheimer’s Disease, age related memory loss, major depressive disorder, depression, anxiety, bacterial infections-induced depression, optic neuropathies including glaucoma, age-related macular degeneration (AMD), geographic atrophy, Leber’s Hereditary Optic Neuropathy (LHON) and retinitis pigmentosa; and wherein the neurodevelopmental disease or disorder is Rett syndrome (RTT) or Fragile X Syndrome (FXS).P-636238-PC36. The dosage forms according to anyone of claims 23-27, for use in treating, slowing the progression, lessening the decline, delaying onset of symptoms, or slowing the progression of symptoms of a mitochondrial diseases or dysfunctions, Wolfram disease or viral infection (i.e. COVID-19).

37. The dosage form for use of claim 36, wherein the mitochondrial disease or dysfunction is: Lysosomal storage disease (LSD), leukodystrophies, vanishing white matter (VWM) disease, or any combination thereof.

38. A pharmaceutical dosage form comprising a plurality of particles according to any one of claims 23-27, for use in the treatment of a patient in need thereof by: a. sprinkling the plurality of particles on soft food; and b. administering the soft food orally.

39. A pharmaceutical dosage form comprising a plurality of particles according to any one of claims 23-27, for use in the treatment of a patient in need thereof by: a. administering the particles orally; and b. subsequent administration of a liquid.

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