Matrix tablets of dexpramipexole and methods of manufacturing and use thereof

Abstract

The present disclosure relates to sustained release pharmaceutical compositions of dexpramipexole, or a pharmaceutically acceptable salt thereof. In some aspects, the present disclosure relates to sustained release pharmaceutical compositions in the form of orally deliverable tablets. In some aspects, the sustained release pharmaceutical compositions of the present disclosure comprise one or more anionic polymers at specific amounts. In some aspects, the sustained release pharmaceutical compositions of the present disclosure comprise one or more neutral polymers at specific amounts. The present disclosure further relates to methods of manufacturing the sustained release pharmaceutical compositions (or intermediate products thereof) and methods of using the sustained release pharmaceutical compositions to treat and prevent certain diseases, such as eosinophilic disorders, in a human subject.

Description

MATRIX TABLETS OF DEXPRAMIPEXOLE AND METHODS OF MANUFACTURING AND USE THEREOFRELATED APPLICATIONS

[0001] This application claims priority to US Provisional Application No. 63 / 706,522 filed on October 11, 2024 and US Provisional Application No. 63 / 612,916 filed on December 20, 2023, both of which are incorporated hereby by reference in their entirety.FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to sustained release pharmaceutical compositions of dexpramipexole, or a pharmaceutically acceptable salt thereof. In certain particular aspects, the present disclosure relates to sustained release pharmaceutical compositions in the form of orally deliverable tablets. The present disclosure further relates to methods of manufacturing the sustained release pharmaceutical compositions (or intermediate products thereof), as well as uses of the sustained release pharmaceutical compositions to treat or prevent certain diseases or conditions in human subjects, in particular such diseases or conditions that are related to elevated eosinophilic levels.BACKGROUND OF THE DISCLOSURE(0003] Dexpramipexole ((6A)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole; (formula I)) is the enantiomer of pramipexole ((65)-2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole; (formula II)).|0004] Pramipexole is a dopamine D2 receptor agonist used in the treatment of Parkinson’s disease. Pramipexole is sold in the form of orally deliverable tablets under the brand Mirapex®, among others. Mirapex® tablets are available as immediate release (IR) and extended release (ER) formulations, and contain pramipexole as thedihydrochloride monohydrate salt. Mirapex® ER tablets for oral administration are available at a dose of 0.375 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, or 4.5 mg of pramipexole dihydrochloride monohydrate per tablet given once daily (QD; quaque die). Inactive ingredients are, according to the manufacturer, hypromellose (hydroxypropyl methylcellulose), cornstarch, carbomer homopolymer, colloidal silicon dioxide, and magnesium stearate. The term “extended release” or “ER” is used herein synonymously with “sustained release.”

[0005] In contrast, the affinity of dexpramipexole for dopamine receptors was found to be greatly reduced when compared to pramipexole, which renders dexpramipexole unsuitable as a dopamine agonist. Instead, dexpramipexole was shown to selectively and significantly lower eosinophil counts in human blood and tissues. The drug is currently under clinical development for eosinophil-associated diseases, including eosinophilic asthma and chronic obstructive pulmonary disease (COPD).

[0006] In literature reporting testing of dexpramipexole compositions, the dexpramipexole compositions were immediate release (IR) tablets that are given twice a day (BID; bis in die). Doses evaluated include 37.5 mg, 75 mg and 150 mg of dexpramipexole dihydrochloride equivalent per tablet (corresponding to a daily dose of 75 mg, 150 mg, and 300 mg, respectively, which is up to 800-fold higher than the lowest daily dose of 0.375 mg pramipexole salt provided by Mirapex® ER tablets).

[0007] Because of the relatively high amount of dexpramipexole that is typically used per day (e.g., about 75 mg, about 150 mg, or about 300 mg dexpramipexole dihydrochloride equivalent per day), it could not have been reasonably expected that formulating the drug as a composition suitable for once-daily oral administration to a human would be possible. A pharmaceutical composition that is intended for oral use, such as a tablet, must be swallowable by a human. This means, a certain maximum composition weight (typically about 1500 mg) should not be exceeded. If, however, the amount of the active ingredient is relatively high (such as in the event of dexpramipexole, or a pharmaceutically acceptable salt thereof, at doses typically used), the amount of additional ingredients that can be added to the pharmaceutical composition for formulation is limited and formulation possibilities are thus restricted. This can be problematic because, in general, a higher amount of active ingredient also requires a higher amount of additional ingredients such as release-controlling polymers, diluents, glidants, lubricants, and / or binders to allow a pharmaceutical composition (such as atablet) to be manufactured and sufficiently slow down the release of the active ingredient for a once daily formulation. See, for example, Encyclopedia of Pharmaceutical Technology, Volume 1, Third Edition, edited by James Swarbrick, Chapter “Drug Delivery: Controlled Release” by Chien and Lin. In contrast, as outlined above, for pramipexole, significantly lower amounts of drug are used per day (the highest dose in Mirapex® ER once daily formulations being 4.5 mg pramipexole dihydrochloride monohydrate).[0008| Further, in the context of matrix tablets for which the drug release mechanism is based on a combination of diffusion and erosion, the higher the solubility of a drug, the greater are the challenges for developing a matrix tablet that is suitable for once daily oral administration to a human. Diffusion is related to solubility of the drug contained in the matrix tablet. The higher the solubility, the greater the driving force for diffusion, and hence the harder it is to slow down the drug release. In the case of dexpramipexole, the salt form that is commonly used, dexpramipexole dihydrochloride monohydrate, is freely soluble across the physiological pH range. Moreover, additional formulation challenges generally encountered with a sustained release matrix tablet are the achievement of a steady release across the physiological pH range, as well as a substantially complete release within a desired time period. Surprisingly, the present disclosure provides dexpramipexole, or a pharmaceutically acceptable salt thereof, in the form of an orally deliverable pharmaceutical composition (such as in the form of an orally deliverable tablet) that is suitable for once daily administration to a human, which would not have been expected in view of constraints on composition size coupled with the high amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, needed for once daily administration, and in view of the high solubility of dexpramipexole and pharmaceutically acceptable salts thereof. Moreover, as shown herein, the orally deliverable matrix tablets of the present disclosure provide for a steady release across the physiological pH range, as well as high terminal release rates.BRIEF SUMMARY OF THE DISCLOSURE100091 Although, as outlined above, it could not have been reasonably expected that formulating dexpramipexole, or a pharmaceutically acceptable salt thereof, as a sustained release composition suitable for once daily oral administration to a human would be possible, the present disclosure inter alia provides such a sustained releasepharmaceutical composition. The sustained release pharmaceutical compositions of the present disclosure allow simplification of a patient’s administration scheme by reducing the number of recommended daily intakes compared to immediate release dexpramipexole formulations known in the art, which improves patient’s compliance and attenuates potential adverse events that are related, e.g., to high plasma concentration peaks.

[0010] In some aspects, the present disclosure provides a pharmaceutical composition in the form of an orally deliverable tablet comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides for a sustained release of dexpramipexole, or a pharmaceutically acceptable salt thereof, that makes the tablet suitable for once daily oral administration to a human.

[0011] Further, in some aspects, the present disclosure provides sustained release pharmaceutical compositions in alternative dosage forms than tablets (such as in the form of an orally deliverable capsule) comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides for a sustained release of dexpramipexole, or a pharmaceutically acceptable salt thereof, that makes the tablet suitable for once daily oral administration to a human.

[0012] In some aspects, the present disclosure provides a sustained release pharmaceutical composition in the form of an orally deliverable tablet comprising a tablet core and dexpramipexole, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg to about 400 mg of dexpramipexole dihydrochloride equivalent, wherein the tablet core comprises a homogeneous mixture of the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more anionic polymers, wherein the one or more anionic polymers constitute about 30% to about 60% by weight of the tablet core, and wherein the weight of the tablet is about 1500 mg or less.

[0013] In some aspects, the present disclosure provides a sustained release pharmaceutical composition in the form of an orally deliverable tablet comprising a tablet core and dexpramipexole, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg to about 500 mg of dexpramipexole dihydrochloride equivalent, wherein the tablet core comprises a homogeneous mixture of the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers, wherein the one or more anionic polymers constitute about 5% to about 60% by weight of the tablet core, and wherein the weight of the tablet is about 1500 mg or less.100141 In some aspects, the present disclosure provides a sustained release pharmaceutical composition in the form of an orally deliverable tablet comprising a tablet core and dexpramipexole, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg to about 400 mg of dexpramipexole dihydrochloride equivalent, wherein the tablet core comprises a homogeneous mixture of the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more neutral polymers, wherein the one or more neutral polymers constitute about 5% to about 60% by weight of the tablet core, and wherein the weight of the tablet is about 1500 mg or less.10015] As shown in the Example section (see in particular Examples 3 and 9), the matrix tablets comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, according to the present disclosure provide for in vitro dissolution profiles of the drug that render the matrix tablets suitable for once daily oral administration to a human. Moreover, in addition to such beneficial in vitro dissolution profiles, the matrix tablets according to the present disclosure are of sufficient mechanical strength for efficient tablet manufacturing (in particular on a routine, large-scale basis).|0016] Also matrix tablets that do not comprise the amounts or types of polymers as specified herein resulted in an in vitro drug dissolution profile unsuitable for a once daily sustained release formulation (the dexpramipexole pharmaceutically acceptable salt in the manufactured tablets dissolved too fast), even when prepared with different manufacturing methods such as direct compression and melt granulation (see in particular Example 2, in which the tablets were not formulated according to the present disclosure).

[0017] An in general beneficial in vitro dissolution profile was observed for matrix tablets that do not comprise the amounts or the types of one or more polymers as specified herein, but instead comprise corresponding amounts of a lipophilic material (such as about 50% Compritol 888 ATO by weight of the tablet core) when manufactured by melt granulation. However, although the in vitro dissolution profile was in principle suitable for a once daily sustained release formulation, the corresponding matrix tablets were mechanically weak rendering them unsuitable for manufacturing of such tablets (in particular on a routine, large-scale basis; see in particular Example 2, in which the tablets were not formulated according to the present disclosure).

[0018] In strong contrast to the formulations that did not result in a suitable in vitro dissolution profile for a once daily sustained release formulation and / or that resulted in mechanically weak tablets, it was shown that inclusion of one or more anionic polymersat the amounts specified herein in the tablet core (i.e., at about 30% to about 60% by weight of the tablet core) resulted in matrix tablets showing desirable properties (an in vitro dissolution suitable for once daily administration to a human and sufficient mechanic strength). In particular, such beneficial properties were observed over a wide % w / w-range of anionic polymers (such as from about 30% to about 50% by weight of the tablet core). Further, the desirable properties were observed with a single anionic polymer and also with a combination of different anionic polymers (such as tablets comprising a combination of sodium carboxymethylcellulose and a crosslinked acrylic acid polymer) in the tablet core at the amounts specified herein (such as from about 30% to about 50% by weight of the tablet core). It was shown that in vitro dissolution and mechanical properties were also generally independent of specific ratios of anionic polymers towards each other, if more than one anionic polymer was present in the tablet core (such as a weight ratio of an acrylic acid polymer to sodium carboxymethylcellulose of about 3:2 to about 2:8). See in particular Example 3. Tablets formulated according to the present disclosure were also stable for several weeks under controlled room temperature (CRT) conditions (see in particular Example 6). Additionally, the desirable properties were observed with a single hydrophilic neutral polymer in the tablet core at the amounts specified herein (such as from about 5% to about 25% by weight of the tablet core). Advantageously, tablets with a signle neutral polymer demonstrated suitable in vitro dissolution profile for a once daily sustained release formulation and resulted in mechanically strong tablets, making them an ideal clinical candidate. In sum, it was discovered that these desirable properties could be replicated for tablets with two anionic polymers, a single anionic polymer, or a single neutral polymer. See in particular Example 9. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 75 mg to about 300 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 50 mg to about 100 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 75 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 100 mg to aboutamount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 275 mg to about 325 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 300 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 125 mg to about 175 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 150 mg of dexpramipexole dihydrochloride equivalent.

[0020] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 150 mg to about 400 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 200 mg to about 350 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 300 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 300 mg to about 400 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 350 mg to about 385 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is 376 mg of dexpramipexole dihydrochloride equivalent.

[0021] In some embodiments, the homogeneous mixture comprises one or more polymers. In some embodiments, the one or more polymers are anionic polymers. In some embodiments, the one or more polymers are neutral polymers. In some embodiments, the one or more anionic polymers constitute about 30% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 25% by weight of the tablet core. In some embodiments, the homogeneous mixture comprises no more than one anionic polymer. In some embodiments, the one anionic polymer constitutes about 20% to about 40% by weight of the tablet core. In some embodiments, the homogeneous mixture comprises no more than one neutral polymer. In some embodiments, the one neutral polymer constitutes about 5% to about 25% by weight of the tablet core.

[0022] In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more anionic polymers is about 0.5: 1 to about 1 : 1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more anionic polymers is about 0.7:1 to about 0.9: 1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more anionic polymers is about 0.7: 1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more anionic polymers is about 0.9: 1.(0023] In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.5 : 1 to about 3.5 : 1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.7: 1 to about 3.0: 1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.7: 1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.9: 1.

[0024] In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more neutral polymers is about 0.5: 1 to about 3.5: 1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one anionic polymer is about 0.5: 1 to about 3.5: 1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one neutral polymer is about 0.5: 1 to about 3.5: 1.(0025] In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is a methane sulfonic acid salt, sulfuric acid salt, tartaric acid salt, -toluene sulfonic acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, malic acid salt, citric acid salt, succinic acid salt, or any combination thereof. In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride or a hydrate thereof. In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride monohydrate.

[0026] In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose, an acrylic acid polymer, a methyl methacrylic acid polymer, a methyl methacrylic acid copolymer, a methacrylic acid polymer, a methacrylic acid copolymer, alignate, carrageenan, xanthan gum, or arabic gum. In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose and an acrylic acid polymer. In some embodiments, carboxymethylcellulose is sodiumcarboxymethylcellulose. In some embodiments, the acrylic acid polymer is a crosslinked acrylic acid polymer.

[0027] In some embodiments, the one or more anionic polymers constitute about 35% to about 55% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 38% to about 42% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 40% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 45% to about 49% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 47% by weight of the tablet core.100281 In some embodiments, the one or more anionic polymers constitute about 25% to about 55% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 28% to about 48% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 28% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 40% to about 48% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 42% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 40% by weight of the tablet core.100291 In some embodiments, the one anionic polymer constitutes about 20% to about40% by weight of the tablet core. In some embodiments, the one anionic polymer constitutes about 25% to about 35% by weight of the tablet core. In some embodiments, the one anionic polymer constitutes about 28% by weight of the tablet core.

[0030] In some embodiments, the one or more neutral polymers constitute about 5% to about 25% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 10% to about 20% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 15% by weight of the tablet core.100311 In some embodiments, the one or more neutral polymers constitute between about5% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 10% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 15% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 20% and about 60% by weight of the tablet core. Insome embodiments, the one or more neutral polymers constitute about 25% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 30% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 35% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 40% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 45% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 50% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 55% to about 60% by weight of the tablet core.

[0032] In some embodiments, the one or more neutral polymers constitute about 5% to about 55% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 50% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 45% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 40% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 35% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 30% by weight of the tablet core.

[0033] In some embodiments, the one or more neutral polymers constitute about 20% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 25% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 30% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 35% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 40% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 45% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 50% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 55% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 60% by weight of the tablet core.

[0034] In some embodiments, the one neutral polymer constitutes about 5% to about 25% by weight of the tablet core. In some embodiments, the one neutral polymer constitutes about 10% to about 20% by weight of the tablet core. In some embodiments, the one neutral polymer constitutes about 15% by weight of the tablet core.

[0035] In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 250 mg to about 550 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 320 mg to about 360 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 340 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 400 mg to about 440 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 425 mg.

[0036] In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 150 mg to about 550 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 200 mg to about 500 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 210 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 300 mg to about 480 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 475 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 425 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 340 mg.

[0037] In some embodiments, the homogeneous mixture comprises no more than one anionic polymer. In some embodiments, the anionic polymer is carboxymethylcellulose. In some embodiments, the carboxymethylcellulose is sodium carboxymethylcellulose. In some embodiments, the amount of carboxymethylcellulose is about 23% to about 38% of sodium carboxymethylcellulose equivalent by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 25% to about 30% of sodium carboxymethylcellulose equivalent by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 28% of sodium carboxymethylcellulose equivalent by weight of the tablet core.

[0038] In some embodiments, the amount of carboxymethylcellulose is about 100 mg to about 300 mg of sodium carboxymethylcellulose equivalent. In some embodiments, theamount of carboxymethylcellulose is about 200 mg to about 250 mg of sodium carboxymethylcellulose equivalent. In some embodiments, the amount of carboxymethylcellulose is about 210 mg of sodium carboxymethylcellulose equivalent.

[0039] In some embodiments, the homogeneous mixture comprises a first anionic polymer and a second anionic polymer and wherein the first anionic polymer is carboxymethylcellulose and the second anionic polymer is an acrylic acid polymer. In some embodiments, the acrylic acid polymer is a crosslinked acrylic acid polymer. In some embodiments, carboxymethylcellulose is sodium carboxymethylcellulose.

[0040] In some embodiments, the amount of carboxymethylcellulose is about 23% to about 38% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 7% to about 22% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 27% to about 34% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 11% to about 15% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 27% to about 29% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 11% to about 13% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 28% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 12% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 30% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 13% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 32% to about 34% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 13% to about 15% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 33% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 14% by weight of the tablet core.

[0041] In some embodiments, the amount of carboxymethylcellulose is about 190 mg to about 350 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 60 mg to about 200 mg. In some embodiments, the amount of carboxymethylcellulose is about 205 mg to about 335 mg of sodiumcarboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 100 mg to about 145 mg. In some embodiments, the amount of carboxymethylcellulose is about 333 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 143 mg. In some embodiments, the amount of carboxymethylcellulose is about 200 mg to about 250 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 75 mg to about 125 mg. In some embodiments, the amount of carboxymethylcellulose is about 235 mg to about 245 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 95 mg to about 105 mg. In some embodiments, the amount of carboxymethylcellulose is about 238 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 102 mg. In some embodiments, the amount of carboxymethylcellulose is about 275 mg to about 325 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 100 mg to about 150 mg. In some embodiments, the amount of carboxymethylcellulose is about 298 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 128 mg. In some embodiments, the amount of carboxymethylcellulose is about 295 mg to about 305 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 125 mg to about 135 mg. In some embodiments, the amount of carboxymethylcellulose is about 298 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 128 mg.

[0042] In some embodiments, the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 3:2 to about 2:8. In some embodiments, the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 2:3 to about 2:8. In some embodiments, the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 3:7.

[0043] In some embodiments, the one or more polymers are neutral polymers. In some embodiments, the one or more neutral polymers is hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose. In some embodiments, the one or more neutral polymers is hydroxypropyl methylcellulose. In some embodiments, the one or more neutral polymers is silicified hydroxypropyl methylcellulose. In some embodiments, the one or more neutral polymers constitute about 5% to about 25% by weight of the tabletcore. In some embodiments, the neutral polymer constitute about 15% by weight of the tablet core.

[0044] In some embodiments, the homogeneous mixture comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and two anionic polymers. In some embodiments, the homogeneous mixture comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and no more than one anionic polymer. In some embodiments, the homogeneous mixture comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and two neutral polymers. In some embodiments, the homogeneous mixture comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and no more than one neutral polymer. In some embodiments, the homogeneous mixture comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and does not comprise an anionic polymer. In some embodiments, the homogeneous mixture comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and does not comprise a neutral polymer.

[0045] In some embodiments, the homogeneous mixture consists essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, and two anionic polymers. In some embodiments, the homogeneous mixture consists essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, and no more than one anionic polymer. In some embodiments, the homogeneous mixture consists essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, and two neutral polymers.

[0046] In some embodiments, the homogeneous mixture further comprises a microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide, or any combination thereof. In some embodiments, the homogeneous mixture further comprises a microcrystalline cellulose, magnesium stearate and colloidal silicon dioxide. In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

[0047] In some embodiments, the homogeneous mixture consists essentially of:(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 235 mg to about 245 mg sodium carboxymethylcellulose;(c) about 95 mg to about 105 mg crosslinked acrylic acid polymer;(d) about 175 mg to about 185 mg silicified microcrystalline cellulose;(e) about 5 mg to about 7 mg magnesium stearate; and(f) about 3 mg to about 5 mg colloidal silicon dioxide.

[0048] In some embodiments, the homogeneous mixture consists essentially of:(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 238 mg sodium carboxymethylcellulose;(c) about 102 mg crosslinked acrylic acid polymer;(d) about 180 mg silicified microcrystalline cellulose;(e) about 6 mg magnesium stearate; and(f) about 4 mg colloidal silicon dioxide.

[0049] In some embodiments, the homogeneous mixture consists essentially of:(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 295 mg to about 305 mg sodium carboxymethylcellulose;(c) about 125 mg to about 135 mg crosslinked acrylic acid polymer;(d) about 140 mg to about 150 mg silicified microcrystalline cellulose;(e) about 6 mg to about 8 mg magnesium stearate; and(f) about 4 mg to about 6 mg colloidal silicon dioxide.

[0050] In some embodiments, the homogeneous mixture consists essentially of(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 298 mg sodium carboxymethylcellulose;(c) about 128 mg crosslinked acrylic acid polymer;(d) about 145 mg silicified microcrystalline cellulose;(e) about 7 mg magnesium stearate; and(f) about 5 mg colloidal silicon dioxide.

[0051] In some embodiments, the homogeneous mixture consists essentially of(a) about 390 mg to about 410 mg dexpramipexole dihydrochloride monohydrate;(b) about 325 mg to about 341 mg sodium carboxymethylcellulose;(c) about 135 mg to about 145 mg crosslinked acrylic acid polymer;(d) about 230 mg to about 240 mg microcrystalline cellulose or silicified microcrystalline cellulose;(e) about 5 mg to about 10 mg magnesium stearate; and(f) about 4 mg to about 7 mg colloidal silicon dioxide.

[0052] In some embodiments, the homogeneous mixture consists essentially of(a) about 400 mg dexpramipexole dihydrochloride monohydrate;(b) about 333 mg sodium carboxymethylcellulose;(c) about 143 mg crosslinked acrylic acid polymer;(d) about 236 mg microcrystalline cellulose or silicified microcrystalline cellulose;(e) about 8 mg magnesium stearate; and(f) about 6 mg colloidal silicon dioxide.

[0053] In some embodiments, the homogeneous mixture consists essentially of:(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 110 mg to about 120 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose;(c) about 310 mg to about 320 mg microcrystalline cellulose or silicified microcrystalline cellulose;(d) about 3 mg to about 5 mg magnesium stearate; and(e) about 3 mg to about 5 mg colloidal silicon dioxide.

[0054] In some embodiments, the homogeneous mixture consists essentially of:(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 113 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose;(c) about 313 mg microcrystalline cellulose or silicified microcrystalline cellulose;(d) about 4 mg magnesium stearate; and(e) about 4 mg colloidal silicon dioxide.

[0055] In some embodiments, the homogeneous mixture consists essentially of:(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 110 mg to about 120 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose;(c) about 305 mg to about 315 mg silicified microcrystalline cellulose;(d) about 5 mg to about 7 mg magnesium stearate; and(e) about 3 mg to about 5 mg colloidal silicon dioxide.

[0056] In some embodiments, the homogeneous mixture consists essentially of:(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 113 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose;(c) about 310 mg silicified microcrystalline cellulose;(d) about 6 mg magnesium stearate; and(e) about 4 mg colloidal silicon dioxide.

[0057] In some embodiments, the homogeneous mixture consists essentially of:(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 110 mg to about 120 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose;(c) about 305 mg to about 315 mg microcrystalline cellulose;(d) about 5 mg to about 7 mg magnesium stearate; and(e) about 3 mg to about 5 mg colloidal silicon dioxide.

[0058] In some embodiments, the homogeneous mixture consists essentially of:(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 113 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose;(c) about 310 mg microcrystalline cellulose;(d) about 6 mg magnesium stearate; and(e) about 4 mg colloidal silicon dioxide.

[0059] In some embodiments, the homogeneous mixture consists essentially of(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 200 mg to about 220 mg sodium carboxymethylcellulose;(c) about 210 mg to about 220 mg microcrystalline cellulose or silicified microcrystalline cellulose;(d) about 3 mg to about 5 mg magnesium stearate; and(e) about 3 mg to about 5 mg colloidal silicon dioxide.

[0060] In some embodiments, the homogeneous mixture consists essentially of(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 210 mg sodium carboxymethylcellulose;(c) about 214 mg microcrystalline cellulose or silicified microcrystalline cellulose;(d) about 4 mg magnesium stearate; and(e) about 4 mg colloidal silicon dioxide.

[0061] In some embodiments, the composition further comprises a film coating surrounding the tablet core. In some embodiments, the film coating comprises polyvinyl alcohol. In some embodiments, the film coating further comprises titanium dioxide, polyethylene glycol and talc.

[0062] In some embodiments, the weight of the tablet is about 1300 mg or less. In some embodiments, the weight of the tablet is about 1159 mg. In some embodiments, the weight of the tablet is about 1000 mg or less. In some embodiments, the weight of the tablet is about 927 mg. In some embodiments, the weight of the tablet is about 850 mg toabout 950 mg. In some embodiments, the weight of the tablet is about 850 mg to about 900 mg. In some embodiments, the weight of the tablet is about 900 mg to about 950 mg. In some embodiments, the weight of the tablet is about 750 mg to about 900 mg. In some embodiments, the weight of the tablet is about 876 mg. In some embodiments, the weight of the tablet is about 773 mg.

[0063] In some embodiments, the tablet is a capsule shaped tablet. In some embodiments, the tablet is an oval shaped tablet. In some embodiments, the length of the short axis of the tablet is about 7.5 mm to about 9.5 mm, the length of the long axis of the tablet is about 18 mm to about 20 mm, and the thickness of the tablet is about 5 mm to about 7 mm.

[0064] In some embodiments, about 40% to about 80% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 12 hours of incubation of the tablet in about 900 mL of 50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm.

[0065] In some embodiments, dexpramipexole, or the pharmaceutically acceptable salt thereof, has a chiral purity for dexpramipexole, or the pharmaceutically salt thereof, of 99.96% or more. In some embodiments, the composition comprises 0.02% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. In some embodiments, the composition comprises 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet.(0066] It was further shown that the tablets according to the present disclosure (comprising one or more anionic polymers at the amounts specified herein) can be prepared by different production processes (including direct compression; wet granulation, in particular high shear wet granulation; and roller compaction) and at different scales without affecting the general advantageous properties (such as the beneficial in vitro dissolution profiles) of the tablets (see in particular Example 4).

[0067] However, although the in vitro dissolution profiles were similar, independent of how the matrix tablets with the one or more anionic polymers were manufactured, a manufacturing method comprising preparing densified granules (such as by dry or wet granulation) was shown to be a particular beneficial manufacturing method for the matrix tablets of the present disclosure (see in particular Examples 4 and 5).

[0068] Thus, the present disclosure is further directed to methods of manufacturing the pharmaceutical compositions comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, of the present disclosure. In some aspects, the present disclosure provides a method of manufacturing a sustained release pharmaceutical composition in the form of an orally deliverable tablet comprising a tablet core with dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more anionic polymers; preparing densified granules from the pre-blend; preparing a blend by mixing the densified granules with a glidant and a lubricant; and compressing the blend into a tablet core; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the blend and the one or more anionic polymers constitute about 30% to about 55% by weight of the blend.

[0069] In some aspects, the present disclosure provides a method of manufacturing a sustained release pharmaceutical composition in the form of an orally deliverable tablet comprising a tablet core with dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers; preparing densified granules from the pre-blend; preparing a final blend by mixing the densified granules with a glidant and a lubricant; and compressing the blend into a tablet core; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 50% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules and the one or more polymers constitute about 5% to about 60% by weight of the densified granules.

[0070] In some aspects, the present disclosure provides a method of manufacturing a sustained release pharmaceutical composition in the form of an orally deliverable tabletcomprising a tablet core with dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers; preparing a final blend by mixing the pre-blend with a glidant and a lubricant; and compressing the blend into a tablet core; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 50% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules and the one or more polymers constitute about 5% to about 60% by weight of the densified granules.

[0071] In some embodiments, the pre-blend further comprises additional excipients. In some embodiments, the pre-blend further comprises a microcrystalline cellulose, magnesium stearate, or a combination thereof. In some embodiments, the pre-blend further comprises a microcrystalline cellulose and magnesium stearate. In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

[0072] In some embodiments, the final blend further comprises additional excipients. In some embodiments, the final further comprises a microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide, or any combination thereof. In some embodiments, the final further comprises a microcrystalline cellulose, magnesium stearate and colloidal silicon dioxide. In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

[0073] In some embodiments, the one or more polymers are anionic polymers. In some embodiments, the one or more anionic polymers constitute about 20% to about 55% by weight of the blend. In some embodiments, the one or more neutral polymers constitute about 5% to about 25% by weight of the blend.

[0074] In some embodiments, the pre-blend comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and no more than one anionic polymer. In some embodiments, the anionic polymer constitutes about 20% to about 55% by weight of the blend.

[0075] In some embodiments, the pre-blend comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and no more than one neutral polymer. In some embodiments, the anionic polymer constitutes about 5% to about 25% by weight of the blend.

[0076] In some embodiments, the pre-blend comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and does not comprise an anionic polymer. In some embodiments, the pre-blend comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and does not comprise a neutral polymer.

[0077] In some embodiments, the method further comprises coating the tablet core with a film coating. In some embodiments, the film coating comprises polyvinyl alcohol. In some embodiments, the film coating further comprises titanium dioxide, polyethylene glycol and talc.

[0078] In some embodiments, the glidant is colloidal silicon dioxide and the lubricant is magnesium stearate.

[0079] In some embodiments, the one or more anionic polymers constitute about 35% to about 50% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 38% to about 42% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 40% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 45% to about 49% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 47% by weight of the blend.

[0080] In some embodiments, the one or more anionic polymers constitute about 25% to about 50% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 28% to about 48% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 28% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 40% to about 48% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 48% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 43% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 40% by weight of the blend.

[0081] In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose, an acrylic acid polymer, a methacrylic acid polymer, a methacrylic acid copolymer, alignate, carrageenan, xanthan gum, or arabic gum. In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose and an acrylic acid polymer. In some embodiments, carboxymethylcellulose is sodium carboxymethylcellulose. In some embodiments, theacrylic acid polymer is a crosslinked acrylic acid polymer. In some embodiments, the preblend comprises a first anionic polymer and a second anionic polymer and wherein the first anionic polymer is carboxymethylcellulose and the second anionic polymer is an acrylic acid polymer. In some embodiments, the acrylic acid polymer is a crosslinked acrylic acid polymer. In some embodiments, carboxymethylcellulose is sodium carboxymethylcellulose.

[0082] In some embodiments, carboxymethylcellulose constitutes about 27% to about 34% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 11% to about 15% by weight of the blend. In some embodiments, carboxymethylcellulose constitutes about 30% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 13% by weight of the blend. In some embodiments, carboxymethylcellulose constitutes about 27% to about 29% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 11% to about 13% by weight of the blend. In some embodiments, carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 12% by weight of the blend. In some embodiments, carboxymethylcellulose constitutes about 32% to about 34% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 13% to about 15% by weight of the blend. In some embodiments, carboxymethylcellulose constitutes about 33% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 14% by weight of the blend.

[0083] In some embodiments, the pre-blend comprises no more than one anionic polymer and wherein the anionic polymer is carboxymethylcellulose. In some emdodiments, the carboxymethylcellulose is sodium carboxymethylcellulose. In some embodiments, the carboxymethylcellulose constitutes about 27% to about 29% of sodium carboxymethylcellulose equivalent by weight of the densified granules. In some embodiments, the carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the densified granules.

[0084] In some embodiments, the pre-blend comprises one or more neutral polymers. In some embodiments, the one or more neutrals polymer are hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose. In some embodiments, the one or moreneutral polymers constitute about 5% to about 25% by weight of the blend. In some embodiments, the one or more neutral polymers constitute about 15% by weight of the blend. In some embodiments, the pre-blend comprises no more than one neutral polymer. In some embodiments, the neutral polymer is hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose. In some embodiments, the neutral polymer constitutes about 5% to about 25% by weight of the blend. In some embodiments, the neutral polymer constitutes about 15% by weight of the blend.

[0085] In some embodiments, the densified granules constitute about 99% by weight of the blend. In some embodiments, the glidant constitutes about 0.5% by weight of the blend and the lubricant constitutes about 0.5% by weight of the blend.

[0086] In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is a methane sulfonic acid salt, sulfuric acid salt, tartaric acid salt, p-toluene sulfonic acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, malic acid salt, citric acid salt, succinic acid salt, or any combination thereof. In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride or a hydrate thereof. In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride monohydrate.

[0087] In some embodiments, the blend consists essentially of:(a) about 35% to about 40% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 25% to about 30% sodium carboxymethylcellulose by weight of the blend;(c) about 10% to about 15% crosslinked acrylic acid polymer by weight of the blend;(d) about 18% to about 23% silicified microcrystalline cellulose by weight of the blend;(e) about 0.5% to about 1.0% magnesium stearate by weight of the blend; and(f) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

[0088] In some embodiments, the blend consists essentially of:(a) about 38% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 28% sodium carboxymethylcellulose by weight of the blend;(c) about 12% crosslinked acrylic acid polymer by weight of the blend;(d) about 21% silicified microcrystalline cellulose by weight of the blend;(e) about 0.75% magnesium stearate by weight of the blend; and(f) about 0.5% colloidal silicon dioxide by weight of the blend.|0089| In some embodiments, the blend consists essentially of:(a) about 33% to about 38% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 30% to about 35% sodium carboxymethylcellulose by weight of the blend;(c) about 12% to about 17% crosslinked acrylic acid polymer by weight of the blend;(d) about 13% to about 18% silicified microcrystalline cellulose by weight of the blend;(e) about 0.5% to about 1.0% magnesium stearate by weight of the blend; and(f) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.|0090| In some embodiments, the blend consists essentially of:(a) about 35% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 33% sodium carboxymethylcellulose by weight of the blend;(c) about 14% crosslinked acrylic acid polymer by weight of the blend;(d) about 16% silicified microcrystalline cellulose by weight of the blend;(e) about 0.75% magnesium stearate by weight of the blend; and(f) about 0.5% colloidal silicon dioxide by weight of the blend.

[0091] In some embodiments, the blend consists essentially of:(a) about 33% to about 39% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 27% to about 33% sodium carboxymethylcellulose by weight of the blend;(c) about 10% to about 16% crosslinked acrylic acid polymer by weight of the blend;(d) about 18% to about 24% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(e) about 0.5% to about 1.0% magnesium stearate by weight of the blend; and(f) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

[0092] In some embodiments, the blend consists essentially of:(a) about 36% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 30% sodium carboxymethylcellulose by weight of the blend;(c) about 13% crosslinked acrylic acid polymer by weight of the blend;(d) about 21% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(e) about 0.75% magnesium stearate by weight of the blend; and(f) about 0.5% colloidal silicon dioxide by weight of the blend.

[0093] In some embodiments, the blend consists essentially of:(a) about 40% to about 46% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 10% to about 20% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend;(c) about 38% to about 46% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(d) about 0.25% to about 0.75% magnesium stearate by weight of the blend; and(e) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

[0094] In some embodiments, the blend consists essentially of:(a) about 43% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 15% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend;(c) about 42% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(d) about 0.5% magnesium stearate by weight of the blend; and(e) about 0.5% colloidal silicon dioxide by weight of the blend.

[0095] In some embodiments, the blend consists essentially of:(a) about 40% to about 46% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 10% to about 20% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend;(c) about 37% to about 45% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(d) about 0.5% to about 1.0% magnesium stearate by weight of the blend; and(e) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

[0096] In some embodiments, the blend consists essentially of:(a) about 43% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 15% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend;(c) about 41% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(d) about 0.75% magnesium stearate by weight of the blend; and(e) about 0.5% colloidal silicon dioxide by weight of the blend.

[0097] In some embodiments, the blend consists essentially of:(a) about 40% to about 46% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 10% to about 20% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend;(c) about 37% to about 45% microcrystalline cellulose by weight of the blend;(d) about 0.5% to about 1.0% magnesium stearate by weight of the blend; and(e) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.|0098| In some embodiments, the blend consists essentially of:(a) about 43% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 15% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend;(c) about 41% microcrystalline cellulose by weight of the blend;(d) about 0.75% magnesium stearate by weight of the blend; and(e) about 0.5% colloidal silicon dioxide by weight of the blend.(0099] In some embodiments, the blend consists essentially of:(a) about 40% to about 46% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 24% to about 32% sodium carboxymethylcellulose by weight of the blend;(c) about 25% to about 34% silicified microcrystalline cellulose by weight of the blend;(d) about 0.25% to about 0.75% magnesium stearate by weight of the blend; and(e) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

[0100] In some embodiments, the blend consists essentially of:(a) about 43% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 28% sodium carboxymethylcellulose by weight of the blend;(c) about 29% silicified microcrystalline cellulose by weight of the blend;(d) about 0.5% magnesium stearate by weight of the blend; and(e) about 0.5% colloidal silicon dioxide by weight of the blend.(0101] In some embodiments, preparing the blend comprises: mixing the densified granules with the glidant thereby providing a mixture of the densified granules and the glidant; andmixing the mixture of the densified granules and the glidant with the lubricant thereby providing the blend.

[0012] In some embodiments, preparing the pre-blend comprises: mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more anionic polymers and a microcrystalline cellulose thereby providing a mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more anionic polymers and the microcrystalline cellulose; and mixing the mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more anionic polymers and the microcrystalline cellulose with magnesium stearate thereby providing the pre-blend.

[0103] In some embodiments, preparing the pre-blend comprises: mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more polymers and a microcrystalline cellulose thereby providing a mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more anionic polymers and the microcrystalline cellulose; and mixing the mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more polymers and the microcrystalline cellulose with magnesium stearate thereby providing the pre-blend.101041 In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

[0105] In some embodiments, the pre-blend further comprises additional excipients. In some embodiments, the pre-blend further comprises a microcrystalline cellulose, magnesium stearate, or a combination thereof. In some embodiments, the pre-blend further comprises a microcrystalline cellulose and magnesium stearate. In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

[0106] In some embodiments, the pre-blend comprises an antioxidant. In some embodiments, the antioxidant is capable of acting as a nitrite scavenger. Non-limiting examples of nitrite scavengers include, but are not limitd to, ascorbic acid, L-cysteine, caffeic acid, cysteine HCL, methionine, tartaric acid, gallic acid, uric acid, and sodium sulphite. In some embodiments, the pre-blend comprises one nitrite scavenger. In another embodiment, the pre-blend comprises multiple nitrite scavengers. In some embodiments, the nitrite scavengers constitute about 0.1% to about 1.5% by weight of the tablet core. In some embodiments, the nitrite scavenger constitutes about 0.1% to about 1.0% by weightof the tablet core. In some embodiments, the nitrite scavenger constitutes about 0.1% to about 0.5% by weight of the tablet core. In some embodiments, the nitrite scavenger constitutes about 0.5% to about 1.5% by weight of the tablet core. In some embodiments, the nitrite scavenger constitutes about 1% to about 1.5% by weight of the tablet core. In some embodiments, the nitrite scavenger constitutes about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5% by weight of the tablet core.

[0107] In some embodiments, the densified granules are prepared by dry granulation. In some embodiments, the densified granules are prepared by roller compaction.

[0108] The sustained release pharmaceutical compositions comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, of the present disclosure are generally not limited to the form of orally deliverable tablets, but can be provided in alternative dosage forms to tablets, such as capsules.

[0109] The present disclosure thus further provides also methods of manufacturing intermediate products (such as densified granules and blends) of sustained release pharmaceutical compositions comprising dexpramipexole, or a pharmaceutically acceptable salt thereof (which pharmaceutical compositions might, for example, be in the form of orally deliverable tablets or alternative dosage forms than tablets, such as capsules).

[0110] Thus, in some aspects, the present disclosure is also directed to a method of manufacturing densified granules for preparing a sustained release pharmaceutical composition comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more anionic polymers; and preparing densified granules from the pre-blend; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules and the one or more anionic polymers constitute about 30% to about 55% by weight of the densified granules.101 1 1 1 In some aspects, the present disclosure is also directed to a method of manufacturing densified granules for preparing a sustained release pharmaceuticalcomposition comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers; and preparing densified granules from the pre-blend; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 50% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules and the one or more polymers constitute about 5% to about 60% by weight of the densified granules.|01121 In some aspects, the present disclosure is also directed to a method of manufacturing densified granules for preparing a sustained release pharmaceutical composition comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 50% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules and the one or more polymers constitute about 5% to about 60% by weight of the densified granules.[0113| In some embodiments, the pre-blend further comprises additional excipients. In some embodiments, the pre-blend further comprises a microcrystalline cellulose, magnesium stearate, or a combination thereof. In some embodiments, the pre-blend further comprises a microcrystalline cellulose and magnesium stearate. In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

[0114] In some embodiments, dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 35% to about 44% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules. In some embodiments, dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 35% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules.

[0115] In some embodiments, the one or more polymers are anionic polymers. In some embodiments, the one or more anionic polymers constitute about 20% to about 55% by weight of the densified granules.

[0116] In some embodiments, the one or more anionic polymers constitute about 25% to about 50% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 28% to about 48% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 28% by weight of the densified granules.

[0117] In some embodiments, the one or more anionic polymers constitute about 35% to about 50% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 40% to about 48% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 38% to about 42% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 46% to about 50% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 48% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 43% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 40% by weight of the densified granules.

[0118] In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose, an acrylic acid polymer, a methacrylic acid polymer, a methacrylic acid copolymer, alignate, carrageenan, xanthan gum, or arabic gum. In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose and an acrylic acid polymer. In some embodiments, carboxymethylcellulose is sodium carboxymethylcellulose. In some embodiments, the acrylic acid polymer is a crosslinked acrylic acid polymer.

[0119] In some embodiments, the pre-blend comprises a first anionic polymer and a second anionic polymer and wherein the first anionic polymer is carboxymethylcellulose and the second anionic polymer is an acrylic acid polymer. In some embodiments, the acrylic acid polymer is a crosslinked acrylic acid polymer. In some embodiments, carboxymethylcellulose is sodium carboxymethylcellulose. .In some embodiments, carboxymethylcellulose constitutes about 27% to about 34% of sodium carboxymethylcellulose equivalent by weight of the densified granules and the acrylic acid polymer constitutes about 11% to about 15% by weight of the densified granules. In some embodiments, carboxymethylcellulose constitutes about 30% of sodium carboxymethylcellulose equivalent by weight of the densified granules and the acrylic acid polymer constitutes about 13% by weight of the densified granules. In someembodiments, carboxymethylcellulose constitutes about 27% to about 29% of sodium carboxymethylcellulose equivalent by weight of the densified granules and the acrylic acid polymer constitutes about 11% to about 13% by weight of the densified granules. In some embodiments, carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the densified granules and the acrylic acid polymer constitutes about 12% by weight of the densified granules. In some embodiments, carboxymethylcellulose constitutes about 32% to about 34% of sodium carboxymethylcellulose equivalent by weight of the densified granules and the acrylic acid polymer constitutes about 13% to about 15% by weight of the densified granules. In some embodiments, carboxymethylcellulose constitutes about 33% of sodium carboxymethylcellulose equivalent by weight of the densified granules and the acrylic acid polymer constitutes about 14% by weight of the densified granules.

[0120] In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is a methane sulfonic acid salt, sulfuric acid salt, tartaric acid salt, p-toluene sulfonic acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, malic acid salt, citric acid salt, succinic acid salt, or any combination thereof. In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride or a hydrate thereof. In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride monohydrate.[01211 In some embodiments, the pre-blend comprises one anionic polymer and wherein the anionic polymer is carboxymethylcellulose. In some emdodiments, the carboxymethylcellulose is sodium carboxymethylcellulose. In some embodiments, the carboxymethylcellulose constitutes about 27% to about 29% of sodium carboxymethylcellulose equivalent by weight of the densified granules. In some embodiments, the carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the densified granules.

[0122] In some embodiments, the one or more polymers are neutral polymers. In some embodiments, the one or more neutrals polymers is hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose. In some embodiments, the one or more neutral polymers is hydroxypropyl methylcellulose. In some embodiments, the one or more neutral polymers is silicified hydroxypropyl methylcellulose. In some embodiments, the one or more neutral polymers constitute about 5% to about 25% by weight of thedensified granules. In some embodiments, the one or more neutral polymers constitute about 15% by weight of the densified granules.

[0123] In some embodiments, the pre-blend comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and does not comprise an anionic polymer. In some embodiments, the pre-blend comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and does not comprise a neutral polymer.

[0124] In some embodiments, preparing the pre-blend comprises: mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more anionic polymers and a microcrystalline cellulose thereby providing a mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more anionic polymers and the microcrystalline cellulose; and mixing the mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more anionic polymers and the microcrystalline cellulose with magnesium stearate thereby providing the pre-blend.

[0125] In some embodiments, preparing the pre-blend comprises: mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more polymers and a microcrystalline cellulose thereby providing a mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more polymers and the microcrystalline cellulose; and mixing the mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more polymers and the microcrystalline cellulose with magnesium stearate thereby providing the pre-blend.

[0126] In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

[0127] In some embodiments, the pre-blend further comprises additional excipients. In some embodiments, the pre-blend further comprises a microcrystalline cellulose, magnesium stearate, or a combination thereof. In some embodiments, the pre-blend further comprises a microcrystalline cellulose and magnesium stearate. In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

[0128] In some embodiments, the densified granules are prepared by dry granulation. In some embodiments, the densified granules are prepared by roller compaction.

[0129] In some aspects, the present disclosure is further also directed to a method of manufacturing a blend for preparing a sustained release pharmaceutical compositioncomprising dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more anionic polymers; preparing densified granules from the pre-blend; and preparing a blend by mixing the densified granules with a glidant and a lubricant; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the blend and the one or more anionic polymers constitute about 30% to about 55% by weight of the blend.

[0130] In some aspects, the present disclosure is further also directed to a method of manufacturing a blend for preparing a sustained release pharmaceutical composition comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers; preparing densified granules from the pre-blend; and preparing a final blend by mixing the densified granules with a glidant and a lubricant; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 50% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the blend and the one or more polymers constitute about 5% to about 60% by weight of the blend.

[0131] In some aspects, the present disclosure is further also directed to a method of manufacturing a blend for preparing a sustained release pharmaceutical composition comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers; and preparing a final blend by mixing the pre-blend with a glidant and a lubricant; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 50% of dexpramipexole dihydrochloride monohydrateequivalent by weight of the blend and the one or more polymers constitute about 5% to about 60% by weight of the blend.

[0132] In some embodiments, the pre-blend further comprises additional excipients. In some embodiments, the final blend further comprises additional excipients.101331 In some embodiments, the glidant is colloidal silicon dioxide and the lubricant is magnesium stearate.

[0134] In some embodiments, the one or more polymers are anionic polymers. In some embodiments, the one or more anionic polymers constitute about 20% to about 55% by weight of the densified granules.10135 [ In some embodiments, the one or more polymers are neutral polymers. In some embodiments, the one or more polymers are hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose. In some embodiments, the one or more neutral polymers is hydroxypropyl methylcellulose. In some embodiments, the one or more neutral polymers is silicified hydroxypropyl methylcellulose. In some embodiments, the one or more neutral polymers constitute about 5% to about 25% by weight of the blend.

[0136] In some embodiments, the one or more anionic polymers constitute about 35% to about 50% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 38% to about 42% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 40% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 45% to about 49% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 47% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 43% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 40% by weight of the blend. In some embodiments, the one or more anionic polymers constitute about 28% by weight of the blend.

[0137] In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose, an acrylic acid polymer, a methacrylic acid polymer, a methacrylic acid copolymer, alignate, carrageenan, xanthan gum, or arabic gum. In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose and an acrylic acid polymer. In some embodiments, carboxymethylcellulose is sodium carboxymethylcellulose. In some embodiments, the acrylic acid polymer is a crosslinked acrylic acid polymer. In some embodiments, the pre-blend comprises a first anionic polymer and a second anionic polymer and wherein the first anionic polymer is carboxymethylcellulose and the second anionic polymer is an acrylic acid polymer. In some embodiments, the acrylic acid polymer is a crosslinked acrylic acid polymer. In some embodiments, carboxymethylcellulose is sodium carboxymethylcellulose.

[0138] In some embodiments, carboxymethylcellulose constitutes about 27% to about 34% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 11% to about 15% by weight of the blend. In some embodiments, carboxymethylcellulose constitutes about 30% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 13% by weight of the blend. In some embodiments, carboxymethylcellulose constitutes about 27% to about 29% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 11% to about 13% by weight of the blend. In some embodiments, carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 12% by weight of the blend. In some embodiments, carboxymethylcellulose constitutes about 32% to about 34% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 13% to about 15% by weight of the blend. In some embodiments, carboxymethylcellulose constitutes about 33% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 14% by weight of the blend.

[0139] In some embodiments, the densified granules constitute about 99% by weight of the blend. In some embodiments, the glidant constitutes about 0.5% by weight of the blend and the lubricant constitutes about 0.5% by weight of the blend.

[0140] In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is a methane sulfonic acid salt, sulfuric acid salt, tartaric acid salt, p-toluene sulfonic acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, malic acid salt, citric acid salt, succinic acid salt, or any combination thereof. In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride or a hydrate thereof. In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride monohydrate.

[0141] In some embodiments, the blend consists essentially of(a) about 35% to about 40% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 25% to about 30% sodium carboxymethylcellulose by weight of the blend;(c) about 10% to about 15% crosslinked acrylic acid polymer by weight of the blend;(d) about 18% to about 23% silicified microcrystalline cellulose by weight of the blend;(e) about 0.5% to about 1.0% magnesium stearate by weight of the blend; and(f) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

[0142] In some embodiments, the blend consists essentially of:(a) about 38% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 28% sodium carboxymethylcellulose by weight of the blend;(c) about 12% crosslinked acrylic acid polymer by weight of the blend;(d) about 21% silicified microcrystalline cellulose by weight of the blend;(e) about 0.75% magnesium stearate by weight of the blend; and(f) about 0.5% colloidal silicon dioxide by weight of the blend.

[0143] In some embodiments, the blend consists essentially of:(a) about 33% to about 38% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 30% to about 35% sodium carboxymethylcellulose by weight of the blend;(c) about 12% to about 17% crosslinked acrylic acid polymer by weight of the blend;(d) about 13% to about 18% silicified microcrystalline cellulose by weight of the blend;(e) about 0.5% to about 1.0% magnesium stearate by weight of the blend; and(f) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

[0144] In some embodiments, the blend consists essentially of:(a) about 35% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 33% sodium carboxymethylcellulose by weight of the blend;(c) about 14% crosslinked acrylic acid polymer by weight of the blend;(d) about 16% silicified microcrystalline cellulose by weight of the blend;(e) about 0.75% magnesium stearate by weight of the blend; and(f) about 0.5% colloidal silicon dioxide by weight of the blend.|0145| In some embodiments, the blend consists essentially of:(a) about 33% to about 39% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 27% to about 33% sodium carboxymethylcellulose by weight of the blend;(c) about 10% to about 16% crosslinked acrylic acid polymer by weight of the blend;(d) about 18% to about 24% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(e) about 0.5% to about 1.0% magnesium stearate by weight of the blend; and(f) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

[0146] In some embodiments, the blend consists essentially of:(a) about 36% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 30% sodium carboxymethylcellulose by weight of the blend;(c) about 13% crosslinked acrylic acid polymer by weight of the blend;(d) about 21% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(e) about 0.75% magnesium stearate by weight of the blend; and(f) about 0.5% colloidal silicon dioxide by weight of the blend.

[0147] In some embodiments, the blend consists essentially of:(a) about 40% to about 46% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 10% to about 20% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend;(c) about 38% to about 46% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(d) about 0.25% to about 0.75% magnesium stearate by weight of the blend; and(e) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

[0148] In some embodiments, the blend consists essentially of:(a) about 43% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 15% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend;(c) about 42% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(d) about 0.5% magnesium stearate by weight of the blend; and(e) about 0.5% colloidal silicon dioxide by weight of the blend.

[0149] In some embodiments, the blend consists essentially of:(a) about 40% to about 46% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 10% to about 20% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend;(c) about 37% to about 45% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(d) about 0.5% to about 1.0% magnesium stearate by weight of the blend; and(e) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

[0150] In some embodiments, the blend consists essentially of:(a) about 43% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 15% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend;(c) about 41% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(d) about 0.75% magnesium stearate by weight of the blend; and(e) about 0.5% colloidal silicon dioxide by weight of the blend.

[0151] In some embodiments, the blend consists essentially of:(a) about 40% to about 46% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 10% to about 20% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend;(c) about 37% to about 45% microcrystalline cellulose by weight of the blend;(d) about 0.5% to about 1.0% magnesium stearate by weight of the blend; and(e) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

[0152] In some embodiments, the blend consists essentially of:(a) about 43% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 15% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend;(c) about 41% microcrystalline cellulose by weight of the blend;(d) about 0.75% magnesium stearate by weight of the blend; and(e) about 0.5% colloidal silicon dioxide by weight of the blend.

[0153] In some embodiments, the blend consists essentially of:(a) about 40% to about 46% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 24% to about 32% sodium carboxymethylcellulose by weight of the blend;(c) about 25% to about 34% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(d) about 0.25% to about 0.75% magnesium stearate by weight of the blend; and(e) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

[0154] In some embodiments, the blend consists essentially of:(a) about 43% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 28% sodium carboxymethylcellulose by weight of the blend;(c) about 29% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the blend;(d) about 0.5% magnesium stearate by weight of the blend; and(e) about 0.5% colloidal silicon dioxide by weight of the blend.

[0155] In some embodiments, preparing the blend comprises: mixing the densified granules with the glidant thereby providing a mixture of the densified granules and the glidant; and mixing the mixture of the densified granules and the glidant with the lubricant thereby providing the blend.

[0156] In some embodiments, preparing the pre-blend comprises: mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more anionic polymers and a microcrystalline cellulose thereby providing a mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more anionic polymers and the microcrystalline cellulose; and mixing the mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more anionic polymers and the microcrystalline cellulose with magnesium stearate thereby providing the pre-blend.[0.157] In some embodiments, preparing the pre-blend comprises: mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more polymers and a microcrystalline cellulose thereby providing a mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more anionic polymers and the microcrystalline cellulose; andmixing the mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more polymers and the microcrystalline cellulose with magnesium stearate thereby providing the pre-blend.

[0158] In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

[0159] In some embodiments, the pre-blend further comprises a microcrystalline cellulose, magnesium stearate, or a combination thereof. In some embodiments, the preblend further comprises a microcrystalline cellulose and magnesium stearate. In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

[0160] In some embodiments, the densified granules are prepared by dry granulation. In some embodiments, the densified granules are prepared by roller compaction.

[0161] In the context of the methods of manufacturing provided herein, preparing the densified granules by roller compaction was shown to be particular robust as it minimized the variability amongst different manufacturing batches and showed minimal formulation sensitivity (see in particular Examples 4 and 5).

[0162] As outlined above and demonstrated in the Examples with regards to orally deliverable tablets, an amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, typically used (such as about 300 mg or about 376 mg dexpramipexole dihydrochloride equivalent) can be delivered in a sustained release pharmaceutical composition suitable for once daily oral administration to a human when mixed with one or more anionic polymers at the amounts specified herein.(0163] Thus, in some aspects, the present disclosure is also directed to a mixture comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, constituting about 30% to about 40% of dexpramipexole hydrochloride monohydrate equivalent by weight of the mixture and about 30% to about 55% of one or more anionic polymers by weight of the mixture. In some aspects, the present disclosure is also directed to a mixture comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, constituting about 30% to about 50% of dexpramipexole hydrochloride monohydrate equivalent by weight of the mixture.

[0164] In some embodiments, the one or more polymers are anionic polymers.

[0165] In some embodiments, the one or more anionic polymers constitute about 35% to about 50% by weight of the mixture. In some embodiments, the one or more anionic polymers constitute about 38% to about 42% by weight of the mixture. In someembodiments, the one or more anionic polymers constitute about 40% by weight of the mixture. In some embodiments, the one or more anionic polymers constitute about 45% to about 49% by weight of the mixture. In some embodiments, the one or more anionic polymers constitute about 47% by weight of the mixture.10166] In some embodiments, the one or more anionic polymers constitute about 20% to about 55% by weight of the mixture. In some embodiments, the one or more anionic polymers constitute about 28% to about 48% by weight of the mixture. In some embodiments, the one or more anionic polymers constitute about 28% by weight of the mixture. In some embodiments, the one or more anionic polymers constitute about 40% to about 48% by weight of the mixture. In some embodiments, the one or more anionic polymers constitute about 40% by weight of the mixture. In some embodiments, the one or more anionic polymers constitute about 43% by weight of the mixture. In some embodiments, the one or more anionic polymers constitute about 48% by weight of the mixture.

[0167] In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is a methane sulfonic acid salt, sulfuric acid salt, tartaric acid salt, p-toluene sulfonic acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, malic acid salt, citric acid salt, succinic acid salt, or any combination thereof. In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride or a hydrate thereof. In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride monohydrate.(0168] In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose, an acrylic acid polymer, a methacrylic acid polymer, a methacrylic acid copolymer, alignate, carrageenan, xanthan gum, or arabic gum. In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose and an acrylic acid polymer. In some embodiments, carboxymethylcellulose is sodium carboxymethylcellulose. In some embodiments, the acrylic acid polymer is a crosslinked acrylic acid polymer.

[0169] In some embodiments, the mixture comprises a first anionic polymer and a second anionic polymer, wherein the first anionic polymer is carboxymethylcellulose and the second anionic polymer is an acrylic acid polymer. In some embodiments, the acrylic acid polymer is a crosslinked acrylic acid polymer. In some embodiments, carboxymethylcellulose is sodium carboxymethylcellulose.101701 In some embodiments, carboxymethylcellulose constitutes about 27% to about34% of sodium carboxymethylcellulose equivalent by weight of the mixture and the acrylic acid polymer constitutes about 11% to about 15% by weight of the mixture. In some embodiments, carboxymethylcellulose constitutes about 30% of sodium carboxymethylcellulose equivalent by weight of the mixture and the acrylic acid polymer constitutes about 13% by weight of the mixture. In some embodiments, carboxymethylcellulose constitutes about 27% to about 29% of sodium carboxymethylcellulose equivalent by weight of the mixture and the acrylic acid polymer constitutes about 11% to about 13% by weight of the mixture. In some embodiments, carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the mixture and the acrylic acid polymer constitutes about 12% by weight of the mixture. In some embodiments, carboxymethylcellulose constitutes about 32% to about 34% of sodium carboxymethylcellulose equivalent by weight of the mixture and the acrylic acid polymer constitutes about 13% to about 15% by weight of the mixture. In some embodiments, carboxymethylcellulose constitutes about 33% of sodium carboxymethylcellulose equivalent by weight of the mixture and the acrylic acid polymer constitutes about 14% by weight of the mixture.

[0171] In some embodiments, the mixture comprises one anionic polymer and wherein the anionic polymer is carboxymethylcellulose. In some emdodiments, the carboxymethylcellulose is sodium carboxymethylcellulose. In some embodiments, the carboxymethylcellulose constitutes about 27% to about 29% of sodium carboxymethylcellulose equivalent by weight of the densified granules. In some embodiments, the carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the densified granules.[0172| In some embodiments, the one or more polymers are neutral polymers. In some embodiments, the one or more neutral polymers are hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose. In some embodiments, the one or more neutral polymers is hydroxypropyl methylcellulose. In some embodiments, the one or more neutral polymers is silicified hydroxypropyl methylcellulose. In some embodiments, the one or more neutral polymers constitute about 5% to about 25% by weight of the densified granules. In some embodiments, the one or more neutral polymers constitute about 15% by weight of the densified granules.101.731 In some embodiments, the mixture comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and does not comprise an anionic polymer. In some embodiments, the mixture comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, and does not comprise a neutral polymer.10.1741 In some embodiments, the mixture consists essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, and two anionic polymers.

[0175] In some embodiments, the mixture consists essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one anionic polymer.|0.l 76] In some embodiments, the mixture consists essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one neutral polymer.

[0177] In some embodiments, the mixture further comprises additional excipients. In some embodiments, the mixture further comprises a microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide, or any combination thereof.] 0178] In some embodiments, dexpramipexole, or the pharmaceutically acceptable salt thereof, has a chiral purity for dexpramipexole, or the pharmaceutically salt thereof, of 99.96% or more. In some embodiments, the mixture comprises 0.02% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the mixture. In some embodiments, the mixture comprises 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the mixture.

[0179] The mixture of the present disclosure can be formulated into sustained release pharmaceutical compositions that is suitable for once daily oral administration to a human. Such sustained release pharmaceutical compositions comprising the mixture of the present disclosure can be, for example, in the form of orally deliverable capsules or orally deliverable tablets.

[0180] Thus, in some aspects, the present disclosure is further directed to a sustained release pharmaceutical composition comprising the mixture as described herein.

[0181] In some embodiments, the pharmaceutical composition comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg to about 500 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the pharmaceutical composition comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg to about 400 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 75 mg to about300 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 75 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 150 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 300 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 376 mg of dexpramipexole dihydrochloride equivalent.

[0182] In some embodiments, the weight of the composition is about 1500 mg or less. In some embodiments, the weight of the composition is about 1300 mg or less. In some embodiments, the weight of the composition is about 1000 mg or less.

[0183] In some embodiments, the composition is an orally deliverable capsule. In some embodiments, the capsule comprises the mixture enclosed in one or more beads.

[0184] In some embodiments, the composition is an orally deliverable tablet.]0185[ Further, the present disclosure provides methods of treating or preventing certain diseases in a human subject in need thereof, the methods comprising orally administering to the human subject the pharmaceutical compositions as described herein. As dexpramipexole lowers eosinophil counts in vivo, the pharmaceutical compositions as described herein can generally be applied for treating or preventing eosinophilic disorders in humans. Non-limiting examples of diseases that can be treated or prevented with the pharmaceutical compositions as described herein are asthma and chronic obstructive pulmonary disease (COPD).

[0186] Examples 5.4 and 7 describe formulation and preparation of different exemplary matrix tablets according to the present disclosure comprising anionic polymers at amounts specified herein (one providing for a comparably faster and the other providing for a comparably slower release of drug) for evaluation in clinical trials. Example 9 also describes formulation and preparation of different exemplary matrix tablets according to the present disclosure comprising one or more anionic polymers or a netural polymer at amounts specified herein for evaluation in clinical trials. The exemplary tablet for evaluation in clinical trials providing for faster release comprises a comparably lower amount of anionic polymers, whereas the exemplary tablet for evaluation in clinical trials providing for slower release comprises a comparably higher amount of anionic polymers.A Phase I clinical trial for evaluation of the exemplary matrix tablets is conducted (see Example 8).

[0187] In some aspects, the present disclosure is further directed to a method of treating or preventing asthma in a human subject in need thereof, the method comprising orally administering to the human subject the composition as described herein. In some embodiments, the asthma is eosinophilic asthma.

[0188] In some aspects, the present disclosure is further directed to a method of treating or preventing chronic obstructive pulmonary disease in a human subject in need thereof, the method comprising orally administering to the human subject the composition as described herein.

[0189] In some aspects, the present disclosure is further directed to a method of treating or preventing an eosinophilic disorder in a human subject in need thereof, the method comprising orally administering to the human subject the composition as described herein. In some embodiments, the eosinophilic disorder is selected from the group consisting of hypereosinophilic syndrome, chronic rhinosinusitis with nasal polyps, nasal polyposis, atopic dermatitis, eosinophilic granulomatosis with polyangiitis, eosinophilic gastroenteritis, eosinophilic esophagitis, and any combination thereof.

[0190] In some embodiments, the composition is administered once daily.10191 J In some aspects, the present disclosure is also directed to the composition as described herein for use as a medicament. In some aspects, the present disclosure is also directed to the composition as described for use in a method of treating or preventing as described herein.

[0192] In some aspects, the present disclosure is also directed to the use of the composition as described herein in the manufacture of a medicament for a method of treating or preventing as described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0193] FIG. 1 In vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate and hydrophilic neutral polymers in 50 mM monobasic potassium phosphate buffer, pH 6.8 (P: Paddles at 50 rpm; B: Baskets at 100 rpm). HPMC = Hydroxypropyl methylcellulose, HPC = Hydroxypropyl cellulose.

[0194] FIG. 2 Impact of manufacturing process (direct compression, DC, vs. twin-screw wet-granulation, TSWG) on the in vitro dissolution profiles of sustained release matrixtablets comprising dexpramipexole dihydrochloride monohydrate and hydrophilic neutral polymers in 50 mM monobasic potassium phosphate buffer, pH 6.8 (P: Paddles at 50 rpm).

[0195] FIG. 3 In vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate and lipophilic materials manufactured using direct compression (DC) in 50 mM monobasic potassium phosphate buffer, pH 6.8 (P: Paddles at 50 rpm). HPC = Hydroxypropyl cellulose.

[0196] FIG. 4 Comparison of the effects of direct compression (DC) and melt granulation (Melt) manufacturing processes on the in vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate and lipophilic materials in 50 mM monobasic potassium phosphate buffer, pH 6.8 (P: Paddles at 50 rpm). HPC = Hydroxypropyl cellulose.

[0197] FIG. 5 Comparison of effects of the lipophilic materials glycerol dibehenate (Compritol 888 ATO) and carnuba wax on the in vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate manufactured using melt granulation (Melt) in 50 mM monobasic potassium phosphate buffer, pH 6.8 (P: Paddles at 50 rpm).

[0198] FIG. 6 Tablet shape and dimensions for tensile strength calculation (from Pitt, K.G. and Heasley M.G . Determination of the tensile strength of elongated tablets. Powder Technology 238 (2013) 169-175).

[0199] FIG. 7 Impact of the anionic polymer carbomer (Carbopol 97 IP) level on the in vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate in 50 mM monobasic potassium phosphate buffer, pH 6.8 (P: Paddles at 50 rpm).

[0200] FIG. 8 Impact of the total amount of anionic polymer at a fixed anionic polymer ratio of 3:2 carbomer: sodium carboxymethylcellulose (NaCMC) on the in vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate in 50 mM monobasic potassium phosphate buffer, pH 6.8 (B: Baskets at 100 rpm).

[0201] FIG. 9 Impact of the anionic polymer ratio of carbomer: sodium carboxymethylcellulose (NaCMC) at a fixed total anionic polymer amount of 40% (w / w) on the in vitro dissolution profiles of sustained release matrix tablets comprisingdexpramipexole dihydrochloride monohydrate in 50 mM monobasic potassium phosphate buffer, pH 6.8 (B: Baskets at 100 rpm).

[0202] FIG. 10 In vitro dissolution profiles of fast and slow prototypes of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate in 0.1 N HC1 (B: Baskets at 100 rpm). NaCMC = sodium carboxymethylcellulose.

[0203] FIG. 11 In vitro dissolution profiles of fast and slow prototypes of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate in Mcllvaine Buffer, pH 4.5 (B: Baskets at 100 rpm). NaCMC = sodium carboxymethylcellulose.

[0204] FIG. 12 In vitro dissolution profiles of fast and slow prototypes of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate in 50 mM monobasic potassium phosphate buffer, pH 6.8 (B: Baskets at 100 rpm). NaCMC = sodium carboxymethylcellulose.

[0205] FIG. 13 In vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate in 50 mM monobasic potassium phosphate buffer, pH 6.8 prepared at larger scale (1 kg blend) and with different processes (B: Baskets at 100 rpm). HSG = high sear wet-granulation, RC = roller compaction, NaCMC = sodium carboxymethylcellulose.

[0206] FIG. 14 Impact of type of manufacturing process and manufacturing scale on in vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate in 50 mM monobasic potassium phosphate buffer, pH 6.8 (B: Baskets at 100 rpm). HSG = high sear wet-granulation, DC = direct compression, RC = roller compaction, NaCMC = sodium carboxymethylcellulose; Feasibility scale = 12.75 g blend, and scale of RC and HSG = 1 kg blend).

[0207] FIG. 15 Particle diameter distribution (PSD) comparison of roller compacted batches.

[0208] FIG. 16 Compression study #1 - weight variation plot with roller compaction (RC) parameters of 2.5 kN, 0.8 mm mesh screen and 25 rpm press speed.

[0209] FIG. 17 Compression study #2 - weight variation plot with roller compaction (RC) parameters of 3.0 kN, 1.0 mm mesh screen and 20 rpm press speed.

[0210] FIG. 18 Evaluation of reproducibility between smaller (1 kg: R&D) and larger (10 kg; Eng batch) scale manufacturing. The graph shows the in vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloridemonohydrate in 50 mM monobasic potassium phosphate buffer, pH 6.8 (B: Baskets at 100 rpm).

[0211] FIG. 19 Effect of tablet hardness on in vitro dissolution. The graph shows the in vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate in 50 mM monobasic potassium phosphate buffer, pH 6.8 (B: Baskets at 100 rpm).

[0212] FIG. 20 Weight variation plot for engineering batches with 20 rpm press speed.

[0213] FIG. 21 Evaluation of reproducibility between smaller (R&D) and larger (Eng batch and GMP clinical batch) scale manufacturing. The graph shows the in vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate in 50 mM monobasic potassium phosphate buffer, pH 6.8 (B: Baskets at 100 rpm).

[0214] FIG. 22 Weight variation plot for clinical trial batches with 20 rpm press speed.

[0215] FIG. 23 Coated tablets of clinical trial batch 23JM-107 (fast prototype).

[0216] FIG. 24 In vitro dissolution profiles of sustained release matrix tablets (batches 030444-36 and 030444-38) comprising dexpramipexole dihydrochloride monohydrate in 50 mM monobasic potassium phosphate buffer, pH 6.8 (B: Baskets at 100 rpm).

[0217] FIG. 25 In vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate (batch 030444-36; fast prototype) in 50 mM monobasic potassium phosphate buffer, pH 6.8 (B: Baskets at 100 rpm). Dissolution profiles are shown for tablets after manufacturing (initial), after 1 month storage under CRT conditions (IM), and after 11 weeks storage under CRT conditions (11W).

[0218] FIG. 26 In vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole dihydrochloride monohydrate (batch 030444-38; slow prototype) in 50 mM monobasic potassium phosphate buffer, pH 6.8 (B: Baskets at 100 rpm). Dissolution profiles are shown for tablets after manufacturing (initial), after 1 month storage under CRT conditions (IM), and after 11 weeks storage under CRT conditions (11W).

[0219] FIG. 27 Schematic outline of Phase I Clinical Trial EXHALE-6.

[0220] FIG. 28 In vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole 280 mg (equivalent to 376 mg Dexpramipexole Dihydrochloride) in 0.1N HC1. The impact of total polymer level was evaluated. Polymers indicated in the legend include sodium carboxymethylcellulose and carbomer.

[0221] FIG. 29 In vitro dissolution profile of sustained release matrix tablet comprising dexpramipexole 223 mg (equivalent to 300 mg Dexpramipexole Dihydrochloride) in 0.1 N HC1.

[0222] FIG. 30 In vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole 223 mg (equivalent to 300 mg Dexpramipexole Dihydrochloride) in 0.1 N HC1. The impact of HPMC KI OOM level was evaluated.

[0223] FIG. 31 In vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole 223 mg (equivalent to 300 mg Dexpramipexole Dihydrochloride) in 0.1 N HC1. The impact of NaCMC 7HXF level was evaluated.

[0224] FIG. 32 In vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole 223 mg (equivalent to 300 mg Dexpramipexole Dihydrochloride) in 0.1 N HC1. The impact of NaCMC 7HXF level was evaluated.

[0225] FIG. 33 Process schematic chart of Dexpramipexole ER matrix 280 mg tablets (376 mg diHCl) confirmation batch lots 031466-17 and 031466-29.

[0226] FIG. 34 Weight variation plot with roller compaction (RC) at 40 rpm turret speed.

[0227] FIG. 35 Weight variation plot with roller compaction (RC) at 20 rpm turret speed.

[0228] FIG. 36 Coated tablets of Dexpramipexole ER matrix 280 mg tablets (376mg diHCl) confirmation batch, lot 031466-29.

[0229] FIG. 37 In vitro dissolution profiles of sustained release matrix tablets comprising dexpramipexole 280 mg (equivalent to 376 mg Dexpramipexole Dihydrochloride) in 0.1 N HC1 compared to ER2 clinical batch.

[0230] FIG. 38 Process schematic chart of Dexpramipexole ER matrix 223mg tablets (300mg diHCl) confirmation batch lots 031466-19 and 031466-24.

[0231] FIG. 39 Tabletability study of ER7H lot 031466-19.

[0232] FIG. 40 Weight variation plot of ER7H lot 031466-19.

[0233] FIG. 41 Tablet appearance of ER7H lot 031466-19.

[0234] FIG. 42 In vitro dissolution profiles of ER7H lots 031466-19A and 031466-19B.

[0235] FIG. 43 Tabletability study of ER7H lot 031466-24.

[0236] FIG. 44 Weight variation plot of ER7H lot 031466-24.

[0237] FIG. 45 Tablet appearance of ER7H lot 031466-24.|02381 FIG. 46 In vitro dissolution profiles of ER7H lot 031466-24 second confirmation batch.

[0239] FIG. 47 Tabletability study of the impact of HPMC grade.

[0240] FIG. 48 In vitro dissolution profiles of ER7H lots 031466-24, 031466-31, and031466-32 in 0.1 N HC1. The impact of HPMC grade was evaluated.

[0241] FIG. 49 Tabletability study of ER7H lot 031466-20.

[0242] FIG. 50 Weight variation plot of ER7H lot 031466-20.

[0243] FIG. 51 Tablet appearance of ER7H lot 031466-20.

[0244] FIG. 52 Weight variation plot of ER7H lot 031466-23.

[0245] FIG. 53 In vitro dissolution profiles of ER9 lot 031466-23.

[0246] FIG. 54 Particle size distribution of final blend from 2nd confirmation batch (withAPI co-mill process) vs. development batch (without API co-mill process).

[0247] FIG. 55 Tabletability study of ER9 lot 031466-26.

[0248] FIG. 56 Weight variation plot of ER7H lot 031466-26.

[0249] FIG. 57 Tablet appearance of ER7H lot 031466-26.

[0250] FIG. 58 In vitro dissolution profiles of ER9 lot 031466-26 confirmation batches.

[0251] FIG. 59 Process schematic chart of Dexpramipexole ER5 matrix 280mg tablets(376mg diHCI) Clinical Trial Material (CTM) batch.

[0252] FIG. 60 In-process tablet weight of Dexpramipexole ER5 matrix 280mg tablets (376mg diHCI) CTM batch.

[0253] FIG. 61 In-process tablet thickness of Dexpramipexole ER5 matrix 280mg tablets (376mg diHCI) CTM batch.

[0254] FIG. 62 In-process tablet hardness of Dexpramipexole ER5 matrix 280mg tablets (376mg diHCI) CTM batch.

[0255] FIG. 63 Tablet appearance of Dexpramipexole ER5 matrix 280mg tablets (376mg diHCI) CTM batch.

[0256] FIG. 64 In vitro dissolution profile of ER5 CTM batch.

[0257] FIG. 65 Process schematic chart of Dexpramipexole ER7H matrix 223mg tablets(300mg diHCI) CTM batch.]0258] FIG. 66 In-process tablet weight of Dexpramipexole ER7H matrix 223mg tablets (300mg diHCI) CTM batch.

[0259] FIG. 67 In-process tablet thickness of Dexpramipexole ER7H matrix 223mg tablets (300mg diHCI) CTM batch.102601 FIG. 68 In-process tablet hardness of Dexpramipexole ER7H matrix 223mg tablets (300mg diHCI) CTM batch.

[0261] FIG. 69 Tablet appearance of Dexpramipexole ER7H matrix 223mg tablets (300mg diHCI) CTM batch.

[0262] FIG. 70 In vitro dissolution profile of ER7H CTM batch.

[0263] FIG. 71 Process schematic chart of Dexpramipexole ER9 matrix 223mg tablets(300mg diHCI) CTM batch.

[0264] FIG. 72 In-process tablet weight of Dexpramipexole ER9 matrix 223mg tablets (300mg diHCI) CTM batch.

[0265] FIG. 73 In-process tablet thickness of Dexpramipexole ER9 matrix 223mg tablets (300mg diHCI) CTM batch.

[0266] FIG. 74 In-process tablet hardness of Dexpramipexole ER9 matrix 223mg tablets (300mg diHCI) CTM batch.

[0267] FIG. 75 Tablet appearance of Dexpramipexole ER9 matrix 223mg tablets (300mg diHCI) CTM batch.

[0268] FIG. 76 In vitro dissolution profile of ER9 CTM batch.

[0269] FIG. 77 Process schematic chart of lab scale batch using milled DexpramipexoleDihydrochloride Monohydrate.

[0270] FIG. 78 Tabletability study of (A) Lot 031466-33 milled- API and (B) Lot 031466-24 ER7H 2nd confirmation batch compressed at 20 rpm turret speed.

[0271] FIG. 79 In vitro dissolution profile of batch 031466-33 vs. ER7H CTM batch 24JM-083.

[0272] FIG. 80 Tabletability of Lot 031466-34 with 0.75% Magnesium Stearate and Lot 031466-34 with 0.50% Magnesium Stearate.

[0273] FIG. 81 In vitro dissolution profile of batch 031466-34 vs. ER7H CTM batch 24JM-083.DETAILED DESCRIPTION OF THE DISCLOSURE

[0274] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of conflict, the present application including the definitions will control. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. In general, the headings provided herein arenot to be understood as limiting the various aspects and embodiments of the present disclosure. All publications, patents and other references mentioned herein are incorporated by reference in their entireties for all purposes as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

[0275] Although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods and examples are illustrative only and are not intended to be limiting. Other features and advantages of the disclosure will be apparent from the detailed description and from the claims.I - Definitions

[0276] In the following, some definitions are provided to further define the present disclosure. Additional definitions may be found throughout the specification.

[0277] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. The terms “a” (or “an”), as well as the terms “one or more” and “at least one” can be used interchangeably herein. In certain aspects, the term “a” or “an” means “single.” In other aspects, the term “a” or “an” includes “two or more” or “multiple.”(0278] The term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term “about” is used in conjunction with a numerical value or range, it modifies that value or range by extending the boundaries above and below the numerical value(s) set forth by a variance of 10 percent, up or down (higher or lower). For example, within the meaning of the present disclosure, “about 50%” means in the range of 45%-55%, and “about 50% to about 60%” means in the range of 45%-66%. In addition, when the term “about” is used in conjunction with a “%” value, the recited value or range cannot exceed 100%. For example, within the meaning of the present disclosure, “about 99%” means in the range of 89.1%-100%.(0279] The term “and / or,” where used herein, is to be taken as specific disclosure of each of the specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B”, “A or B”, “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as“A, B, and / or C” is intended to encompass each of the following aspects: “A, B, and C”,“A, B, or C ”, “A or C ”, “A or B”, “B or C ”, “A and C ”, “A and B”, “B and C ”, “A” (alone), “B” (alone), and “C” (alone).

[0280] As used herein, the term “comprising” means “including, but not limited to”.

[0281] As used herein, the term “consisting essentially of’ means the method, composition or mixture includes the steps or components specifically recited, and may also include those that do not materially affect the basic and novel characteristics of the method, composition, or mixture. The basic and novel characteristics of the compositions of the present disclosure (such as of the tablets described herein) are that the compositions are suitable for oral administration to a human (z.e., the compositions described herein do not exceed a weight of about 1500 mg) once daily and thereby provide for an amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, as specified herein (i.e., for an amount of about 50 mg to about 400 mg dexpramipexole dihydrochloride equivalent). Accordingly, the basic and novel characteristics of the methods of manufacturing of the present disclosure are that the methods result in the compositions (such as the tablets) as described in this paragraph or in intermediate products of the compositions (such as densified granules or blends). Further, the basic and novel characteristics of the mixture of the present disclosure are that with this mixture, the preparation of the compositions (such as tablets) as described in this paragraph is possible.

[0282] As used herein, the term “consisting of’ means the method, composition, or mixture includes only the steps or components specifically recited thereafter.10283] As used herein, the term “any combination thereof’ or “a combination thereof’ covers any combination of the components or steps recited before the term. For example, the expression “a composition further comprising A, B, C, D, or any combination thereof’ includes inter alia “a composition further comprising A,” “a composition further comprising A and B,” “a composition further comprising B and D,” “a composition further comprising A, B and C,” and “a composition further comprising A, B, C, and D”.

[0284] The term “homogeneous mixture,” as used herein, refers to a mixture wherein all of the ingredients have been thoroughly mixed such that the composition of the mixture is substantially the same throughout different portions of the mixture.

[0285] As used herein, the terms “pre-blend” and “blend” refer to homogeneous mixtures of the corresponding ingredients in the pre-blend or blend, respectively. A “blend” refersto a homogeneous mixture that comprises additional ingredients compared to a corresponding “pre-blend”.

[0286] The term “orally deliverable,” as used herein, means that a corresponding pharmaceutical composition (such as a tablet) is suitable for oral administration to a human by swallowing the composition as a whole.

[0287] The term “tablet core,” as used herein, refers to the part of the orally deliverable tablets described herein that provides for sustained release of dexpramipexole, or a pharmaceutically acceptable salt thereof. The tablet core comprises the amounts of dexpramipexole, or a pharmaceutically acceptable salt as specified herein and the amounts of one or more anionic polymers as specified herein and may comprise additional components such as a lubricant, a diluent, and / or a glidant. The tablet core might be coated (in particular with a non-functional film coating), but not necessarily has to be coated. In embodiments wherein the tablet core is not coated, the weight of the tablet (as defined further below) corresponds to the weight of the tablet core. The tablet core may be, for example, a single-layer tablet core or a multi-layer tablet core (e.g., bilayer, tri-layer, etc.). In some embodiments, the tablet core is a single-layer tablet core (also referred to as a unitary core that is not divided into two or more layers).

[0288] The term “dexpramipexole,” as used herein, refers to (6 / ?)-2-amino-4, 5,6,7- tetrahydro-6-(propylamino)benzothiazole. The chemical structure of dexpramipexole is given above in formula (I). The term “dexpramipexole” refers to the “free base” (i.e., the neutral form of dexpramipexole as shown above in formula (I)) unless the context clearly dictates otherwise.

[0289] The term “pharmaceutically acceptable salt” is meant to indicate those salts that are suitable for use in contact with the tissues of a human without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. For example, Remington’s Pharmaceutical Sciences, 23thed. (2020) and Berge et al. (1977), J. Pharm. Sciences, Vol 6., 1-19 describe pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts can generally also be in the form of hydrates (such as in the form of a monohydrate). In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride or a hydrate thereof (such as the monohydrate). Examples of suitable pharmaceutically acceptable salts of dexpramipexole within the scope of the present disclosure include, but are not limited to, dexpramipexole dihydrochloride and dexpramipexole dihydrochloridemonohydrate. Further suitable “pharmaceutically acceptable salts” of dexpramipexole within the scope of the present disclosure are described throughout the present specification.

[0290] The term “equivalent” is used herein to specify a certain amount of an ingredient with reference to a more specific form (such as a specific salt) of the ingredient. For example, the term “dexpramipexole dihydrochloride equivalent” is used to specify the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition that corresponds the same quantity as dexpramipexole dihydrochloride. For instance, an amount of 319 mg dexpramipexole dihydrochloride monohydrate corresponds to 300 mg dexpramipexole dihydrochloride equivalent, and an amount of 223 mg dexpramipexole corresponds to 300 mg dexpramipexole dihydrochloride equivalent. As another example, an amount of 160 mg dexpramipexole dihydrochloride monohydrate corresponds to 150 mg dexpramipexole dihydrochloride equivalent, and an amount of 112 mg dexpramipexole corresponds to 150 mg dexpramipexole dihydrochloride equivalent.{0291 ] The term “weight of the tablet,” as used herein, refers to the weight of the entire tablet including the weight of any potential coating surrounding the tablet core. For example, in embodiments wherein the tablet core is surrounded by a film coating, the term “weight of the tablet” also includes the weight of the film coating. However, as explained in this chapter (“I - Definitions”) above in the context of “tablet core”, the tablet core does not necessarily have to be coated. In embodiments wherein the tablet core is not surrounded by a coating, the “weight of the tablet” equals the “weight of the tablet core”.

[0292] “Immediate release,” as used herein, means that no effort is taken either through formulation or processing to modify the release of the drug from the dosage form. Typically, greater than 80% of drug is dissolved within 1 hour when analyzed with a USP method.

[0293] “Sustained release,” as used herein, refers to products where the time period of release is extended through formulation and / or processing of the drug product. Sustained release of an active agent to an environment occurs over a period of about eight hours, about 12 hours, about 16 hours, about 18 hours, about 20 hours, about 24 hours, or more than about 24 hours. A sustained release can begin within a few minutes after administration (such as within about 5 min or about 10 min after administration); therelease can also begin after an expiration of a delay period (lag time) after administration. In some aspects, the active agent is released to an environment over a period of about 5 min to about eight hours, about 5 min to about 12 hours, about 5 min to about 16 hours, about 5 min to about 18 hours, about 5 min to about 20 hours, about 5 min to about 24 hours, or about 5 min to more than about 24 hours after administration. In some aspects, the active agent is released to an environment over a period of about 10 min to about eight hours, about 10 min to about 12 hours, about 10 min to about 16 hours, about 10 min to about 18 hours, about 10 min to about 20 hours, about 10 min to about 24 hours, or about 10 min to more than about 24 hours after administration. In certain embodiments, the drug is released at a substantially constant rate or pulsatile rate over an extended period of time. In some aspects, the sustained release provides for a constant drug level in the blood or target tissue of a human to which the sustained release device (such as a tablet) is administered.

[0294] “Extended release,” as used herein, refers to products where either the rate of release is controlled / reduced or the duration of release is extended through formulation and / or processing of the drug product.(0295] “Controlled release,” as used herein, refers to products where the rate of drug release has been intentionally modified through formulation and / or processing of the drug product.

[0296] The terms “controlled release,” “sustained release,” or “extended release” or “ER” are used interchangeably herein.

[0297] The term “treating” refers to alleviating of the signs or symptoms associated with a specific disorder, disease, or condition, and / or removing of the signs or symptoms associated with a specific disorder, disease, or condition, and / or preventing of the worsening of the signs or symptoms associated with a specific disorder, disease, or condition. In some aspects, the treatment alleviates signs or symptoms associated with a specific disorder, disease, or condition. In other aspects, the treatment removes signs or symptoms associated with a specific disorder, disease, or condition. In other aspects, the treatment prevents worsening of the signs or symptoms associated with a specific disorder, disease, or condition.

[0298] The term “preventing” refers to prophylaxis of a specific disorder, disease, or condition in a human. In certain aspects, the human may be predisposed to the specificdisorder, disease, or condition but does not yet experience or display the pathology, signs, or symptoms of the specific disorder, disease, or condition.

[0299] The term “in need thereof,” as used herein, means that the human subject has a need for the particular treatment or prevention and that the treatment or prevention is being given to the subject for that particular purpose.II - Pharmaceutical Composition (Orally Deliverable Tablet)103001 In certain aspects, the present disclosure is directed to a sustained release pharmaceutical composition in the form of an orally deliverable tablet comprising a tablet core and dexpramipexole, or a pharmaceutically acceptable salt thereof.

[0301] In some aspects, the sustained release pharmaceutical composition comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, at an amount of about 50 mg to about 400 mg of dexpramipexole dihydrochloride equivalent. In some aspects, the tablet core comprises a homogeneous mixture of the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more anionic polymers. In some aspects, the one or more anionic polymers constitute about 30% to about 60% by weight of the tablet core. In some aspects, the weight of the tablet is about 1500 mg or less.

[0302] In some aspects, the sustained release pharmaceutical composition comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, at an amount of about 50 mg to about 500 mg of dexpramipexole dihydrochloride equivalent. In some aspects, the weight of the tablet is about 1500 mg or less.10303 [ In certain aspects, the present disclosure is directed to a sustained release pharmaceutical composition in the form of an orally deliverable tablet comprising a tablet core and dexpramipexole, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg to about 400 mg of dexpramipexole dihydrochloride equivalent, wherein the tablet core comprises a homogeneous mixture of the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more anionic polymers, wherein the one or more anionic polymers constitute about 30% to about 60% by weight of the tablet core, and wherein the weight of the tablet is about 1500 mg or less.

[0304] In certain aspects, the present disclosure is directed to a sustained release pharmaceutical composition in the form of an orally deliverable tablet comprising a tablet core and dexpramipexole, or a pharmaceutically acceptable salt thereof, in an amount ofabout 50 mg to about 500 mg of dexpramipexole dihydrochloride equivalent, wherein the tablet core comprises a homogeneous mixture of the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers, wherein the one or more polymers constitute about 5% to about 60% by weight of the tablet core, and wherein the weight of the tablet is about 1500 mg or less.

[0305] In some aspects, the one or more polymers are anionic polymers or neutral polymers. In some aspects, the one or more polymers are anionic polymers. In some aspects, the one or more anionic polymers constitute about 30% to about 60% by weight of the tablet core.

[0306] In some aspects, the one or more polymers are neutral polymers. In some aspects, the one or more neutral polymers constitute about 5% to about 25% by weight of the tablet core. In some aspects, the one or more netural polymers constitute about 5% to about 60% by weight of the tablet core.

[0307] In some embodiments, the one or more neutral polymers constitute between about 5% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 10% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 15% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 20% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 25% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 30% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 35% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 40% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 45% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 50% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 55% to about 60% by weight of the tablet core.

[0308] In some embodiments, the one or more neutral polymers constitute about 5% to about 55% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 50% by weight of the tablet core. In someembodiments, the one or more neutral polymers constitute about 5% to about 45% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 40% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 35% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 30% by weight of the tablet core.

[0309] In some embodiments, the one or more neutral polymers constitute about 20% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 25% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 30% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 35% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 40% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 45% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 50% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 55% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 60% by weight of the tablet core.103101 The pharmaceutical composition in the form of an orally deliverable tablet according to the present disclosure is further described in the sections below within this chapter (“II - Pharmaceutical Composition (Orally Deliverable Tablet)”). As acknowledged by a person of ordinary skill in the art, the embodiments described below may be combined to further embodiments. For example, one or more embodiments described under section “3. Tablet Core” may be combined with one or more embodiments described under section “4. Film coating” to a further embodiment.1. Pharmaceutically acceptable salts of dexpramipexole

[0311] In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is a halogenic acid salt, an inorganic acid salt, an organic acid salt, or an amino acid salt.

[0312] In some embodiments, the halogenic acid salt is a hydrobromic, hydrochloric, hydrofluoric, or hydroiodic acid salt.103131 In some embodiments, the inorganic acid salt is a nitric, perchloric, sulfuric, or phosphoric acid salt.

[0314] In some embodiments, the organic acid salt is a sulfonic, tartaric acid, acetic, malic, fumaric, succinic, citric, benzoic, gluconic, lactic, mandelic, mucic, pamoic, pantothenic, exalic or maleic acid salt. In some embodiments, the sulfonic acid salt is a methane sulfonic, trifluoromethane sulfonic, ethane sulfonic, benzene sulfonic or p- toluene sulfonic acid salt.

[0315] In some embodiments, the amino acid salt is aspartic or glutamic acid salt.

[0316] In some embodiments, the pharmaceutically acceptable salt is a methane sulfonic acid salt (“mesylate salt”), sulfuric acid salt (“sulfate salt”), tartaric acid salt (“tartrate salt”), -toluene sulfonic acid salt (“tosylate salt”), phosphoric acid salt (“phosphate salt”), maleic acid salt (“maleate salt”), fumaric acid salt (“fumarate salt”), malic acid salt (“malate salt”), citric acid salt (“citrate salt”), succinic acid salt (“succinate salt”), or any combination thereof.

[0317] In some specific embodiments, the pharmaceutically acceptable salt is a methane sulfonic acid salt, phosphoric acid salt, fumaric acid salt, or any combination thereof.

[0318] The acid addition salt may be a mono- or di-acid addition salt, such as dihydrobromic, dihydrochloric, dihydrofluoric, dihydroiodic, disulfuric, diphosphoric, or diorganic acid salt. The acid addition salt may additionally be in the form of a hydrate, such as a dihydrochloride monohydrate.

[0319] In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride or a hydrate thereof (such as the monohydrate).

[0320] In some specific embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride.[03211 In some specific embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride monohydrate.2. Amount of dexpramipexole, or a pharmaceutically acceptable salt thereof

[0322] As outlined above, in some aspects, the sustained release pharmaceutical composition in the form of an orally deliverable tablet comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg to about 400 mg of dexpramipexole dihydrochloride equivalent. In some aspects, the sustained releasepharmaceutical composition in the form of an orally deliverable tablet comprises dexpramipexole, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg to about 500 mg of dexpramipexole dihydrochloride equivalent.

[0323] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 50 mg to about 350 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 55 mg to about 340 mg, about 60 mg to about 330 mg, about 65 mg to about 320 mg, or about 70 mg to about 310 mg of dexpramipexole dihydrochloride equivalent.

[0324] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 50 mg to about 400 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 55 mg to about 395 mg, about 60 mg to about 390 mg, about 65 mg to about 385 mg, or about 70 mg to about 380 mg of dexpramipexole dihydrochloride equivalent.

[0325] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 75 mg to about 300 mg (such as about 75 mg, about 150 mg, or about 300 mg) of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 300 mg to about 400 mg (such as about 300 mg or about 376 mg) of dexpramipexole dihydrochloride equivalent.

[0326] In specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 75 mg of dexpramipexole dihydrochloride equivalent. In other specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 150 mg of dexpramipexole dihydrochloride equivalent. In yet other specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 300 mg of dexpramipexole dihydrochloride equivalent. In yet other specific embodiments, the amount ofdexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 376 mg of dexpramipexole dihydrochloride equivalent.

[0327] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about390 mg, about 395 mg, or about 400 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 75 mg, about 150 mg, about 300 mg, or about 376 mg of dexpramipexole dihydrochloride equivalent.

[0328] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 50 mg to about 100 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 55 mg to about 95 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 60 mg to about 90 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 65 mg to about 85 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 70 mg to about 80 mg of dexpramipexole dihydrochloride equivalent. In specific embodiments, the amount ofdexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 75 mg of dexpramipexole dihydrochloride equivalent.

[0329] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 100 mg to about 350 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 105 mg to about 345 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 110 mg to about 340 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 115 mg to about 335 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 120 mg to about 335 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 120 mg to about 330 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 125 mg to about 325 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 130 mg to about 320 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 135 mg to about 315 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 140 mg to about 310 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 145 mg to about 305 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 150 mg to about 300 mg of dexpramipexole dihydrochloride equivalent.10330] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 200 mg to about 400mg, about 205 mg to about 395 mg, about 210 mg to about 390 mg, about 215 mg to about 385 mg, about 220 mg to about 380 mg, about 225 mg to about 375 mg, about 230 mg to about 370 mg, about 235 mg to about 365 mg, about 240 mg to about 360 mg, or about 245 mg to about 355 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 250 mg to about 350 mg, about 255 mg to about 345 mg, about 260 mg to about 340 mg, about 265 mg to about 335 mg, or about 270 mg to about 330 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 275 mg to about 325 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 280 mg to about 320 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 285 mg to about 315 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 290 mg to about 310 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 295 mg to about 305 mg of dexpramipexole dihydrochloride equivalent. In specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 300 mg of dexpramipexole dihydrochloride equivalent.[03311 In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 300 mg to about 450 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 320 mg to about 440 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 330 mg to about 430 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 340 mg to about 420 mg ofdexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 350 mg to about 410 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 360 mg to about 400 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 370 mg to about 390 mg of dexpramipexole dihydrochloride equivalent. In specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 376 mg of dexpramipexole dihydrochloride equivalent.

[0332] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 50 mg to about 250 mg, about 55 mg to about 245 mg, about 60 mg to about 240 mg, about 65 mg to about 235 mg, about 70 mg to about 230 mg about 75 mg to about 225 mg, about 80 mg to about 220 mg, about 85 mg to about 215 mg, about 90 mg to about 210 mg, about 95 mg to about 205 mg, about 100 mg to about 200 mg, about 105 mg to about 195 mg, about 110 mg to about 190 mg, about 115 mg to about 185 mg, or about 120 mg to about 180 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 125 mg to about 175 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 130 mg to about 170 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 135 mg to about 165 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 140 mg to about 160 mg of dexpramipexole dihydrochloride equivalent. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 145 mg to about 165 mg of dexpramipexole dihydrochloride equivalent. In specific embodiments, the amount ofdexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 150 mg of dexpramipexole dihydrochloride equivalent.

[0333] In some embodiments, the pharmaceutical composition comprises about 60 mg to about 340 mg dexpramipexole dihydrochloride monohydrate.103341 In some embodiments, the pharmaceutical composition comprises about 60 mg to about 100 mg dexpramipexole dihydrochloride monohydrate. In some embodiments, the pharmaceutical composition comprises about 65 mg to about 95 mg dexpramipexole dihydrochloride monohydrate. In some embodiments, the pharmaceutical composition comprises about 70 mg to about 90 mg dexpramipexole dihydrochloride monohydrate. In some embodiments, the pharmaceutical composition comprises about 75 mg to about 85 mg dexpramipexole dihydrochloride monohydrate. In specific embodiments, the pharmaceutical composition comprises about 80 mg dexpramipexole dihydrochloride monohydrate.

[0335] In some embodiments, the pharmaceutical composition comprises about 140 mg to about 180 mg dexpramipexole dihydrochloride monohydrate. In some embodiments, the pharmaceutical composition comprises about 145 mg to about 175 mg dexpramipexole dihydrochloride monohydrate. In some embodiments, the pharmaceutical composition comprises about 150 mg to about 170 mg dexpramipexole dihydrochloride monohydrate. In some embodiments, the pharmaceutical composition comprises about 155 mg to about 165 mg dexpramipexole dihydrochloride monohydrate. In specific embodiments, the pharmaceutical composition comprises about 160 mg dexpramipexole dihydrochloride monohydrate.

[0336] In some embodiments, the pharmaceutical composition comprises about 300 mg to about 340 mg dexpramipexole dihydrochloride monohydrate. In some embodiments, the pharmaceutical composition comprises about 305 mg to about 335 mg dexpramipexole dihydrochloride monohydrate. In some embodiments, the pharmaceutical composition comprises about 310 mg to about 330 mg dexpramipexole dihydrochloride monohydrate. In some embodiments, the pharmaceutical composition comprises about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate. In specific embodiments, the pharmaceutical composition comprises about 319 mg dexpramipexole dihydrochloride monohydrate.

[0337] In some embodiments, the pharmaceutical composition comprises about 300 mg to about 450 mg dexpramipexole dihydrochloride monohydrate.103381 In some embodiments, the pharmaceutical composition comprises about 320 mg to about 440 mg dexpramipexole dihydrochloride monohydrate. In some embodiments, the pharmaceutical composition comprises about 340 mg to about 430 mg dexpramipexole dihydrochloride monohydrate. In some embodiments, the pharmaceutical composition comprises about 360 mg to about 420 mg dexpramipexole dihydrochloride monohydrate. In some embodiments, the pharmaceutical composition comprises about 380 mg to about 410 mg dexpramipexole dihydrochloride monohydrate. In specific embodiments, the pharmaceutical composition comprises about 400 mg dexpramipexole dihydrochloride monohydrate.103391 In some embodiments, the pharmaceutical composition comprises about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about305 mg, about 310 mg, about 315 mg, about 319 mg, about 320 mg, about 325 mg, about330 mg, about 335 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about440 mg, or about 450 mg dexpramipexole dihydrochloride monohydrate.

[0340] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 20% to about 50%, about 21% to about 49%, about 22% to about 48%, about 23% to about 47%, or about 24% to about 46% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 25% to about 45%, about 26% to about 44%, about 27% to about 43%, about 28% to about 42%, or about 29% to about 41% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 30% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core. In some embodiments, the amountof dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 34% to about 39% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 31% to about 39%, about 32% to about 38%, about 33% to about 37%, or about 34% to about 36% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core. In specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 35% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 33% to about 43%, about 34% to about 42%, about 35% to about 41%, about 36% to about 40%, or about 37% to about 39% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core. In specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 38% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 38% to about 48%, about 39% to about 47%, about 40% to about 46%, about 41% to about 45%, or about 42% to about 44% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core. In specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 43% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core. In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride monohydrate.

[0341] In specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 30% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core.

[0342] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 20%, about 22%, about 24%, about 26%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 42%, about 44%, about 46%, about 48%, or about 50% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core.

[0343] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 20% to about 50%, about 21% to about 49%, about 22% to about 48%, about 23% to about 47%, or about 24% to about 46% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 25% to about 45%, about 26% to about 44%, about 27% to about 43%, about 28% to about 42%, or about 29% to about 41% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 30% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 31% to about 39%, about 32% to about 38%, about 33% to about 37%, or about 34% to about 36% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 32% to about 36% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 34% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 30% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 31% to about 39%, about 32% to about 38%, about 33% to about 37%, or about 34% to about 36% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 35% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 34% to about 38% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 36% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In some embodiments, the amount of dexpramipexole,or a pharmaceutically acceptable salt thereof, constitutes about 37% to about 47% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 38% to about 46%, about 39% to about 45%, about 40% to about 44%, or about 41% to about 43% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 42% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet. In some embodiments, the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride monohydrate.

[0344] In specific embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 30% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet.

[0345] In some embodiments, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, constitutes about 20%, about 22%, about 24%, about 26%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 42%, about 44%, about 46%, about 48%, or about 50% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet.

[0346] In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more anionic polymers is about 0.2: 1 to about 1.3: 1, about 0.3 : 1 to about 1.2:1, about 0.4:1 to about 1.1 : 1, or about 0.5: 1 to about 1 :1.

[0347] In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.2: 1 to about 4.0:1, about 0.3 : 1 to about 3.8:1, about 0.4: 1 to about 3.6: 1, about 0.5: 1 to about 3.5: 1, about 0.6: 1 to about 3.4: 1, about 0.7: 1 to about 3.3: 1, about 0.8: 1 to about 3.2: 1, about 0.9: 1 to about 3.1 : 1, about 1.0:1 to about 3.0: 1, about 1.1 : 1 to about 2.9: 1, or about 1.2: 1 to about 2.8: 1.

[0348] In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more anionic polymers is about 0.7: 1 to about 0.9: 1. In some specific embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more anionic polymers is about 0.7: 1. In some other specific embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more anionic polymers is about 0.9: 1.

[0349] In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.7:1 to about 0.9:1. In some specific embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.7:1. In some specific embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.8:1. In some other specific embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.9:1.(0350] In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 1.0: 1 to about 2.0: 1 or about 1.25 : 1 to about 1.75:1. In some specific embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 1.5:1.

[0351] In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 2.0: 1 to about 3.0: 1 or about 2.5:1 to about 2.9:1. In some specific embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 2.8:1.(0352] In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more anionic polymers is about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2.0:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about 2.6:1, about 2.7:1, about 2.8:1, about 2.9:1, about 3.0:1, about 3.1:1, about 3.2:1, about 3.3:1, about 3.4:1, about 3.5:1, about 3.6:1, about 3.7:1, about 3.8:1, about 3.9:1, or about 4.0:1.

[0353] In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about1.9:1, about 2.0:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about2.6:1, about 2.7:1, about 2.8:1, about 2.9:1, about 3.0:1, about 3.1:1, about 3.2:1, about3.3:1, about 3.4:1, about 3.5:1, about 3.6:1, about 3.7:1, about 3.8:1, about 3.9:1, or about4.0:1.

[0354] In some embodiments, dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition has a chiral purity for dexpramipexole, or thepharmaceutically acceptable salt thereof, of 99.95% or more. “Having a chiral purity for dexpramipexole, or the pharmaceutically acceptable salt thereof, of 99.95% or more” means that the portion of pramipexole, or a pharmaceutically acceptable salt of pramipexole (see formula (II) above showing the chemical structure of pramipexole), respectively, within the amount of dexpramipexole, or a pharmaceutically acceptable salt of dexpramipexole in the pharmaceutical composition is 0.05% or less. In some embodiments, dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition has a chiral purity for dexpramipexole, or the pharmaceutically acceptable salt thereof, of 99.96% or more. In some embodiments, dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition has a chiral purity for dexpramipexole, or the pharmaceutically acceptable salt thereof, of 99.97% or more. In some embodiments, dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition has a chiral purity for dexpramipexole, or the pharmaceutically acceptable salt thereof, of 99.98% or more. In some embodiments, dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition has a chiral purity for dexpramipexole, or the pharmaceutically acceptable salt thereof, of 99.99% or more. In some embodiments, dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition has a chiral purity for dexpramipexole, or the pharmaceutically acceptable salt thereof, of 100%. The chiral purity might be determined by analyzing a sample of dexpramipexole, or a pharmaceutically acceptable salt thereof, by high performance liquid chromatography (HPLC).

[0355] In specific embodiments, dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition has a chiral purity for dexpramipexole, or the pharmaceutically acceptable salt thereof, of 99.96% or more.3. Tablet core

[0356] As outlined above, the pharmaceutical composition in the form of an orally deliverable tablet according to the present disclosure comprises a tablet core.

[0357] In some aspects, the tablet core comprises a homogeneous mixture of the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more anionicpolymers. In some aspects, the one or more anionic polymers constitute about 30% to about 60% by weight of the tablet core.

[0358] In some aspects, the tablet core comprises a homogeneous mixture of the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers. In some aspects, the one or more polymers constitute about 5% to about 60% by weight of the tablet core.

[0359] In some embodiments, the one or more polymers are anionic polymers. In some embodiments, the one or more polymers are neutral polymers. In some embodiments, no more than one anionic polymer is included in the homogeneous mixture. In some embodiments, no more than one neutral polymer is included in the homogeneous mixture.

[0360] In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose, an acrylic acid polymer, a methyl methacrylic acid polymer, a methyl methacrylic acid copolymer, a methacrylic acid polymer, a methacrylic acid copolymer, a copolymer of methyl methacrylic acid and methacrylic acid, alignate, carrageenan, xanthan gum, or arabic gum. In some embodiments, the one or more anionic polymers are hydrophilic anionic polymers. A hydrophilic anionic polymer is readily soluble in water. In contrast thereto, a hydrophobic anionic polymer is not readily soluble in water, but instead is soluble in lipids and / or organic solvents. In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose and an acrylic acid polymer.

[0361] In some embodiments, carboxymethylcellulose is sodium carboxymethylcellulose or potassium carboxymethylcellulose. In specific embodiments, carboxymethylcellulose is sodium carboxymethylcellulose. An example of a sodium carboxymethylcellulose is Aquaion CMC 7HXF PH. In more specific embodiments, the viscosity of the sodium carboxymethylcellulose is about 1,500 to about 3,000 cP (centipoise; 1% in water), which corresponds to about 1,500 to about 3,000 mPa-s.

[0362] In specific embodiments, the acrylic acid polymer is a crosslinked acrylic acid polymer. An example of a crosslinked acrylic acid polymer is Carbopol 97 IP. In more specific embodiments, the viscosity of the crosslinked acrylic acid polymer is about 4,000 to about 11,000 cP (centipoise; 0.5% at pH 7.5), which corresponds to about 4,000 to about 11,000 mPa-s.103631 In some embodiments, the one or more anionic polymers constitute about 25% to about 55% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 30% to about 50% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 35% to about 55% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 37% to about 52% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 40% to about 50% by weight of the tablet core.

[0364] In some embodiments, the one or more anionic polymers constitute about 28% to about 48% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 20% to about 36%, about 22% to about 34%, about 24% to about 32%, or about 26% to about 30% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 27% to about 29% by weight of the tablet core. In specific embodiments, the one or more anionic polymers constitute about 28% by weight of the tablet core.{0365] In some embodiments, the one or more anionic polymers constitute about 30% to about 48% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 35% to about 45%, about 36% to about 44%, about 37% to about 43%, or about 38% to about 42% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 39% to about 41% by weight of the tablet core. In specific embodiments, the one or more anionic polymers constitute about 40% by weight of the tablet core.

[0366] In some embodiments, the one or more anionic polymers constitute about 36% to about 48% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 37% to about 47%, about 38% to about 46%, about 39% to about 45%, or about 40% to about 44% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 41% to about 43% by weight of the tablet core. In specific embodiments, the one or more anionic polymers constitute about 42% by weight of the tablet core.

[0367] In some embodiments, the one or more anionic polymers constitute about 42% to about 52%, about 43% to about 51%, about 44% to about 50%, or about 45% to about 49% by weight of the tablet core. In some embodiments, the one or more anionic polymers constitute about 46% to about 48% by weight of the tablet core. In specificembodiments, the one or more anionic polymers constitute about 47% by weight of the tablet core.

[0368] In specific embodiments, the one or more anionic polymers constitute about 30% to about 50% by weight of the tablet core. In more specific embodiments, the one or more anionic polymers constitute about 40% to about 50% by weight of the tablet core.

[0369] In some embodiments, the one or more anionic polymers constitute about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% by weight of the tablet core.

[0370] In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 250 mg to about 550 mg, about 260 mg to about 540 mg, about 270 mg to about 530 mg, about 280 mg to about 520 mg, or about 290 mg to about 510 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 150 mg to about 550 mg, about 160 mg to about 540 mg, about 170 mg to about 530 mg, about 180 mg to about 520 mg, or about 190 mg to about 510 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 200 mg to about 500 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 210 mg.

[0371] In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 300 mg to about 500 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 475 mg.

[0372] In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 300 mg to about 450 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 290 mg to about 390 mg, about 300 mg to about 380 mg, about 310 mg to about 370 mg, about 320 mg to about 360 mg, or about 330 mg to about 350 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 315 mg to about 365 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 340 mg.

[0373] In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 375 mg to about 475 mg, about 385 mg to about 465 mg, about395 mg to about 455 mg, about 405 mg to about 445 mg, or about 415 mg to about 435 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 400 mg to about 450 mg. In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 425 mg.

[0374] In some embodiments, the homogeneous mixture comprises the one or more anionic polymers at about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, or about 550 mg.

[0375] In some embodiments, the tablet core comprises the homogeneous mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, and the one or more polymers in the form of densified granules. In some embodiments, the tablet core comprises the homogeneous mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, and the one or more anionic polymers in the form of densified granules. In some embodiments, the tablet core comprises the homogeneous mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, and the one or more neutral polymers in the form of densified granules. Other ingredients such as a filler or a lubricant may be part of the densified granules. The densified granules may be obtained by roller compaction. A suitable roller compaction process is described, for example, further below in the specification in Chapter “Ill-Methods of Manufacturing,” section “3. Further embodiments of the methods of manufacturing”.

[0376] In some embodiments, the tablet core comprises the homogeneous mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, and the one or more polymers. In some embodiments, the homogeneous mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, and the one or more polymers is not in the form of densified granules. Other ingredients such as a filler or a lubricant may be part of the homogenous mixture. Suitable processes for preparing and processing the homogenous mixture are described, for example, further below in the specification in Chapter “III-Methods of Manufacturing,” section “3. Further embodiments of the methods of manufacturing”.

[0377] In some embodiments, the homogeneous mixture comprises one, but no more than one anionic polymer. In specific embodiments, the homogeneous mixture comprises one, but no more than one anionic polymer and the anionic polymer is carboxymethylcellulose (such as sodium carboxymethylcellulose). An example of a sodium carboxymethylcellulose is Aquaion CMC 7HXF PH and an example of a crosslinked acrylic acid polymer is Carbopol 97 IP. In more specific embodiments, the viscosity of the sodium carboxymethylcellulose is about 1,500 to about 3,000 cP (centipoise; 1% in water) and / or the viscosity of the crosslinked acrylic acid polymer is about 4,000 to about 11,000 cP (centipoise; 0.5% at pH 7.5). In specific embodiments, the homogeneous mixture comprises one, but no more than one anionic polymer and the anionic polymer is an acrylic acid polymer, such as crosslinked acrylic acid polymer. An example of a crosslinked acrylic acid polymer is Carbopol 97 IP. In more specific embodiments, the viscosity of the crosslinked acrylic acid polymer is about 4,000 to about 11,000 cP (centipoise; 0.5% at pH 7.5).

[0378] In some embodiments, the homogeneous mixture comprises more than one anionic polymer, such as two, three, four, or five anionic polymers. Within the meaning of the present disclosure, if the homogeneous mixture comprises more than one anionic polymer, such as a first and a second anionic polymer, the anionic polymers are different anionic polymers. For example, a homogeneous mixture comprising two anionic polymers might comprise sodium carboxymethylcellulose as the first anionic polymer and an acrylic acid polymer as the second anionic polymer.

[0379] In some embodiments, the homogeneous mixture comprises two, but no more than two anionic polymers. In specific embodiments, the homogeneous mixture comprises two, but no more than two anionic polymers and the two anionic polymers are carboxymethylcellulose (such as sodium carboxymethylcellulose) and an acrylic acid polymer (such as a crosslinked acrylic acid polymer). An example of a sodium carboxymethylcellulose is Aquaion CMC 7HXF PH and an example of a crosslinked acrylic acid polymer is Carbopol 97 IP. In more specific embodiments, the viscosity of the sodium carboxymethylcellulose is about 1,500 to about 3,000 cP (centipoise; 1% in water) and / or the viscosity of the crosslinked acrylic acid polymer is about 4,000 to about 11,000 cP (centipoise; 0.5% at pH 7.5).-n -103801 In some embodiments, the homogeneous mixture comprises three, but no more than three anionic polymers. In some embodiments, the homogeneous mixture comprises four, but no more than four anionic polymers. In some embodiments, the homogeneous mixture comprises five, but no more than five anionic polymers.

[0381] In some embodiments, the homogeneous mixture comprises one or more, but no more than five anionic polymers. In some embodiments, the homogeneous mixture comprises one or more, but no more than four anionic polymers. In some embodiments, the homogeneous mixture comprises one or more, but no more than three anionic polymers. In some embodiments, the homogeneous mixture comprises one or more, but no more than two anionic polymers.

[0382] In specific embodiments, the homogeneous mixture comprises two, but no more than two anionic polymers.

[0383] In specific embodiments, the homogeneous mixture comprises one or more, but no more than two anionic polymers.

[0384] In some embodiments, the homogeneous mixture consists essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, at the amounts specified herein (such as at about 75 mg to about 376 mg of dexpramipexole dihydrochloride equivalent) and one, but no more than one anionic polymers at the amounts specified herein (such as at about 30% to about 50% by weight of the tablet core). In some embodiments, the homogeneous mixture consists essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, at the amounts specified herein (such as at about 75 mg to about 300 mg of dexpramipexole dihydrochloride equivalent) and one or more, but no more than two anionic polymers at the amounts specified herein (such as at about 30% to about 50% by weight of the tablet core). If two anionic polymers are present, the two anionic polymers may be carboxymethylcellulose (such as sodium carboxymethylcellulose) and an acrylic acid polymer (such as a crosslinked acrylic acid polymer).

[0385] In specific embodiments, the homogeneous mixture consists essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, at the amounts specified herein (such as at about 75 mg to about 300 mg of dexpramipexole dihydrochloride equivalent) and two anionic polymers at the amounts specified herein (such as at about 30% to about 50% by weight of the tablet core). The two anionic polymers may becarboxymethylcellulose (such as sodium carboxymethylcellulose) and an acrylic acid polymer (such as a crosslinked acrylic acid polymer).

[0386] In some embodiments, the homogeneous mixture comprises a first anionic polymer and a second anionic polymer and the first anionic polymer is carboxymethylcellulose and the second anionic polymer is an acrylic acid polymer. In specific embodiments, carboxymethylcellulose is sodium carboxymethylcellulose and / or the acrylic acid polymer is a crosslinked acrylic acid polymer. An example of a sodium carboxymethylcellulose is Aquaion CMC 7HXF PH and an example of a crosslinked acrylic acid polymer is Carbopol 97 IP. The viscosity of the sodium carboxymethylcellulose may be about 1,500 to about 3,000 cP (centipoise; 1% in water) and / or the viscosity of the crosslinked acrylic acid polymer may be about 4,000 to about 11,000 cP (centipoise; 0.5% at pH 7.5).

[0387] In some embodiments, the amount of carboxymethylcellulose is about 23% to about 38% of sodium carboxymethylcellulose equivalent by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 25% to about 30% of sodium carboxymethylcellulose equivalent by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 28% of sodium carboxymethylcellulose equivalent by weight of the tablet core.[0388 [ In some embodiments, the amount of carboxymethylcellulose is about 100 mg to about 300 mg of sodium carboxymethylcellulose equivalent. In some embodiments, the amount of carboxymethylcellulose is about 200 mg to about 250 mg of sodium carboxymethylcellulose equivalent. In some embodiments, the amount of carboxymethylcellulose is about 210 mg of sodium carboxymethylcellulose equivalent.

[0389] In some embodiments, the amount of carboxymethylcellulose is about 23% to about 38% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 7% to about 22% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 23% to about 33% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 7% to about 17%, about 8% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 24% to about 32% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 8% to about 16% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about25% to about 31% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 9% to about 15% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 26% to about 30% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 10% to about 14% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 27% to about 29% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 11% to about 13% by weight of the tablet core. In specific embodiments, the amount of carboxymethylcellulose is about 28% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 12% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose may also be about 28% to about 38% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer may be about 9% to about 19% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose may also be about 29% to about 37% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer may be about 10% to about 18% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose may also be about 30% to about 36% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer may be about 11% to about 17% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 25% to about 35% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 8% to about 18% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 26% to about 34% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 9% to about 17% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 27% to about 33% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 10% to about 16% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose is about 28% to about 32% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 11% to about 15% by weight of the tablet core. In specific embodiments, theamount of carboxymethylcellulose is about 30% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 13% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose may also be about 31% to about 35% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer may be about 12% to about 16% by weight of the tablet core. In some embodiments, the amount of carboxymethylcellulose may also be about 32% to about 34% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer may be about 13% to about 15% by weight of the tablet core. In specific embodiments, the amount of carboxymethylcellulose is about 33% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 14% by weight of the tablet core.

[0390] In some embodiments, the amount of carboxymethylcellulose is about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, or about 38% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, or about 22% by weight of the tablet core.[03911 In some embodiments, the amount of carboxymethylcellulose is about 190 mg to about 350 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 60 mg to about 200 mg. In some embodiments, the amount of carboxymethylcellulose is about 205 mg to about 335 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 70 mg to about 145 mg. In even more specific embodiments, the amount of carboxymethylcellulose is about 333 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 143 mg. In some embodiments, the amount of carboxymethylcellulose is about 200 mg to about 250 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 75 mg to about 125 mg. In some embodiments, the amount of carboxymethylcellulose is about 220 mg to about 260 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 80 mg to about 120 mg. In some embodiments, the amount of carboxymethylcellulose is about 230 mg to about 250 mg ofsodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 90 mg to about 110 mg. In some embodiments, the amount of carboxymethylcellulose is about 235 mg to about 245 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 95 mg to about 105 mg. In specific embodiments, the amount of carboxymethylcellulose is about 235 mg to about 240 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 100 mg to about 105 mg. In even more specific embodiments, the amount of carboxymethylcellulose is about 238 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 102 mg. In some embodiments, the amount of carboxymethylcellulose is about 275 mg to about 325 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 100 mg to about 150 mg. In some embodiments, the amount of carboxymethylcellulose is about 280 mg to about 320 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 110 mg to about 150 mg. In some embodiments, the amount of carboxymethylcellulose is about 290 mg to about 310 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 120 mg to about 140 mg. In specific embodiments, the amount of carboxymethylcellulose is about 295 mg to about 305 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 125 mg to about 135 mg. In specific embodiments, the amount of carboxymethylcellulose is about 295 mg to about 300 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 125 mg to about 130 mg. In even more specific embodiments, the amount of carboxymethylcellulose is about 298 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 128 mg.

[0392] In some embodiments, the amount of carboxymethylcellulose is about 190 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 238 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, or about 350 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 60 mg, about 65 mg, about 70 mg, about 75mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 102 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg.

[0393] In some embodiments, the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 3:2 to about 2:8. In some embodiments, the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 3:3 (1 : 1) to about 2:7. In some embodiments, the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 3:4 to about 2:6. In some embodiments, the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 2:3 to about 2:8. In specific embodiments, the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 3:5 to about 2:5. In even more specific embodiments, the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 3:7.

[0394] In some embodiments, the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 3:2, about 3:3 (1 : 1), about 3:4, about 3:5, about 3:6, about 3:7, about 3:8, about 3:9, about 2:3, about 2:4, about 2:5, about 2:6, about 2:7, or about 2:8.

[0395] In some embodiments, the homogeneous mixture comprises the first and the second anionic polymer, but no more other anionic polymers than the first and the second anionic polymer.

[0396] In some embodiments, the homogeneous mixture consists essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, and the first and the second anionic polymer.

[0397] In some embodiments, the homogeneous mixture in the tablet core in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more anionic polymers at the amounts specified herein further comprises one or more hydrophilic neutral polymers. In some specific embodiments, the one or more hydrophilic neutral polymers are hypromellose (hydroxy propyl methylcellulose, HPMC), silicified hydroxypropyl methylcellulose, hydroxypropyl cellulose (HPC), and / or poly(ethylene oxide). Non-limiting examples of a HPMC are Methocel® K15M, Methocel® K100M,and Methocel® K200M. A non-limiting example of a HPC is Klucel® Xtend HXF. A non-limiting example of poly(ethylene oxide) is Sentry Polyox® WSR-303.

[0398] In some embodiments, the homogeneous mixture comprises one or more hydrophilic neutral polymers. In some embodiments, the homogeneous mixture comprises one, but no more than one neutral polymer. In some specific embodiments, the one or more hydrophilic neutral polymers are hypromellose (hydroxypropyl methylcellulose, HPMC), silicified hydroxypropyl methylcellulose, hydroxypropyl cellulose (HPC), and / or poly(ethylene oxide). Non-limiting examples of a HPMC are Methocel® K15M, Methocel® KI OOM, and Methocel® K200M. A non-limiting example of a HPC is Klucel® Xtend HXF. A non-limiting example of poly(ethylene oxide) is Sentry Poly ox® WSR-303.

[0399] In some embodiments, the amount of hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose is about 5% to about 25% by weight of the tablet core. In some embodiments, the amount of hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose is about 10% to about 20% by weight of the tablet core. In some embodiments, the amount of hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose is about 15% by weight of the tablet core.

[0400] In some embodiments, the one or more neutral polymers constitute between about 5% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 10% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 15% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 20% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 25% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 30% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 35% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 40% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 45% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 50% and about 60% by weight of the tablet core. In someembodiments, the one or more neutral polymers constitute about 55% to about 60% by weight of the tablet core.

[0401] In some embodiments, the one or more neutral polymers constitute about 5% to about 55% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 50% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 45% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 40% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 35% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 30% by weight of the tablet core.

[0402] In some embodiments, the one or more neutral polymers constitute about 20% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 25% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 30% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 35% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 40% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 45% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 50% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 55% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 60% by weight of the tablet core.

[0403] In some embodiments, the amount of hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose is about 50 mg to about 150 mg. In some embodiments, the amount of hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose is about 80 mg to about 140 mg. In some embodiments, the amount of hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose is about 113 mg.

[0404] In some embodiments, the homogeneous mixture in the tablet core in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more anionic polymers at the amounts specified herein further comprises one or more lipophilic materials. In some specific embodiments, the one or more lipophilic materialsare glycerol dibehenate and / or camuba wax. A non-limiting example of a glycerol dibehenate is Compritol® 888 ATO.

[0405] In some embodiments, the homogeneous mixture in the tablet core in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more polymers at the amounts specified herein further comprises a diluent (in the Examples also referred to as “filler”). In some embodiments, the homogeneous mixture in the tablet core in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more anionic polymers at the amounts specified herein further comprises a diluent (in the Examples also referred to as “filler”). In some embodiments, the homogeneous mixture in the tablet core in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more neutral polymers at the amounts specified herein further comprises a diluent (in the Examples also referred to as “filler”). As used herein, the term "diluent" is intended to mean an inert substance used as filler to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets. Examples of suitable diluents are microcrystalline cellulose (such as silicified microcrystalline cellulose), powdered cellulose, precipitated calcium carbonate, sorbitol, starch, mannitol, anhydrous lactose, lactose monohydrate, and the like.10406] In some embodiments, the diluent constitutes about 10% to about 30%, about 11% to about 29%, about 12% to about 28%, about 13% to about 27%, about 14% to about 26%, or about 15% to about 25% by weight of the tablet core. In some embodiments, the diluent constitutes about 10% to about 50%, about 11% to about 49%, about 12% to about 48%, about 13% to about 47%, about 14% to about 46%, or about 15% to about 45% by weight of the tablet core. In some embodiments, the diluent constitutes about 42% by weight of the tablet core. In some embodiments, the diluent constitutes about 15% to about 40% by weight of the tablet core. In some embodiments, the diluent constitutes about 20% to about 35% by weight of the tablet core. In some embodiments, the diluent constitutes about 29% by weight of the tablet core. In some embodiments, the diluent constitutes about 21% by weight of the tablet core. In some embodiments, the diluent constitutes about 15% to about 20% by weight of the tablet core. In some embodiments, the diluent constitutes about 20% to about 25% by weight of the tablet core. In specific embodiments, the diluent constitutes about 16% by weight of the tablet core. In other specific embodiments, the diluent constitutes about 21% by weight of thetablet core. In some embodiments, the diluent constitutes about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45%. In some embodiments, the tablet core comprises about 50 mg to about 350 mg, about 75 mg to about 325 mg, about 100 mg to about 200 mg, about 110 mg to about 190 mg, about 120 mg to about 180 mg, about 130 mg to about 170 mg, or about 140 mg to about 160 mg diluent. In some embodiments, the tablet core comprises about 100 mg to about 150 mg diluent. In some embodiments, the tablet core comprises about 150 mg to about 200 mg diluent. In some embodiments, the tablet core comprises about 135 mg to about 155 mg diluent. In some embodiments, the tablet core comprises about 170 mg to about 190 mg diluent. In specific embodiments, the tablet core comprises about 145 mg diluent. In other specific embodiments, the tablet core comprises about 180 mg diluent. In other specific embodiments, the tablet core comprises about 214 mg diluent. In other specific embodiments, the tablet core comprises about 236 mg diluent. In other specific embodiments, the tablet core comprises about 312 mg diluent. In some embodiments, the tablet core comprises about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, or about 350 mg diluent. In specific embodiments, the diluent is silicified microcrystalline cellulose. The silicified microcrystalline cellulose may be obtained by co-processing colloidal silicon dioxide and microcrystalline cellulose. In some embodiments, silicified microcrystalline cellulose constitutes about 10% to about 30%, about 11% to about 29%, about 12% to about 28%, about 13% to about 27%, about 14% to about 26%, or about 15% to about 25% by weight of the tablet core. In some embodiments, silicified microcrystallinecellulose constitutes about 10% to about 50%, about 11% to about 49%, about 12% to about 48%, about 13% to about 47%, about 14% to about 46%, or about 15% to about 45% by weight of the tablet core. In some embodiments, silicified microcrystalline cellulose constitutes about 42% by weight of the tablet core. In some embodiments, silicified microcrystalline cellulose constitutes about 15% to about 40% by weight of the tablet core. In some embodiments, silicified microcrystalline cellulose constitutes about 20% to about 35% by weight of the tablet core. In some embodiments, silicified microcrystalline cellulose constitutes about 29% by weight of the tablet core. In some embodiments, silicified microcrystalline cellulose constitutes about 21% by weight of the tablet core. In some embodiments, silicified microcrystalline cellulose constitutes about 15% to about 20% by weight of the tablet core. In some embodiments, silicified microcrystalline cellulose constitutes about 20% to about 25% by weight of the tablet core. In specific embodiments, silicified microcrystalline cellulose constitutes about 16% by weight of the tablet core. In other specific embodiments, silicified microcrystalline cellulose constitutes about 21% by weight of the tablet core. In some embodiments, silicified microcrystalline cellulose constitutes about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45%. In some embodiments, the tablet core comprises about 50 mg to about 350 mg, about 75 mg to about 325 mg, about 100 mg to about 200 mg, about 110 mg to about 190 mg, about 120 mg to about 180 mg, about 130 mg to about 170 mg, or about 140 mg to about 160 mg silicified microcrystalline cellulose. In some embodiments, the tablet core comprises about 100 mg to about 150 mg silicified microcrystalline cellulose. In some embodiments, the tablet core comprises about 150 mg to about 200 mg silicified microcrystalline cellulose. In some embodiments, the tablet core comprises about 135 mg to about 155 mg silicified microcrystalline cellulose. In some embodiments, the tablet core comprises about 170 mg to about 190 mg silicified microcrystalline cellulose. In specific embodiments, the tablet core comprises about 145 mg silicified microcrystalline cellulose. In other specific embodiments, the tablet core comprises about 180 mg silicified microcrystalline cellulose. In other specific embodiments, the tablet core comprises about 214 mg silicified microcrystallinecellulose. In other specific embodiments, the tablet core comprises about 236 mg silicified microcrystalline cellulose. In other specific embodiments, the tablet core comprises about 312 mg silicified microcrystalline cellulose. In some embodiments, the tablet core comprises about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about210 mg, about 215 mg, about 220 mg, about 225 mg, about 235 mg, about 240 mg, about245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about335 mg, about 340 mg, about 345 mg, or about 350 mg silicified microcrystalline cellulose.

[0408] In specific embodiments, the diluent is microcrystalline cellulose. In some embodiments, microcrystalline cellulose constitutes about 10% to about 30%, about 11% to about 29%, about 12% to about 28%, about 13% to about 27%, about 14% to about 26%, or about 15% to about 25% by weight of the tablet core. In some embodiments, microcrystalline cellulose constitutes about 10% to about 50%, about 11% to about 49%, about 12% to about 48%, about 13% to about 47%, about 14% to about 46%, or about 15% to about 45% by weight of the tablet core. In some embodiments, microcrystalline cellulose constitutes about 42% by weight of the tablet core. In some embodiments, microcrystalline cellulose constitutes about 15% to about 40% by weight of the tablet core. In some embodiments, microcrystalline cellulose constitutes about 20% to about 35% by weight of the tablet core. In some embodiments, microcrystalline cellulose constitutes about 29% by weight of the tablet core. In some embodiments, microcrystalline cellulose constitutes about 21% by weight of the tablet core. In some embodiments, microcrystalline cellulose constitutes about 15% to about 20% by weight of the tablet core. In some embodiments, microcrystalline cellulose constitutes about 20% to about 25% by weight of the tablet core. In specific embodiments, microcrystalline cellulose constitutes about 16% by weight of the tablet core. In other specific embodiments, microcrystalline cellulose constitutes about 21% by weight of the tablet core. In some embodiments, microcrystalline cellulose constitutes about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45%. In some embodiments, the tablet core comprises about 50 mg to about 350 mg, about 75 mg to about 325 mg, about 100 mg to about 200 mg, about 110 mg to about 190 mg, about 120 mg to about 180 mg, about 130 mg to about 170 mg, or about 140 mg to about 160 mg microcrystalline cellulose. In some embodiments, the tablet core comprises about 100 mg to about 150 mg microcrystalline cellulose. In some embodiments, the tablet core comprises about 150 mg to about 200 mg microcrystalline cellulose. In some embodiments, the tablet core comprises about 135 mg to about 155 mg microcrystalline cellulose. In some embodiments, the tablet core comprises about 170 mg to about 190 mg microcrystalline cellulose. In specific embodiments, the tablet core comprises about 145 mg microcrystalline cellulose. In other specific embodiments, the tablet core comprises about 180 mg microcrystalline cellulose. In other specific embodiments, the tablet core comprises about 214 mg microcrystalline cellulose. In other specific embodiments, the tablet core comprises about 236 mg microcrystalline cellulose. In other specific embodiments, the tablet core comprises about 312 mg microcrystalline cellulose. In some embodiments, the tablet core comprises about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, or about 350 mg microcrystalline cellulose.[0409| In some embodiments, the homogeneous mixture in the tablet core in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more polymers at the amounts specified herein further comprises a lubricant. In some embodiments, the homogeneous mixture in the tablet core in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more anionicpolymers at the amounts specified herein further comprises a lubricant. In some embodiments, the homogeneous mixture in the tablet core in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more neutral polymers at the amounts specified herein further comprises a lubricant. As used herein, the term "lubricant" is intended to mean substances used in tablet formulations to reduce friction during blending, (dry) granulation, and / or tablet compression. Examples of suitable lubricants are magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate, and the like. Also glycerol dibehenate and carnuba wax might be applied.

[0410] In some embodiments, the lubricant constitutes about 0.25% to about 1.25%, about 0.3% to about 1.2%, about 0.35% to about 1.15%, about 0.4% to about 1.1%, about 0.45% to about 1.05%, or about 0.5% to about 1% by weight of the tablet core. In some embodiments, the lubricant constitutes about 0.55% to about 0.95% by weight of the tablet core. In some embodiments, the lubricant constitutes about 0.6% to about 0.9% by weight of the tablet core. In some embodiments, the lubricant constitutes about 0.65% to about 0.85% by weight of the tablet core. In some embodiments, the lubricant constitutes about 0.7% to about 0.8% by weight of the tablet core. In specific embodiments, the lubricant constitutes about 0.75% by weight of the tablet core. In some embodiments, the lubricant constitutes about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.05%, about 1.1%, about 1.15%, or about 1.2% by weight of the tablet core. In some embodiments, the tablet core comprises about 1 mg to about 12 mg, about 2 mg to about 11 mg, about 3 mg to about 10 mg, or about 4 mg to about 9 mg lubricant. In some embodiments, the tablet core comprises about 5 mg to about 8 mg lubricant. In some embodiments, the tablet core comprises about 6 mg to about 7 mg lubricant. In some embodiments, the tablet core comprises about 6 mg lubricant. In some embodiments, the tablet core comprises about 7 mg lubricant. In some embodiments, the tablet core comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, or about 12 mg lubricant.[0411 [ In specific embodiments, the lubricant is magnesium stearate. In some embodiments, magnesium stearate constitutes about 0.25% to about 1.25%, about 0.3% to about 1.2%, about 0.35% to about 1.15%, about 0.4% to about 1.1%, about 0.45% to about 1.05%, or about 0.5% to about 1% by weight of the tablet core. In someembodiments, magnesium stearate constitutes about 0.55% to about 0.95% by weight of the tablet core. In some embodiments, magnesium stearate constitutes about 0.6% to about 0.9% by weight of the tablet core. In some embodiments, magnesium stearate constitutes about 0.65% to about 0.85% by weight of the tablet core. In some embodiments, magnesium stearate constitutes about 0.7% to about 0.8% by weight of the tablet core. In specific embodiments, magnesium stearate constitutes about 0.75% by weight of the tablet core. In some embodiments, magnesium stearate constitutes about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.05%, about 1.1%, about 1.15%, or about 1.2% by weight of the tablet core. In some embodiments, the tablet core comprises about 1 mg to about 12 mg, about 2 mg to about 11 mg, about 3 mg to about 10 mg, or about 4 mg to about 9 mg magnesium stearate. In some embodiments, the tablet core comprises about 5 mg to about 8 mg magnesium stearate. In some embodiments, the tablet core comprises about 6 mg to about 7 mg magnesium stearate. In some embodiments, the tablet core comprises about 6 mg magnesium stearate. In some embodiments, the tablet core comprises about 7 mg magnesium stearate. In some embodiments, the tablet core comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, or about 12 mg magnesium stearate. In some embodiments, the homogeneous mixture in the tablet core in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more polymers at the amounts specified herein further comprises a glidant. In some embodiments, the homogeneous mixture in the tablet core in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more anionic polymers at the amounts specified herein further comprises a glidant. In some embodiments, the homogeneous mixture in the tablet core in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more neutral polymers at the amounts specified herein further comprises a glidant. As used herein, the term "glidant" is intended to mean substances used in tablet formulations to improve flowability during blending, roller compaction, and / or tablet compression. Examples of suitable glidants are silicon dioxide, colloidal silicon dioxide, ascorbyl palmitate, calcium palmitate, starch, talc, and the like.104131 In some embodiments, the glidant constitutes about 0.1% to about 0.9%, about0.15% to about 0.85%, about 0.2% to about 0.8%, or about 0.25% to about 0.75% by weight of the tablet core. In some embodiments, the glidant constitutes about 0.3% to about 0.7% by weight of the tablet core. In some embodiments, the glidant constitutes about 0.35% to about 0.65% by weight of the tablet core. In some embodiments, the glidant constitutes about 0.4% to about 0.6% by weight of the tablet core. In some embodiments, the glidant constitutes about 0.45% to about 0.55% by weight of the tablet core. In specific embodiments, the glidant constitutes about 0.5% by weight of the tablet core. In some embodiments, the glidant constitutes about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, or about 0.9% by weight of the tablet core. In some embodiments, the tablet core comprises about 1 mg to about 8 mg glidant. In some embodiments, the tablet core comprises about 2 mg to about 7 mg glidant. In some embodiments, the tablet core comprises about 3 mg to about 6 mg glidant. In some embodiments, the tablet core comprises about 4 mg to about 5 mg glidant. In some embodiments, the tablet core comprises about 4 mg glidant. In some embodiments, the tablet core comprises about 5 mg glidant. In some embodiments, the tablet core comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, or about 8 mg glidant.[0414| In specific embodiments, the glidant is colloidal silicon dioxide. In some embodiments, colloidal silicon dioxide constitutes about 0.1% to about 0.9%, about 0.15% to about 0.85%, about 0.2% to about 0.8%, or about 0.25% to about 0.75% by weight of the tablet core. In some embodiments, colloidal silicon dioxide constitutes about 0.3% to about 0.7% by weight of the tablet core. In some embodiments, colloidal silicon dioxide constitutes about 0.35% to about 0.65% by weight of the tablet core. In some embodiments, colloidal silicon dioxide constitutes about 0.4% to about 0.6% by weight of the tablet core. In some embodiments, colloidal silicon dioxide constitutes about 0.45% to about 0.55% by weight of the tablet core. In specific embodiments, colloidal silicon dioxide constitutes about 0.5% by weight of the tablet core. In some embodiments, colloidal silicon dioxide constitutes about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, or about 0.9% by weight of the tablet core. In some embodiments, the tablet core comprisesabout 1 mg to about 8 mg colloidal silicon dioxide. In some embodiments, the tablet core comprises about 2 mg to about 7 mg colloidal silicon dioxide. In some embodiments, the tablet core comprises about 3 mg to about 6 mg colloidal silicon dioxide. In some embodiments, the tablet core comprises about 4 mg to about 5 mg colloidal silicon dioxide. In some embodiments, the tablet core comprises about 4 mg colloidal silicon dioxide. In some embodiments, the tablet core comprises about 5 mg colloidal silicon dioxide. In some embodiments, the tablet core comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, or about 8 mg colloidal silicon dioxide.

[0415] In some embodiments, the homogeneous mixture in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt (such as at about 30% to about 40% dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core) and the one or more polymers at the amounts specified herein (such as at about 10% to about 55% by weight of the tablet core) further comprises about 15% to about 25% diluent (such as silicified microcrystalline cellulose) by weight of the tablet core, about 0.5% to about 1% lubricant (such as magnesium stearate) by weight of the tablet core, and about 0.25% to about 0.75% glidant (such as colloidal silicon dioxide) by weight of the tablet core. In some embodiments, the homogeneous mixture in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt (such as at about 30% to about 40% dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core) and the one or more anionic polymers at the amounts specified herein (such as at about 40% to about 50% by weight of the tablet core) further comprises about 15% to about 25% diluent (such as silicified microcrystalline cellulose) by weight of the tablet core, about 0.5% to about 1% lubricant (such as magnesium stearate) by weight of the tablet core, and about 0.25% to about 0.75% glidant (such as colloidal silicon dioxide) by weight of the tablet core. In some embodiments, the homogeneous mixture in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt (such as at about 30% to about 40% dexpramipexole dihydrochloride monohydrate equivalent by weight of the tablet core) and the one or more neutral polymers at the amounts specified herein (such as at about 5% to about 25% by weight of the tablet core) further comprises about 15% to about 25% diluent (such as silicified microcrystalline cellulose) by weight of the tablet core, about 0.5% to about 1% lubricant (such as magnesium stearate) by weight ofthe tablet core, and about 0.25% to about 0.75% glidant (such as colloidal silicon dioxide) by weight of the tablet core.

[0416] In some embodiments, the homogeneous mixture in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more polymers at the amounts specified herein further comprises a microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide, or any combination thereof. In some embodiments, the homogeneous mixture in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more anionic polymers at the amounts specified herein further comprises a microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide, or any combination thereof. In some embodiments, the homogeneous mixture in addition to the amount of dexpramipexole, or the pharmaceutically acceptable salt and the one or more neutral polymers at the amounts specified herein further comprises a microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide, or any combination thereof. In specific embodiments, the homogeneous mixture further comprises a microcrystalline cellulose, magnesium stearate and colloidal silicon dioxide. The microcrystalline cellulose may be silicified microcrystalline cellulose.

[0417] In some embodiments, the homogeneous mixture in the tablet core consists essentially of:(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 235 mg to about 245 mg sodium carboxymethylcellulose;(c) about 95 mg to about 105 mg crosslinked acrylic acid polymer;(d) about 175 mg to about 185 mg silicified microcrystalline cellulose;(e) about 5 mg to about 7 mg magnesium stearate; and(f) about 3 mg to about 5 mg colloidal silicon dioxide.

[0418] In more specific embodiments, the homogeneous mixture in the tablet core consists essentially of:(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 238 mg sodium carboxymethylcellulose;(c) about 102 mg crosslinked acrylic acid polymer;(d) about 180 mg silicified microcrystalline cellulose;(e) about 6 mg magnesium stearate; and(f) about 4 mg colloidal silicon dioxide.104191 In some embodiments, the homogeneous mixture in the tablet core consists essentially of:(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 295 mg to about 305 mg sodium carboxymethylcellulose;(c) about 125 mg to about 135 mg crosslinked acrylic acid polymer;(d) about 140 mg to about 150 mg silicified microcrystalline cellulose;(e) about 6 mg to about 8 mg magnesium stearate; and(f) about 4 mg to about 6 mg colloidal silicon dioxide.

[0420] In more specific embodiments, the homogeneous mixture consists essentially of:(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 298 mg sodium carboxymethylcellulose;(c) about 128 mg crosslinked acrylic acid polymer;(d) about 145 mg silicified microcrystalline cellulose;(e) about 7 mg magnesium stearate; and(f) about 5 mg colloidal silicon dioxide.[04211 In some embodiments, the homogeneous mixture in the tablet core consists essentially of:(a) about 390 mg to about 410 mg dexpramipexole dihydrochloride monohydrate;(b) about 325 mg to about 341 mg sodium carboxymethylcellulose;(c) about 135 mg to about 145 mg crosslinked acrylic acid polymer;(d) about 230 mg to about 240 mg microcrystalline cellulose or silicified microcrystalline cellulose;(e) about 5 mg to about 10 mg magnesium stearate; and(f) about 4 mg to about 7 mg colloidal silicon dioxide.[0422| In more specific embodiments, the homogeneous mixture consists essentially of:(a) about 400 mg dexpramipexole dihydrochloride monohydrate;(b) about 333 mg sodium carboxymethylcellulose;(c) about 143 mg crosslinked acrylic acid polymer;(d) about 236 mg microcrystalline cellulose or silicified microcrystalline cellulose;(e) about 8 mg magnesium stearate; and(f) about 6 mg colloidal silicon dioxide.

[0423] In some embodiments, the homogeneous mixture in the tablet core consists essentially of:(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 110 mg to about 120 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose;(c) about 310 mg to about 320 mg microcrystalline cellulose or silicified microcrystalline cellulose;(d) about 3 mg to about 5 mg magnesium stearate; and(e) about 3 mg to about 5 mg colloidal silicon dioxide.

[0424] In more specific embodiments, the homogeneous mixture consists essentially of(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 113 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose;(c) about 313 mg microcrystalline cellulose or silicified microcrystalline cellulose;(d) about 4 mg magnesium stearate; and(e) about 4 mg colloidal silicon dioxide.

[0425] In some embodiments, the homogeneous mixture in the tablet core consists essentially of(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 110 mg to about 120 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose;(c) about 305 mg to about 315 mg microcrystalline cellulose or silicified microcrystalline cellulose;(d) about 5 mg to about 7 mg magnesium stearate; and(e) about 3 mg to about 5 mg colloidal silicon dioxide.

[0426] In more specific embodiments, the homogeneous mixture consists essentially of(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 113 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose;(c) about 310 mg microcrystalline cellulose or silicified microcrystalline cellulose;(d) about 6 mg magnesium stearate; and(e) about 4 mg colloidal silicon dioxide.

[0427] In some embodiments, the homogeneous mixture in the tablet core consists essentially of(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 110 mg to about 120 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose;(c) about 305 mg to about 315 mg microcrystalline cellulose;(d) about 5 mg to about 7 mg magnesium stearate; and(e) about 3 mg to about 5 mg colloidal silicon dioxide.

[0428] In more specific embodiments, the homogeneous mixture consists essentially of(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 113 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose;(c) about 310 mg microcrystalline cellulose;(d) about 6 mg magnesium stearate; and(e) about 4 mg colloidal silicon dioxide.

[0429] In some embodiments, the homogeneous mixture in the tablet core consists essentially of(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 200 mg to about 220 mg sodium carboxymethylcellulose;(c) about 210 mg to about 220 mg microcrystalline cellulose or silicified microcrystalline cellulose;(d) about 3 mg to about 5 mg magnesium stearate; and(e) about 3 mg to about 5 mg colloidal silicon dioxide.

[0430] In more specific embodiments, the homogeneous mixture consists essentially of(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 210 mg sodium carboxymethylcellulose;(c) about 214 mg microcrystalline cellulose or silicified microcrystalline cellulose;(d) about 4 mg magnesium stearate; and(e) about 4 mg colloidal silicon dioxide.

[0431] In some embodiments, the homogeneous mixture in the tablet core consists essentially of(a) about 30% to about 40% dexpramipexole dihydrochloride monohydrate by weight of the tablet core;(b) about 25% to about 35% sodium carboxymethylcellulose by weight of the tablet core;(c) about 10% to about 20% crosslinked acrylic acid polymer by weight of the tablet core;(d) about 15% to about 25% silicified microcrystalline cellulose by weight of the tablet core;(e) about 0.5% to about 1.0% magnesium stearate by weight of the tablet core; and(f) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the tablet core.

[0432] In some embodiments, the homogeneous mixture in the tablet core consists essentially of:(a) about 35% to about 40% dexpramipexole dihydrochloride monohydrate by weight of the tablet core;(b) about 28% to about 33% sodium carboxymethylcellulose by weight of the tablet core;(c) about 10% to about 15% crosslinked acrylic acid polymer by weight of the tablet core;(d) about 16% to about 21% silicified microcrystalline cellulose by weight of the tablet core;(e) about 0.5% to about 1.0% magnesium stearate by weight of the tablet core; and(f) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the tablet core.104331 In more specific embodiments, the homogeneous mixture in the tablet core consists essentially of:(a) about 38% dexpramipexole dihydrochloride monohydrate by weight of the tablet core;(b) about 28% sodium carboxymethylcellulose by weight of the tablet core;(c) about 12% crosslinked acrylic acid polymer by weight of the tablet core;(d) about 21% silicified microcrystalline cellulose by weight of the tablet core;(e) about 0.75% magnesium stearate by weight of the tablet core; and(f) about 0.5% colloidal silicon dioxide by weight of the tablet core.104341 In other more specific embodiments, the homogeneous mixture in the tablet core consists essentially of:(a) about 35% dexpramipexole dihydrochloride monohydrate by weight of the tablet core;(b) about 33% sodium carboxymethylcellulose by weight of the tablet core;(c) about 14% crosslinked acrylic acid polymer by weight of the tablet core;(d) about 16% silicified microcrystalline cellulose by weight of the tablet core;(e) about 0.75% magnesium stearate by weight of the tablet core; and(f) about 0.5% colloidal silicon dioxide by weight of the tablet core.

[0435] In more specific embodiments, the homogeneous mixture in the tablet core consists essentially of(a) about 36% dexpramipexole dihydrochloride monohydrate by weight of the tablet core;(b) about 30% sodium carboxymethylcellulose by weight of the tablet core;(c) about 13% crosslinked acrylic acid polymer by weight of the tablet core;(d) about 21% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the tablet core;(e) about 0.75% magnesium stearate by weight of the tablet core; and(f) about 0.5% colloidal silicon dioxide by weight of the tablet core.

[0436] In other more specific embodiments, the homogeneous mixture in the tablet core consists essentially of(a) about 43% dexpramipexole dihydrochloride monohydrate by weight of the tablet core;(b) about 15% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the tablet core;(c) about 42% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the tablet core;(d) about 0.5% magnesium stearate by weight of the tablet core; and(e) about 0.5% colloidal silicon dioxide by weight of the tablet core.

[0437] In other more specific embodiments, the homogeneous mixture in the tablet core consists essentially of(a) about 43% dexpramipexole dihydrochloride monohydrate by weight of the tablet core;(b) about 15% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the tablet core;(c) about 41% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the tablet core;(d) about 0.75% magnesium stearate by weight of the tablet core; and(e) about 0.5% colloidal silicon dioxide by weight of the tablet core.

[0438] In other more specific embodiments, the homogeneous mixture in the tablet core consists essentially of:(a) about 43% dexpramipexole dihydrochloride monohydrate by weight of the tablet core;(b) about 15% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the tablet core;(c) about 41% microcrystalline cellulose by weight of the tablet core;(d) about 0.75% magnesium stearate by weight of the tablet core; and(e) about 0.5% colloidal silicon dioxide by weight of the tablet core.

[0439] In more specific embodiments, the homogeneous mixture in the tablet core consists essentially of(a) about 43% dexpramipexole dihydrochloride monohydrate by weight of the tablet core;(b) about 28% sodium carboxymethylcellulose by weight of the tablet core(c) about 29% microcrystalline cellulose or silicified microcrystalline cellulose by weight of the tablet core;(d) about 0.5% magnesium stearate by weight of the tablet core; and(e) about 0.5% colloidal silicon dioxide by weight of the tablet core.

[0440] In some embodiments, the amount of dexpramipexole dihydrochloride monohydrate, the amount of sodium carboxymethylcellulose, the amount of crosslinked acrylic acid polymer, the amount of silicified microcrystalline cellulose, and one third of the amount of magnesium stearate are in the form of densified granules. The densified granules may be obtained by roller compaction.

[0441] In some embodiments, the weight of the tablet core is about 400 mg to about 1000 mg, about 450 mg to about 950 mg, about 500 mg to about 900 mg, about 550 mg to about 850 mg, or about 600 mg to about 800 mg. In some embodiments, the weight of the tablet core is about 400 mg to about 1400 mg, about 450 mg to about 1350 mg, about 500 mg to about 1300 mg, about 550 mg to about 1250 mg, or about 600 mg to about 1200 mg. In some embodiments, the weight of the tablet core is about 800 mg to about 950 mg. In some embodiments, the weight of the tablet core is about 800 mg to about 900 mg. In some embodiments, the weight of the tablet core is about 810 mg to about 890 mg, about 820 mg to about 880 mg, or about 830 mg to about 870 mg. In some embodiments, the weight of the tablet core is about 840 mg to about 860 mg. In specific embodiments, theweight of the tablet core is about 850 mg. In some embodiments, the weight of the tablet core is about 850 mg to about 950 mg. In some embodiments, the weight of the tablet core is about 860 mg to about 940 mg, about 870 mg to about 930 mg, or about 880 mg to about 920 mg. In some embodiments, the weight of the tablet core is about 890 mg to about 910 mg. In specific embodiments, the weight of the tablet core is about 900 mg. In some embodiments, the weight of the tablet core is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, or about 1400 mg. In some embodiments, the weight of the tablet core is about 1300 mg or less. In some embodiments, the weight of the tablet core is about 1000 mg or less. In some embodiments, the weight of the tablet core is about 950 mg or less. In some embodiments, the weight of the tablet core is about 900 mg or less. In some embodiments, the weight of the tablet core is about 850 mg or less. In some embodiments, the weight of the tablet core is about 800 mg or less. In some embodiments, the weight of the tablet core is at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, or at least about 800 mg.4. Film Coating

[0442] In some embodiments, the pharmaceutical composition further comprises a film surrounding the tablet core. In general, the film coating is applied in an amount sufficient to provide complete coverage of the tablet core.

[0443] In some embodiments, the film coating is a nonfunctional coating. The term “nonfunctional” in this context means having no substantial effect on drug release properties of the pharmaceutical composition, but does not imply that the film coating serves no useful purpose. For example, such film coating can impart a distinctive appearance to the tablet (such as providing for a specific color of the tablets), provide protection against attrition during packaging and transportation, and improve ease of swallowing. In some embodiments, the film coating provides a moisture-barrier.

[0444] In general, a tablet can comprise more than one film coating.

[0445] In some embodiments, the film coating comprises polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methacrylate, methacrylic acid copolymers, ethylcellulose, or any combination thereof.

[0446] In some embodiments, the film coating comprises polyvinyl alcohol. In some specific embodiments, the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. In other specific embodiments, the film coating consists of polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Examples of suitable film coatings are Opadry® II 85F18422 White and Opadry® II 85F130089 Pink.

[0447] In some embodiments, the film coating further comprises a color additive. A color additive, as defined by regulation, is any dye, pigment, or substance that can provide color to a food, drug, or cosmetic. Examples of suitable color additives include but are not limited to iron oxide (e.g., ferric oxide red), lead oxide, and copper sulfate.

[0448] In some embodiments, the pharmaceutical composition comprises about 10 mg to about 40 mg film coating. In some embodiments, the pharmaceutical composition comprises about 15 mg to about 35 mg film coating. In some embodiments, the pharmaceutical composition comprises about 20 mg to about 30 mg film coating. In some embodiments, the pharmaceutical composition comprises about 24 mg to about 28 mg film coating. In some embodiments, the pharmaceutical composition comprises about 26 mg film coating. In some embodiments, the pharmaceutical composition comprises about 25 mg to about 29 mg film coating. In some embodiments, the pharmaceutical composition comprises about 27 mg film coating. In some embodiments, the pharmaceutical composition comprises about 10 mg, about 15 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, or about 40 mg film coating.

[0449] In some embodiments, the weight ratio of the film coating to the tablet core is about 0.01 : 1 to about 0.05: 1. In some embodiments, the weight ratio of the film coating to the tablet core is about 0.02: 1 to about 0.04: 1. In some embodiments, the weight ratio of the film coating to the tablet core is about 0.025: 1 to about 0.035: 1. In specific embodiments, the weight ratio of the film coating to the tablet core is about 0.03 : 1. In some embodiments, the weight ratio of the film coating to the tablet core is about 0.01 : 1, about 0.015: 1, about 0.02: 1, about 0.025: 1, about 0.03: 1, about 0.035: 1, about 0.04: 1, about 0.045: 1, or about 0.05: 1.

[0450] In some embodiments, the film coating constitutes about 1% to about 5% by weight of the tablet. In some embodiments, the film coating constitutes about 2% to about 4% by weight of the tablet. In some embodiments, the film coating constitutes about 3% by weight of the tablet. In some embodiments, the film coating constitutes about 1%, about 2%, about 3%, about 4%, or about 5% by weight of the tablet.5. Further embodiments of the pharmaceutical composition

[0451] In some embodiments, the weight of the tablet is about 1500 mg or less. In some embodiments, the weight of the tablet is about 1400 mg or less. In some embodiments, the weight of the tablet is about 1300 mg or less. In some embodiments, the weight of the tablet is about 1200 mg or less. In some embodiments, the weight of the tablet is about 1100 mg or less. In some embodiments, the weight of the tablet is about 1000 mg or less. In some embodiments, the weight of the tablet is about 950 mg or less. In some embodiments, the weight of the tablet is about 900 mg or less.

[0452] In specific embodiments, the weight of the tablet is about 1000 mg or less.

[0453] In some embodiments, the weight of the tablet is at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, or at least about 900 mg. In specific embodiments, the weight of the tablet is at least about 800 mg. In other specific embodiments, the weight of the tablet is at least about 850 mg. In yet other specific embodiments, the weight of the tablet is at least about 900 mg.

[0454] In some embodiments, the weight of the tablet is about 100 mg to about 1500 mg, about 150 mg to about 1500 mg, about 200 mg to about 1500 mg, about 250 mg to about 1500 mg, about 300 mg to about 1500 mg, about 350 mg to about 1500 mg, about 400 mg to about 1500 mg, about 450 mg to about 1500 mg, or about 500 mg to about 1500 mg. In some embodiments, the weight of the tablet is about 550 mg to about 1500 mg, about 600 mg to about 1500 mg, about 650 mg to about 1500 mg, about 700 mg to about 1500 mg, about 750 mg to about 1500 mg, about 800 mg to about 1500 mg, about 850 mg to about 1500 mg, or about 900 mg to about 1500 mg.

[0455] In some embodiments, the weight of the tablet is about 100 mg to about 1300 mg, about 150 mg to about 1300 mg, about 200 mg to about 1300 mg, about 250 mg to about 1300 mg, about 300 mg to about 1300 mg, about 350 mg to about 1300 mg, about 400 mg to about 1300 mg, about 450 mg to about 1300 mg, or about 500 mg to about 1300 mg. In some embodiments, the weight of the tablet is about 550 mg to about 1300 mg, about 600 mg to about 1300 mg, about 650 mg to about 1300 mg, about 700 mg to about 1300 mg, about 750 mg to about 1300 mg, about 800 mg to about 1300 mg, about 850 mg to about 1300 mg, or about 900 mg to about 1300 mg.

[0456] In some embodiments, the weight of the tablet is about 100 mg to about 1000 mg, about 150 mg to about 1000 mg, about 200 mg to about 1000 mg, about 250 mg to about 1000 mg, about 300 mg to about 1000 mg, about 350 mg to about 1000 mg, about 400 mg to about 1000 mg, about 450 mg to about 1000 mg, or about 500 mg to about 1000 mg. In some embodiments, the weight of the tablet is about 550 mg to about 1000 mg, about 600 mg to about 1000 mg, about 650 mg to about 1000 mg, about 700 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, about 850 mg to about 1000 mg, or about 900 mg to about 1000 mg.

[0457] In some embodiments, the weight of the tablet is about 700 mg to about 1000 mg. In some embodiments, the weight of the tablet is about 800 mg to about 1000 mg. In some embodiments, the weight of the tablet is about 850 mg to about 950 mg.

[0458] In some embodiments, the weight of the tablet is about 750 mg to about 800 mg. In some embodiments, the weight of the tablet is about 760 mg to about 790 mg or about 770 mg to about 780 mg. In some embodiments, the weight of the tablet is about 773 mg.

[0459] In some embodiments, the weight of the tablet is about 850 mg to about 900 mg. In some embodiments, the weight of the tablet is about 860 mg to about 890 mg or about 870 mg to about 880 mg. In some embodiments, the weight of the tablet is about 876 mg.

[0460] In some embodiments, the weight of the tablet is about 900 mg to about 950 mg. In some embodiments, the weight of the tablet is about 910 mg to about 940 mg or about 920 mg to about 930 mg. In some embodiments, the weight of the tablet is about 927 mg.

[0461] In some embodiments, the weight of the tablet is about 1130 mg to about 1190 mg. In some embodiments, the weight of the tablet is about 1140 mg to about 1180 mg or about 1150 mg to about 1170 mg. In some embodiments, the weight of the tablet is about 1159 mg.

[0462] In specific embodiments, the weight of the tablet is about 1000 mg or less. In other specific embodiments, the weight of the tablet is less than about 1000 mg. In some embodiments, the weight of the tablet is at least about 850 mg.

[0463] In some embodiments, the weight of the tablet is about 800 mg, about 805 mg, about 810 mg, about 815 mg, about 820 mg, about 825 mg, about 830 mg, about 835 mg, about 840 mg, about 845 mg, about 850 mg, about 855 mg, about 860 mg, about 865 mg, about 870 mg, about 875 mg, about 876 mg, about 880 mg, about 885 mg, about 890 mg, about 895 mg, about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 927 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, or about 1000 mg.]0464J Tablets can be of any suitable shape, for example round, oval, elliptic, capsule, cylindrical, square, rectangle, or triangle. In some embodiments, the tablet is an oval shaped tablet. An “oval shaped” tablet has a long axis and a short axis with no flat edged sides. The ratio of the long and short axis can vary, thereby resulting in different shaped oval tablets. In other embodiments, the tablet is a capsule shaped tablet. As used herein, the term “capsule shaped tablet” also includes “modified capsule shaped tablet”. In some embodiments, the tablet is a modified capsule shaped tablet. As known by one skilled in the art, in a “modified capsule shaped tablet”, the long edges of the tablet when viewed in top view provide a slight radius. See, for example, Natoli et al., 2017, Developing Solid Oral Dosage Forms (Second Edition), Chapter 33 - Development, Optimization, and Scale-Up of Process Parameters: Tablet Compression, Academic Press, Pages 917-951 (herewith incorporated by reference).

[0465] In some embodiments, the length of the short axis of the tablet is about 7.5 mm to about 9.5 mm, the length of the long axis of the tablet is about 18 mm to about 20 mm, and the thickness of the tablet is about 5 mm to about 7 mm. In some embodiments, the length of the short axis of the tablet is about 8 mm to about 9 mm, the length of the long axis of the tablet is about 18.5 mm to about 19.5 mm, and the thickness of the tablet is about 5.5 mm to about 6.5 mm. In specific embodiments, the length of the short axis of the tablet is about 8.5 mm, the length of the long axis of the tablet is about 19 mm, and / or the thickness of the tablet is about 6 mm.

[0466] In some embodiments, about 20% to about 40%, about 25% to about 30%, or about 30% to about 40% of dexpramipexole, or the pharmaceutically acceptable saltthereof, is released at about 4 hours of incubation of the tablet in about 900 mL of 50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 30% to about 60%, about 35% to about 45%, or about 45% to about 55% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 8 hours of incubation of the tablet in about 900 mL of 50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 40% to about 70%, about 45% to about 55%, or about 60% to about 65% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 12 hours of incubation of the tablet in about 900 mL of50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 50% to about 70%, about 50% to about 60%, or about 60% to about 70% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 16 hours of incubation of the tablet in about 900 mL of50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 55% to about 75%, about 55% to about 65%, or about 65% to about 75% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 20 hours of incubation of the tablet in about 900 mL of50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 60% to about 80%, about 60% to about 70%, or about 70% to about 80% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 24 hours of incubation of the tablet in about 900 mL of50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 40% but no more than about 50% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 12 hours of incubation of the tablet in about 900 mL of 50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP typeI apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 50% but no more than about 60% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 12 hours of incubation of the tablet in about 900 mL of 50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 50% but no more than about 60% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 16 hours of incubation of the tablet in about 900 mL of 50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 60% but no more than about 70% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 16 hours of incubation of the tablet in about 900 mL of 50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 60% but no more than about 70% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 24 hours of incubation of the tablet in about 900 mL of 50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 70% but no more than about 80% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 24 hours of incubation of the tablet in about 900 mL of 50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm.

[0468] In some embodiments, about 20% to about 40% or about 30% to about 40% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 4 hours of incubation of the tablet in about 900 mL of Mcllvaine buffer, pH 4.5, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 40% to about 60%, or about 40% to about 45%, or about 45% to about 55% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 8 hours of incubation of the tablet in about 900 mL of Mcllvaine buffer, pH 4.5, at a temperature of 37 ± 0.5 °C asmeasured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 50% to about 70%, or about 50% to about 60%, or about 60% to about 70% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 12 hours of incubation of the tablet in about 900 mL of Mcllvaine buffer, pH 4.5, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 60% to about 80%, or about 60% to about 70%, or about 65% to about 75% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 16 hours of incubation of the tablet in about 900 mL of Mcllvaine buffer, pH 4.5, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 60% to about 80%, or about 65% to about 75%, or about 75% to about 85% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 20 hours of incubation of the tablet in about 900 mL of Mcllvaine buffer, pH 4.5, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 70% to about 90%, or about 70% to about 80%, or about 80% to about 85% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 24 hours of incubation of the tablet in about 900 mL of Mcllvaine buffer, pH 4.5, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 50% but no more than about 60% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 12 hours of incubation of the tablet in about 900 mL of Mcllvaine buffer, pH 4.5, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 60% but no more than about 70% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 12 hours of incubation of the tablet in about 900 mL of Mcllvaine buffer, pH 4.5, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 60% but no more than about 70% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 16 hours of incubation of the tablet in about 900 mL of Mcllvaine buffer, pH 4.5, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In someembodiments, at least about 70% but no more than about 80% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 16 hours of incubation of the tablet in about 900 mL of Mcllvaine buffer, pH 4.5, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 70% but no more than about 80% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 24 hours of incubation of the tablet in about 900 mL of Mcllvaine buffer, pH 4.5, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 80% but no more than about 90% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 24 hours of incubation of the tablet in about 900 mL of Mcllvaine buffer, pH 4.5, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm.

[0470] In some embodiments, about 50% to about 70% or about 55% to about 65% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 4 hours of incubation of the tablet in about 900 mL of 0.1 N HC1 at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 75% to about 95%, about 75% to about 85%, or about 85% to about 95% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 8 hours of incubation of the tablet in about 900 mL of 0.1 N HC1 at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 90% to about 100% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 12 hours of incubation of the tablet in about 900 mL of 0.1 N HC1 at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 90% to about 100% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 16 hours of incubation of the tablet in about 900 mL of 0.1 N HC1 at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, about 90% to about 100% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 20 hours of incubation of the tablet in about 900 mL of 0.1 N HC1 at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed ofabout 100 rpm. In some embodiments, about 90% to about 100% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 24 hours of incubation of the tablet in about 900 mL of 0.1 N HC1 at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm.

[0471] In some embodiments, at least about 90% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 12 hours of incubation of the tablet in about 900 mL of 0.1 N HC1 at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 90% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 16 hours of incubation of the tablet in about 900 mL of 0.1 N HC1 at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm. In some embodiments, at least about 90% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 24 hours of incubation of the tablet in about 900 mL of 0.1 N HC1 at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm.

[0472] In some embodiments, the in vitro dissolution profile measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm and incubating the tablet in about 900 mL of 50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C, is substantially the same after storing the tablet under controlled room temperature (CRT) conditions (i.e., at a temperature of 20 °C to 25 °C) for about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks. In some embodiments, the in vitro dissolution profile measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm and incubating the tablet in about 900 mL of 50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C, is substantially the same after storing the tablet under controlled room temperature (CRT) conditions (i.e., at a temperature of 20 °C to 25 °C) for at least about 4 weeks (such as for about 4 to about 12 weeks, or about 4 to about 11 weeks), at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, or at least about 12 weeks.

[0473] In some embodiments, the pharmaceutical composition is capable of providing a sigmoidal, pseudo-zero order, or zero order release of dexpramipexole, or a- I l l -pharmaceutically acceptable salt thereof. In specific embodiments, the release is a zero order release.

[0474] In some embodiments, the pharmaceutical composition comprises 0.05% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. In some embodiments, the pharmaceutical composition comprises 0.04% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. In some embodiments, the pharmaceutical composition comprises 0.03% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. In some embodiments, the pharmaceutical composition comprises 0.02% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. In some embodiments, the pharmaceutical composition comprises 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. In some embodiments, the pharmaceutical composition comprises 0.014% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. In some embodiments, the pharmaceutical composition comprises 0.01% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet.

[0475] In specific embodiments, the pharmaceutical composition comprises 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet.10476 [ In some embodiments, the pharmaceutical composition does not comprise pramipexole, or a pharmaceutically acceptable salt thereof, at the detection limit when analyzed with high performance liquid chromatography (HPLC).

[0477] In some embodiments, the one or more polymers in the compositions described herein are anionic polymers or neutral polymers. In some embodiments, the one or more polymers are anionic polymers. In some embodiments, the one or more anionic polymers constitute about 30% to about 60% by weight of the tablet. In some embodiments, the one or more anionic polymers constitute about 30% to about 50% by weight of the tablet. In specific embodiments, the one or more anionic polymers constitute about 38% to about 48% (such as about 39% or about 46%) by weight of the tablet.

[0478] In specific embodiments of the present disclosure, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 50 mg to about 350 mg (such as about 75 mg, about 150 mg, or about 300 mg) dexpramipexole dihydrochloride equivalent and the one or more anionic polymers constitute about 30% to about 55% (such as about 30% to about 50%) by weight of thetablet core. In these specific embodiments, the one or more anionic polymers may be a carboxymethylcellulose and / or a crosslinked acrylic acid polymer. In the specific embodiments described in this paragraph, the pharmaceutical composition may comprise 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. The weight of the tablet may be about 1000 mg or less (such as about 800 mg to about 1000 mg).

[0479] In specific embodiments of the present disclosure, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 75 mg to about 300 mg (such as about 75 mg, about 150 mg, or about 300 mg) dexpramipexole dihydrochloride equivalent and the one or more anionic polymers constitute about 30% to about 50% (such as about 40% to about 50%) by weight of the tablet core. In specific embodiments of the present disclosure, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 75 mg to about 300 mg (such as about 75 mg, about 150 mg, or about 300 mg) dexpramipexole dihydrochloride equivalent and the one or more anionic polymers constitute about 30% to about 60% (such as about 40% to about 50%) by weight of the tablet core. In these specific embodiments, the one or more anionic polymers may be a carboxymethylcellulose and / or a crosslinked acrylic acid polymer. In the specific embodiments described in this paragraph, the pharmaceutical composition may comprise 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. The weight of the tablet may be about 1000 mg or less (such as about 800 mg to about 1000 mg).

[0480] In some embodiments, the one or more polymers are neutral polymers. In some embodiments, the one or more neutral polymers constitute about 5% to about 25% by weight of the tablet. In some embodiments, the one or more neutral polymers constitute about 10% to about 20% by weight of the tablet. In specific embodiments, the one or more neutral polymers constitute about 13% to about 17% (such as about 15%) by weight of the tablet.[04811 In some embodiments, the one or more neutral polymers constitute between about 5% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 10% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 15% to about 60% by weight of the tablet core. In some embodiments, the one or more neutralpolymers constitute between about 20% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 25% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 30% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 35% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 40% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 45% to about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute between about 50% and about 60% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 55% to about 60% by weight of the tablet core.

[0482] In some embodiments, the one or more neutral polymers constitute about 5% to about 55% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 50% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 45% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 40% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 35% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 5% to about 30% by weight of the tablet core.

[0483] In some embodiments, the one or more neutral polymers constitute about 20% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 25% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 30% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 35% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 40% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 45% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 50% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 55% by weight of the tablet core. In some embodiments, the one or more neutral polymers constitute about 60% by weight of the tablet core.

[0484] In specific embodiments of the present disclosure, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 50 mg to about 350 mg (such as about 75 mg, about 150 mg, or about 300 mg) dexpramipexole dihydrochloride equivalent and the one or more neutral polymers constitute about 5% to about 25% (such as about 10% to about 20%) by weight of the tablet core. In these specific embodiments, the one or more neutral polymers may be a hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose. In the specific embodiments described in this paragraph, the pharmaceutical composition may comprise 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. The weight of the tablet may be about 1000 mg or less (such as about 800 mg to about 1000 mg).]0485J In specific embodiments of the present disclosure, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 75 mg to about 300 mg (such as about 75 mg, about 150 mg, or about 300 mg) dexpramipexole dihydrochloride equivalent and the one or more neutral polymers constitute about 5% to about 25% (such as about 10% to about 20%) by weight of the tablet core. In specific embodiments of the present disclosure, the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 75 mg to about 300 mg (such as about 75 mg, about 150 mg, or about 300 mg) dexpramipexole dihydrochloride equivalent and the one or more neutral polymers constitute about 5% to about 25% (such as about 10% to about 20%) by weight of the tablet core. In these specific embodiments, the one or more neutral polymers may be a hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose. In the specific embodiments described in this paragraph, the pharmaceutical composition may comprise 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. The weight of the tablet may be about 1000 mg or less (such as about 800 mg to about 1000 mg).

[0486] In some embodiments, the tensile strength of the orally deliverable tablet is about 1.7 MPa or more. In specific embodiments, the tensile strength of the orally deliverable tablet is about 1.7 MPa to about 2.5 MPa.

[0487] In some embodiments, the hardness of the orally deliverable tablet is about 15 to about 30 kilopond (kp). In some embodiments, the hardness of the orally deliverable tablet is about 20 to about 25 kp, such as about 22 kp. In some embodiments, the hardnessof the orally deliverable tablet is about 15 kp, about 16 kp, about 17 kp, about 18 kp, about 19 kp, about 20 kp, about 21 kp, about 22 kp, about 23 kp, about 24 kp, about 25 kp, about 26 kp, about 27 kp, about 28 kp, about 29 kp, or about 30 kp.

[0488] In specific embodiments of the present disclosure, the homogeneous mixture consists essentially of about 50 mg to about 350 mg (such as about 75 mg, about 150 mg, or about 300 mg) dexpramipexole dihydrochloride equivalent and the one or more anionic polymers, wherein the one or more anionic polymers constitute about 30% to about 55% (such as about 30% to about 50%) by weight of the tablet core. In these specific embodiments, the one or more anionic polymers may be a carboxymethylcellulose and / or a crosslinked acrylic acid polymer. In the specific embodiments described in this paragraph, the pharmaceutical composition may comprise 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. The weight of the tablet may be about 1000 mg or less (such as about 800 mg to about 1000 mg).

[0489] In specific embodiments of the present disclosure, the homogeneous mixture consists essentially of about 75 mg to about 300 mg (such as about 75 mg, about 150 mg, or about 300 mg) dexpramipexole dihydrochloride equivalent and the one or more anionic polymers, wherein the one or more anionic polymers constitute about 30% to about 50% (such as about 40% to about 50%) by weight of the tablet core. In these specific embodiments, the one or more anionic polymers may be a carboxymethylcellulose and / or a crosslinked acrylic acid polymer. In the specific embodiments described in this paragraph, the pharmaceutical composition may comprise 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. The weight of the tablet may be about 1000 mg or less (such as about 800 mg to about 1000 mg).

[0490] In specific embodiments of the present disclosure, the homogeneous mixture consists essentially of about 50 mg to about 350 mg (such as about 75 mg, about 150 mg, or about 300 mg) dexpramipexole dihydrochloride equivalent and the one or more neutral polymers, wherein the one or more neutral polymers constitute about 5% to about 25% (such as about 10% to about 20%) by weight of the tablet core. In these specific embodiments, the one or more neutral polymers may be a hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose. In the specific embodiments described in this paragraph, the pharmaceutical composition may comprise 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. The weight of the tablet may be about 1000 mg or less (such as about 800 mg to about 1000 mg).

[0491] In specific embodiments of the present disclosure, the homogeneous mixture consists essentially of about 75 mg to about 300 mg (such as about 75 mg, about 150 mg, or about 300 mg) dexpramipexole dihydrochloride equivalent and the one or more neutral polymers, wherein the one or more neutral polymers constitute about 5% to about 25% (such as about 10% to about 20%) by weight of the tablet core. In these specific embodiments, the one or more neutral polymers may be a hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose. In the specific embodiments described in this paragraph, the pharmaceutical composition may comprise 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet. The weight of the tablet may be about 1000 mg or less (such as about 800 mg to about 1000 mg).

[0492] In some embodiments, one or more of the ingredients of the pharmaceutical composition other than dexpramipexole, or the pharmaceutically acceptable salt thereof, such as one or more of an (anionic) polymer, a lubricant, a glidant, and / or a diluent, are “generally recognized as safe” (in short: “GRAS”) by the United States Food and Drug Administration (FDA) and / or are recognized as safe by the provisions of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). In some embodiments, one or more of the ingredients of the pharmaceutical composition other than dexpramipexole, or the pharmaceutically acceptable salt thereof, such as one or more of an (anionic) polymer, a lubricant, a glidant, and / or a diluent, are such ingredients that are listed in a Pharmacopoeia, such as the European and / or US Pharmacopoeia.

[0493] In some embodiments, the pharmaceutical composition can be part of a kit comprising the pharmaceutical composition packaged into a container (which might be, for example, a blister package or a bottle), the container being accompanied by a package insert providing pertinent information such as, for example, dosage and administration information, contraindications, precautions, drug interactions and adverse reactions. In some embodiments, the kit further comprises a desiccant. A desiccant is a hygroscopic substance that is used to induce or sustain a state of dryness (desiccation) in its vicinity. Examples of desiccants are silica gel, activated charcoal, calcium sulfate, calcium chloride, and molecular sieves (typically, zeolites).III - Methods of Manufacturing[04941 In certain aspects, the present disclosure further relates to methods of manufacturing as described in this chapter below.1. Method of manufacturing densified granules

[0495] The present disclosure relates to a method of manufacturing densified granules for preparing a sustained release pharmaceutical composition comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers; and preparing densified granules from the pre-blend; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules and the one or more polymers constitute about 5% to about 60% by weight of the densified granules.

[0496] The present disclosure relates to a method of manufacturing densified granules for preparing a sustained release pharmaceutical composition comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more anionic polymers; and preparing densified granules from the pre-blend; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules and the one or more anionic polymers constitute about 30% to about 55% by weight of the densified granules. The densified granules prepared by the method described in the above paragraph can be used in the production of a sustained release orally deliverable pharmaceutical composition, for example, in the form of a tablet or capsule.

[0497] The present disclosure relates to a method of manufacturing densified granules for preparing a sustained release pharmaceutical composition comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising:preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more anionic polymers; and preparing densified granules from the pre-blend; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules and the one or more anionic polymers constitute about 30% to about 55% by weight of the densified granules.

[0498] In some embodiments, the pre-blend further comprises additional excipients. In some embodiments, the pre-blend further comprises a microcrystalline cellulose, magnesium stearate, or a combination thereof. In some embodiments, the pre-blend further comprises a microcrystalline cellulose and magnesium stearate. In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

[0499] In some embodiments, the pre-blend comprises an antioxidant. In some embodiments, the antioxidant is capable of acting as a nitrite scavenger. Non-limiting examples of nitrite scavengers include, but are not limitd to, ascorbic acid, L-cysteine, caffeic acid, cysteine HCL, methionine, tartaric acid, gallic acid, uric acid, and sodium sulphite. In some embodiments, the pre-blend comprises one nitrite scavenger. In another embodiment, the pre-blend comprises multiple nitrite scavengers. In some embodiments, the nitrite scavengers constitute about 0.1% to about 1.5% by weight of the tablet core. In some embodiments, the nitrite scavenger constitutes about 0.1% to about 1.0% by weight of the tablet core. In some embodiments, the nitrite scavenger constitutes about 0.1% to about 0.5% by weight of the tablet core. In some embodiments, the nitrite scavenger constitutes about 0.5% to about 1.5% by weight of the tablet core. In some embodiments, the nitrite scavenger constitutes about 1% to about 1.5% by weight of the tablet core. In some embodiments, the nitrite scavenger constitutes about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5% by weight of the tablet core.

[0500] In some embodiments, dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 35% to about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules. In some embodiments, dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 35% to about 44% of dexpramipexole dihydrochloride monohydrate equivalent by weight of thedensified granules. In some embodiments, dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 36% to about 38% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules. In some embodiments, dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 36% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules. In some embodiments, dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 38% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules. In some embodiments, dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more anionic polymers is about 0.2:1 to about 1.3:1, about 0.3:1 to about 1.2:1, about 0.4:1 to about 1.1:1, or about 0.5:1 to about 1:1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.2:1 to about 4.0:1, about 0.3:1 to about 3.8:1, about 0.4:1 to about 3.6:1, about 0.5:1 to about 3.5:1, about 0.6:1 to about 3.4:1, about 0.7:1 to about 3.3:1, about 0.8:1 to about 3.2:1, about 0.9:1 to about 3.1:1, about 1.0:1 to about 3.0:1, about 1.1:1 to about 2.9:1, or about 1.2:1 to about 2.8:1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more anionic polymers is about 0.7:1 to about 0.9:1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more anionic polymers is about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, or about 1.3:1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.7:1 to about 0.9:1. In some embodiments, the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2.0:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about 2.6:1, about 2.7:1, about 2.8:1, about 2.9:1, about 3.0:1, about 3.1:1, about 3.2:1, about 3.3:1, about 3.4:1, about 3.5:1, about 3.6:1, about 3.7:1, about 3.8:1, about 3.9:1, or about 4.0:1.[0501 [ In some embodiments, the one or more polymers are anionic polymers or neutral polymers. In some embodiments, the one or more polymers are anionic polymers.

[0502] In some embodiments, the one or more anionic polymers constitute about 20% to about 55% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 35% to about 50% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 40% to about 50% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 35% to about 45%, about 36% to about 44%, about 37% to about 43%, or about 38% to about 42% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 39% to about 41% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 40% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 43% to about 53%, about 44%, to about 52%, about 45% to about 51%, or about 46% to about 50% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 47% to about 49% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 48% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 48% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 43% by weight of the densified granules. In some embodiments, the one or more anionic polymers constitute about 40% by weight of the densified granules.

[0503] In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose, an acrylic acid polymer, a methacrylic acid polymer, a methacrylic acid copolymer, alignate, carrageenan, xanthan gum, or arabic gum. In some embodiments, the one or more anionic polymers are hydrophilic anionic polymers. In some embodiments, the one or more anionic polymers are selected from carboxymethylcellulose and an acrylic acid polymer. The carboxymethylcellulose may be sodium carboxymethylcellulose. An example of a sodium carboxymethylcellulose isAquaion CMC 7HXF PH. In more specific embodiments, the viscosity of the sodium carboxymethylcellulose is about 1,500 to about 3,000 cP (centipoise; 1% in water). The acrylic acid polymer may be crosslinked acrylic acid polymer. An example of a crosslinked acrylic acid polymer is Carbopol 97 IP. In more specific embodiments, the viscosity of the crosslinked acrylic acid polymer is about 4,000 to about 11,000 cP (centipoise; 0.5% at pH 7.5).

[0504] In some embodiments, the pre-blend comprises one, but no more than one anionic polymer. In specific embodiments, the pre-blend comprises one, but no more than one anionic polymer and the anionic polymer is carboxymethylcellulose, such as sodium carboxymethylcellulose. In specific embodiments, the pre-blend comprises one, but no more than one anionic polymer and the anionic polymer is an acrylic acid polymer, such as crosslinked acrylic acid polymer.

[0505] In some embodiments, the pre-blend comprises more than one anionic polymer, such as two, three, four, or five anionic polymers. Within the meaning of the present disclosure, if the pre-blend comprises more than one anionic polymer, such as a first and a second anionic polymer, the anionic polymers are different anionic polymers. For example, a pre-blend comprising two anionic polymers might comprise sodium carboxymethylcellulose as the first anionic polymer and an acrylic acid polymer as the second anionic polymer.

[0506] In some embodiments, the pre-blend comprises one or more, but no more than five anionic polymers. In some embodiments, the pre-blend comprises one or more, but no more than four anionic polymers. In some embodiments, the pre-blend comprises one or more, but no more than three anionic polymers. In some embodiments, the pre-blend comprises one or more, but no more than two anionic polymers.

[0507] In some embodiments, the pre-blend comprises two, but no more than two anionic polymers. In specific embodiments, the pre-blend comprises two, but no more than two anionic polymers and the two anionic polymers are carboxymethylcellulose (such as sodium carboxymethylc...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A sustained release pharmaceutical composition in the form of an orally deliverable tablet comprising a tablet core and dexpramipexole, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg to about 500 mg of dexpramipexole dihydrochloride equivalent, wherein the tablet core comprises a homogeneous mixture of the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers, wherein the one or anionic polymers constitute about 5% to about 60% by weight of the tablet core, and wherein the weight of the tablet is about 1500 mg or less.

2. The composition of claim 1, wherein the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 150 mg to about 400 mg of dexpramipexole dihydrochloride equivalent.

3. The composition of claim 2, wherein the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 200 mg to about 350 mg of dexpramipexole dihydrochloride equivalent.

4. The composition of claim 3, wherein the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 300 mg of dexpramipexole dihydrochloride equivalent.

5. The composition of claim 1, wherein the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 300 mg to about 400 mg of dexpramipexole dihydrochloride equivalent.

6. The composition of claim 5, wherein the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 350 mg to about 385 mg of dexpramipexole dihydrochloride equivalent.

7. The composition of claim 6, wherein the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 376 mg of dexpramipexole dihydrochloride equivalent.

8. The composition of any one of claims 1 to 7, wherein the one or more polymers are anionic polymers or neutral polymers.

9. The composition of claim 8, wherein the one or more polymers are anionic polymers.

10. The composition of claim 8, wherein the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.5 : 1 to about 3.5:1.

11. The composition of claim 10, wherein the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.7: 1 to about 3.0: 1.

12. The composition of claim 11, wherein the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.7: 1.

13. The composition of claim 11, wherein the weight ratio of dexpramipexole dihydrochloride equivalent to the one or more polymers is about 0.9: 1.

14. The composition of any one of claims 1 to 13, wherein the pharmaceutically acceptable salt of dexpramipexole is a methane sulfonic acid salt, sulfuric acid salt, tartaric acid salt, p- toluene sulfonic acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, malic acid salt, citric acid salt, succinic acid salt, or any combination thereof.

15. The composition of any one of claims 1 to 13, wherein the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride or a hydrate thereof.

16. The composition of claim 15, wherein the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride monohydrate.

17. The composition of claim 9, wherein the one or more anionic polymers are selected from carboxymethylcellulose, an acrylic acid polymer, a methyl methacrylic acid polymer, a methyl methacrylic acid copolymer, a methacrylic acid polymer, a methacrylic acid copolymer, alignate, carrageenan, xanthan gum, or arabic gum.

18. The composition of claim 17, wherein the one or more anionic polymers are selected from carboxymethylcellulose and an acrylic acid polymer.

19. The composition of claim 17 or 18, wherein carboxymethylcellulose is sodium carboxymethylcellulose.

20. The composition of any one of claims 17 to 19, wherein the acrylic acid polymer is a crosslinked acrylic acid polymer.

21. The composition of claim 9, wherein the one or more anionic polymers constitute about 25% to about 55% by weight of the tablet core.

22. The composition of claim 21, wherein the one or more anionic polymers constitute about 28% to about 48% by weight of the tablet core.

23. The composition of claim 22, wherein the one or more anionic polymers constitute about 28% by weight of the tablet core.

24. The composition of claim 21, wherein the one or more anionic polymers constitute about 40% to about 48% by weight of the tablet core.

25. The composition of claim 24, wherein the one or more anionic polymers constitute about 47% by weight of the tablet core.

26. The composition of claim 24, wherein the one or more anionic polymers constitute about 42% by weight of the tablet core.

27. The composition of claim 24, wherein the one or more anionic polymers constitute about 40% by weight of the tablet core.

28. The composition of claim 9, wherein the homogeneous mixture comprises the one or more anionic polymers at about 150 mg to about 550 mg.

29. The composition of claim 28, wherein the homogeneous mixture comprises the one or more anionic polymers at about 200 mg to about 500 mg.

30. The composition of claim 29, wherein the homogeneous mixture comprises the one or more anionic polymers at about 210 mg.

31. The composition of claim 28, wherein the homogeneous mixture comprises the one or more anionic polymers at about 300 mg to about 480 mg.

32. The composition of claim 31, wherein the homogeneous mixture comprises the one or more anionic polymers at about 475 mg.

33. The composition of claim 31, wherein the homogeneous mixture comprises the one or more anionic polymers at about 425 mg.

34. The composition of claim 31, wherein the homogeneous mixture comprises the one or more anionic polymers at about 340 mg.

35. The composition of claim 9, wherein the homogeneous mixture comprises one anionic polymer and wherein the anionic polymer is carboxymethylcellulose.

36. The composition of claim 35, wherein carboxymethylcellulose is sodium carboxymethylcellulose.

37. The composition of claim 35 or 36, wherein the amount of carboxymethylcellulose is about 23% to about 38% of sodium carboxymethylcellulose equivalent by weight of the tablet core.

38. The composition of claim 37, wherein the amount of carboxymethylcellulose is about 25% to about 30% of sodium carboxymethylcellulose equivalent by weight of the tablet core.

39. The composition of claim 38, wherein the amount of carboxymethylcellulose is about 28% of sodium carboxymethylcellulose equivalent by weight of the tablet core.

40. The composition of any one of claims 35 to 39, wherein the amount of carboxymethylcellulose is about 100 mg to about 300 mg of sodium carboxymethylcellulose equivalent.

41. The composition of claim 40, wherein the amount of carboxymethylcellulose is about 200 mg to about 250 mg of sodium carboxymethylcellulose equivalent.

42. The composition of claim 40, wherein the amount of carboxymethylcellulose is about 210 mg of sodium carboxymethylcellulose equivalent.

43. The composition of claim 9, wherein the homogeneous mixture comprises a first anionic polymer and a second anionic polymer and wherein the first anionic polymer is carboxymethylcellulose and the second anionic polymer is an acrylic acid polymer.

44. The composition of claim 43, wherein the acrylic acid polymer is a crosslinked acrylic acid polymer.

45. The composition of claim 43 or 44, wherein carboxymethylcellulose is sodium carboxymethylcellulose.

46. The composition of any one of claims 43 to 45, wherein the amount of carboxymethylcellulose is about 23% to about 38% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 7% to about 22% by weight of the tablet core.

47. The composition of claim 46, wherein the amount of carboxymethylcellulose is about 27% to about 34% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 11% to about 15% by weight of the tablet core.

48. The composition of claim 47, wherein the amount of carboxymethylcellulose is about 28% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 12% by weight of the tablet core.

49. The composition of claim 47, wherein the amount of carboxymethylcellulose is about 30% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 13%by weight of the tablet core.

50. The composition of claim 47, wherein the amount of carboxymethylcellulose is about 33% of sodium carboxymethylcellulose equivalent by weight of the tablet core and the amount of the acrylic acid polymer is about 14% by weight of the tablet core.

51. The composition of any one of claims 35 to 45, wherein the amount of carboxymethylcellulose is about 190 mg to about 350 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 60 mg to about 200 mg.

52. The composition of claim 51, wherein the amount of carboxymethylcellulose is about 205 mg to about 335 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 100 mg to about 145 mg.

53. The composition of claim 52, wherein the amount of carboxymethylcellulose is about 238 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 102 mg.

54. The composition of claim 52, wherein the amount of carboxymethylcellulose is about 298 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 128 mg.

55. The composition of claim 52, wherein the amount of carboxymethylcellulose is about 333 mg of sodium carboxymethylcellulose equivalent and the amount of the acrylic acid polymer is about 143 mg.

56. The composition of any one of claims 35 to 45, wherein the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 3:2 to about 2:8.

57. The composition of claim 56, wherein the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 2:3 to about 2:8.

58. The composition of claim 57, wherein the weight ratio of the acrylic acid polymer to sodium carboxymethylcellulose equivalent is about 3:7.

59. The composition of claim 8, wherein the one or more polymers are neutral polymers.

60. The composition of claim 59, wherein the one or more neutral polymers is hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose.

61. The composition of claim 59 or 60, wherein the one or more neutral polymers constitutes about 5% to about 25% by weight of the tablet core.

62. The composition of claim 61, wherein the neutral polymer constitutes about 15% by weight of the tablet core.

63. The composition of any one of claims 1 to 62, wherein the homogeneous mixture further comprises a microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide, or any combination thereof.

64. The composition of claim 63, wherein the homogeneous mixture further comprises a microcrystalline cellulose, magnesium stearate and colloidal silicon dioxide.

65. The composition of claim 63 or 64, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

66. The composition of claim 1, wherein the homogeneous mixture consists essentially of:(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 235 mg to about 245 mg sodium carboxymethylcellulose;(c) about 95 mg to about 105 mg crosslinked acrylic acid polymer;(d) about 175 mg to about 185 mg silicified microcrystalline cellulose;(e) about 5 mg to about 7 mg magnesium stearate; and(f) about 3 mg to about 5 mg colloidal silicon dioxide.

67. The composition of claim 66, wherein the homogeneous mixture consists essentially of:(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 238 mg sodium carboxymethylcellulose;(c) about 102 mg crosslinked acrylic acid polymer;(d) about 180 mg silicified microcrystalline cellulose;(e) about 6 mg magnesium stearate; and(f) about 4 mg colloidal silicon dioxide.

68. The composition of claim 1, wherein the homogeneous mixture consists essentially of:(a) about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate;(b) about 295 mg to about 305 mg sodium carboxymethylcellulose;(c) about 125 mg to about 135 mg crosslinked acrylic acid polymer;(d) about 140 mg to about 150 mg silicified microcrystalline cellulose;(e) about 6 mg to about 8 mg magnesium stearate; and(f) about 4 mg to about 6 mg colloidal silicon dioxide.

69. The composition of claim 68, wherein the homogeneous mixture consists essentially of:(a) about 319 mg dexpramipexole dihydrochloride monohydrate;(b) about 298 mg sodium carboxymethylcellulose;(c) about 128 mg crosslinked acrylic acid polymer;(d) about 145 mg silicified microcrystalline cellulose;(e) about 7 mg magnesium stearate; and(f) about 5 mg colloidal silicon dioxide.

70. The composition of claim 1, wherein the homogeneous mixture consists essentially of: a. about 390 mg to about 410 mg dexpramipexole dihydrochloride monohydrate; b. about 325 mg to about 341 mg sodium carboxymethylcellulose; c. about 135 mg to about 145 mg crosslinked acrylic acid polymer; d. about 230 mg to about 240 mg silicified microcrystalline cellulose; e. about 5 mg to about 10 mg magnesium stearate; and f. about 4 mg to about 7 mg colloidal silicon dioxide.

71. The composition of claim 70, wherein the homogeneous mixture consists essentially of: a. about 400 mg dexpramipexole dihydrochloride monohydrate; b. about 333 mg sodium carboxymethylcellulose; c. about 143 mg crosslinked acrylic acid polymer; d. about 236 mg silicified microcrystalline cellulose; e. about 8 mg magnesium stearate; and f. about 6 mg colloidal silicon dioxide.

72. The composition of claim 1, wherein the homogeneous mixture consists essentially of: a. about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate; b. about 110 mg to about 120 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose; c. about 310 mg to about 320 mg silicified microcrystalline cellulose; d. about 3 mg to about 5 mg magnesium stearate; and e. about 3 mg to about 5 mg colloidal silicon dioxide.

73. The composition of claim 72, wherein the homogeneous mixture consists essentially of: a. about 319 mg dexpramipexole dihydrochloride monohydrate; b. about 113 mg hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose; c. about 313 mg silicified microcrystalline cellulose; d. about 4 mg magnesium stearate; and e. about 4 mg colloidal silicon dioxide.

74. The composition of claim 1, wherein the homogeneous mixture consists essentially of: a. about 315 mg to about 325 mg dexpramipexole dihydrochloride monohydrate; b. about 200 mg to about 220 mg sodium carboxymethylcellulose; c. about 210 mg to about 220 mg silicified microcrystalline cellulose; d. about 3 mg to about 5 mg magnesium stearate; and e. about 3 mg to about 5 mg colloidal silicon dioxide.

75. The composition of claim 74, wherein the homogeneous mixture consists essentially of: a. about 319 mg dexpramipexole dihydrochloride monohydrate; b. about 210 mg sodium carboxymethylcellulose; c. about 214 mg silicified microcrystalline cellulose; d. about 4 mg magnesium stearate; and e. about 4 mg colloidal silicon dioxide.

76. The composition of any one of claims 1 to 75, further comprising a film coating surrounding the tablet core.

77. The composition of claim 76, wherein the film coating comprises polyvinyl alcohol.

78. The composition of claim 77, wherein the film coating further comprises titanium dioxide, polyethylene glycol and talc.

79. The composition of any one of claims 1 to 78, wherein the weight of the tablet is about 1300 mg or less.

80. The composition of claim 79, wherein the weight of the tablet is about 1159 mg.

81. The composition of claim 79, wherein the weight of the tablet is about 1000 mg or less.

82. The composition of claim 81, wherein the weight of the tablet is about 927 mg.

83. The composition of claim 79, wherein the weight of the tablet is about 750 mg to about 900 mg.

84. The composition of claim 83, wherein the weight of the tablet is about 876 mg.

85. The composition of claim 83, wherein the weight of the tablet is about 773 mg.

86. The composition of any one of claims 1 to 85, wherein the tablet is a capsule shaped tablet.

87. The composition of any one of claims 1 to 85, wherein the tablet is an oval shaped tablet.

88. The composition of any one of claims 1 to 87, wherein the length of the short axis of the tablet is about 7.5 mm to about 9.5 mm, the length of the long axis of the tablet is about 18 mm to about 20 mm, and the thickness of the tablet is about 5 mm to about 7 mm.

89. The composition of any one of claims 1 to 88, wherein about 40% to about 80% of dexpramipexole, or the pharmaceutically acceptable salt thereof, is released at about 12 hours of incubation of the tablet in about 900 mL of 50 mM monobasic potassium phosphate buffer, pH 6.8, at a temperature of 37 ± 0.5 °C as measured using an USP type I apparatus operated at a spindle rotation speed of about 100 rpm.

90. The composition of any one of claims 1 to 89, wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, has a chiral purity for dexpramipexole, or the pharmaceutically salt thereof, of 99.96% or more.

91. The composition of any one of claims 1 to 90, comprising 0.02% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet.

92. The composition of claim 91, comprising 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the tablet.

93. A method of treating or preventing asthma in a human subject in need thereof, the method comprising orally administering to the human subject the composition of any one of claims 1 to 92.

94. The method of claim 93, wherein the asthma is eosinophilic asthma.

95. A method of treating or preventing chronic obstructive pulmonary disease in a human subject in need thereof, the method comprising orally administering to the human subject the composition of any one of claims 1 to 92.

96. A method of treating or preventing an eosinophilic disorder in a human subject in need thereof, the method comprising orally administering to the human subject the composition of any one of claims 1 to 92.

97. The method of claim 96, wherein the eosinophilic disorder is selected from the group consisting of hypereosinophilic syndrome, chronic rhinosinusitis with nasal polyps, nasal polyposis, atopic dermatitis, eosinophilic granulomatosis with polyangiitis, eosinophilic gastroenteritis, eosinophilic esophagitis, and any combination thereof.

98. The method of any one of claims 93 to 97, wherein the composition is administered once daily.

99. The composition of any one of claims 1 to 92 for use as a medicament.

100. The composition of any one of claims 1 to 92 for use in a method of any one of claims 93 to 98.

101. Use of the composition of any one of claims 1 to 92 in the manufacture of a medicament for a method of any one of claims 93 to 98.

102. A method of manufacturing densified granules for preparing a sustained release pharmaceutical composition comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers; and preparing densified granules from the pre-blend; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 50% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules and the one or more anionic polymers constitute about 5% to about 60% by weight of the densified granules.

103. The method of claim 102, wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 35% to about 44% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the densified granules.

104. The method of claim 102, wherein the one or more polymers are anionic polymers.

105. The method of claim 104, wherein the one or more anionic polymers constitute about 20% to about 55% by weight of the densified granules.

106. The method of claim 104 or 105, wherein the one or more anionic polymers constitute about 25% to about 50% by weight of the densified granules.

107. The method of claim 106, wherein the one or more anionic polymers constitute about 28% to about 48% by weight of the densified granules.

108. The method of claim 107, wherein the one or more anionic polymers constitute about 28% by weight of the densified granules.

109. The method of claim 106, wherein the one or more anionic polymers constitute about 40% to about 48% by weight of the densified granules.

110. The method of claim 109, wherein the one or more anionic polymers constitute about 48% by weight of the densified granules.

111. The method of claim 109, wherein the one or more anionic polymers constitute about 43% by weight of the densified granules.

112. The method of claim 109, wherein the one or more anionic polymers constitute about 40% by weight of the densified granules.

113. The method of any one of claims 104 to 112, wherein the one or more anionic polymers are selected from carboxymethylcellulose, an acrylic acid polymer, a methacrylic acid polymer, a methacrylic acid copolymer, alignate, carrageenan, xanthan gum, or arabic gum.

114. The method of claim 113, wherein the one or more anionic polymers are selected from carboxymethylcellulose and an acrylic acid polymer.

115. The method of claim 113 or 114, wherein carboxymethylcellulose is sodium carboxymethylcellulose.

116. The method of any one of claims 113 to 115, wherein the acrylic acid polymer is a crosslinked acrylic acid polymer.

117. The method of any one of claims 104 to 116, wherein the pre-blend comprises a first anionic polymer and a second anionic polymer and wherein the first anionic polymer is carboxymethylcellulose and the second anionic polymer is an acrylic acid polymer.

118. The method of claim 117, wherein the acrylic acid polymer is a crosslinked acrylic acid polymer.

119. The method of claim 117 or 118, wherein carboxymethylcellulose is sodium carboxymethylcellulose.

120. The method of any one of claims 117 to 119, wherein carboxymethylcellulose constitutes about 27% to about 34% of sodium carboxymethylcellulose equivalent by weight of the densified granules and the acrylic acid polymer constitutes about 11% to about 15% by weight of the densified granules.

121. The method of claim 120, wherein carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the densified granules and the acrylic acid polymer constitutes about 12% by weight of the densified granules.

122. The method of claim 120, wherein carboxymethylcellulose constitutes about 30% of sodium carboxymethylcellulose equivalent by weight of the densified granules and the acrylic acid polymer constitutes about 12% by weight of the densified granules.

123. The method of claim 120, wherein carboxymethylcellulose constitutes about 33% of sodium carboxymethylcellulose equivalent by weight of the densified granules and the acrylic acid polymer constitutes about 14% by weight of the densified granules.

124. The method of claim 102, wherein the pre-blend comprises one anionic polymer and wherein the anionic polymer is carboxymethylcellulose.

125. The method of claim 124, wherein carboxymethylcellulose is sodium carboxymethylcellulose.

126. The method of claim 124 or 125, wherein carboxymethylcellulose constitutes about 27% to about 29% of sodium carboxymethylcellulose equivalent by weight of the densified granules.

127. The method of claim 126, wherein carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the densified granules.

128. The method of claim 102, wherein the one or more polymers are neutral polymers.

129. The method of claim 128, wherein the one or more neutrals polymer are hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose.

130. The method of claim 128 or 129, wherein the one or more neutral polymers constitute about 5% to about 25% by weight of the densified granules.

131. The method of claim 130, wherein the one or more neutral polymers constitute about 15% by weight of the densified granules.

132. A method of manufacturing a blend for preparing a sustained release pharmaceutical composition comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers; preparing densified granules from the pre-blend; and preparing a blend by mixing the densified granules with a glidant and a lubricant; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 50% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the blend and the one or more polymers constitute about 5% to about 60% by weight of the blend.

133. The method of claim 132, wherein the one or more polymers are anionic polymers.

134. The method of claim 133, wherein the one or more anionic polymers constitute about 20% to about 55% by weight of the blend.

135. The method of claim 132, wherein the one or more polymers are neutral polymers.

136. The method of claiml35, wherein the one or more neutral polymers constitute about 5% to about 25% by weight of the blend.

137. A method of manufacturing a sustained release pharmaceutical composition in the form of an orally deliverable tablet comprising a tablet core with dexpramipexole, or a pharmaceutically acceptable salt thereof, the method comprising: preparing a pre-blend by mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, and one or more polymers;preparing densified granules from the pre-blend; preparing a blend by mixing the densified granules with a glidant and a lubricant; and compressing the blend into a tablet core; wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, constitutes about 30% to about 50% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the blend and the one or more polymers constitute about 5% to about 50% by weight of the blend.

138. The method of claim 137, wherein the one or more polymers are anionic polymers.

139. The method of claim 138, wherein the one or more anionic polymers constitute about 20% to about 55% by weight of the blend.

140. The method of claim 137, further comprising: coating the tablet core with a film coating.

141. The method of claim 140, wherein the film coating comprises polyvinyl alcohol.

142. The method of claim 141, wherein the film coating further comprises titanium dioxide, polyethylene glycol and talc.

143. The method of any one of claims 137 to 142, wherein the glidant is colloidal silicon dioxide and the lubricant is magnesium stearate.

144. The method of any one of claims 137 to 143, wherein the one or more anionic polymers constitute about 25% to about 50% by weight of the blend.

145. The method of claim 144, wherein the one or more anionic polymers constitute about 28% to about 48% by weight of the blend.

146. The method of claim 145, wherein the one or more anionic polymers constitute about 28% by weight of the blend.

147. The method of claim 144, wherein the one or more anionic polymers constitute about 40% to about 48% by weight of the blend.

148. The method of claim 147, wherein the one or more anionic polymers constitute about 48% by weight of the blend.

149. The method of claim 147, wherein the one or more anionic polymers constitute about 43% by weight of the blend.

150. The method of claim 147, wherein the one or more anionic polymers constitute about 40% by weight of the blend.

151. The method of any one of claims 138 to 150, wherein the one or more anionic polymers are selected from carboxymethylcellulose, an acrylic acid polymer, a methacrylic acid polymer, a methacrylic acid copolymer, alignate, carrageenan, xanthan gum, or arabic gum.

152. The method of any one of claims 138 to 151, wherein the one or more anionic polymers are selected from carboxymethylcellulose and an acrylic acid polymer.

153. The method of claim 151 or 152, wherein carboxymethylcellulose is sodium carboxymethylcellulose.

154. The method of any one of claims 151 to 153, wherein the acrylic acid polymer is a crosslinked acrylic acid polymer.

155. The method of any one of claims 138 to 154, wherein the pre-blend comprises a first anionic polymer and a second anionic polymer and wherein the first anionic polymer is carboxymethylcellulose and the second anionic polymer is an acrylic acid polymer.

156. The method of claim 155, wherein the acrylic acid polymer is a crosslinked acrylic acid polymer.

157. The method of claim 155 or 156, wherein carboxymethylcellulose is sodium carboxymethylcellulose.

158. The method of any one of claims 155 to 157, wherein carboxymethylcellulose constitutes about 27% to about 34% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 11% to about 15% by weight of the blend.

159. The method of claim 158, wherein carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 12% by weight of the blend.

160. The method of claim 158, wherein carboxymethylcellulose constitutes about 30% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 13% by weight of the blend.

161. The method of claim 158, wherein carboxymethylcellulose constitutes about 33% of sodium carboxymethylcellulose equivalent by weight of the blend and the acrylic acid polymer constitutes about 14% by weight of the blend.

162. The method of claim 137, wherein the pre-blend comprises one anionic polymer and wherein the anionic polymer is carboxymethylcellulose.

163. The method of claim 162, wherein carboxymethylcellulose is sodium carboxymethylcellulose.

164. The method of any one of claims 162 to 163, wherein carboxymethylcellulose constitutes about 27% to about 29% of sodium carboxymethylcellulose equivalent by weight of the blend.

165. The method of claim 164, wherein carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the blend.

166. The method of claim 137, wherein the one or more polymers are neutral polymers.

167. The method of claim 166, wherein the one or more neutral polymers are hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose.

168. The method of claim 166 or 167, wherein the one or more neutral polymers constitute about 5% to about 25% by weight of the blend.

169. The method of claim 168, wherein the one or more neutral polymers constitute about 15% by weight of the blend.

170. The method of any one of claims 137 to 169, wherein the densified granules constitute about 99% by weight of the blend.

171. The method of claim 170, wherein the glidant constitutes about 0.5% by weight of the blend and the lubricant constitutes about 0.5% by weight of the blend.

172. The method of any one of claims 102 to 171, wherein the pharmaceutically acceptable salt of dexpramipexole is a methane sulfonic acid salt, sulfuric acid salt, tartaric acid salt, - toluene sulfonic acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, malic acid salt, citric acid salt, succinic acid salt, or any combination thereof.

173. The method of any one of claims 102 to 171, wherein the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride or a hydrate thereof.

174. The method of claim 173, wherein the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride monohydrate.

175. The method of claim 137, wherein the blend consists essentially of:(a) about 35% to about 40% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 25% to about 30% sodium carboxymethylcellulose by weight of the blend;(c) about 10% to about 15% crosslinked acrylic acid polymer by weight of the blend;(d) about 18% to about 23% silicified microcrystalline cellulose by weight of the blend;(e) about 0.5% to about 1.0% magnesium stearate by weight of the blend; and(f) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

176. The method of claim 175, wherein the blend consists essentially of:(a) about 38% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 28% sodium carboxymethylcellulose by weight of the blend;(c) about 12% crosslinked acrylic acid polymer by weight of the blend;(d) about 21% silicified microcrystalline cellulose by weight of the blend;(e) about 0.75% magnesium stearate by weight of the blend; and(f) about 0.5% colloidal silicon dioxide by weight of the blend.

177. The method of claim 137, wherein the blend consists essentially of:(a) about 33% to about 38% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 30% to about 35% sodium carboxymethylcellulose by weight of the blend;(c) about 12% to about 17% crosslinked acrylic acid polymer by weight of the blend;(d) about 13% to about 18% silicified microcrystalline cellulose by weight of the blend;(e) about 0.5% to about 1.0% magnesium stearate by weight of the blend; and(f) about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

178. The method of claim 177, wherein the blend consists essentially of:(a) about 35% dexpramipexole dihydrochloride monohydrate by weight of the blend;(b) about 33% sodium carboxymethylcellulose by weight of the blend;(c) about 14% crosslinked acrylic acid polymer by weight of the blend;(d) about 16% silicified microcrystalline cellulose by weight of the blend;(e) about 0.75% magnesium stearate by weight of the blend; and(f) about 0.5% colloidal silicon dioxide by weight of the blend.

179. The method of claim 137, wherein the blend consists essentially of: a. about 33% to about 39% dexpramipexole dihydrochloride monohydrate by weight of the blend; b. about 27% to about 33% sodium carboxymethylcellulose by weight of the blend; c. about 10% to about 16% crosslinked acrylic acid polymer by weight of the blend; d. about 18% to about 24% silicified microcrystalline cellulose by weight of the blend; e. about 0.5% to about 1.0% magnesium stearate by weight of the blend; and f. about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

180. The method of claim 179, wherein the blend consists essentially of: a. about 36% dexpramipexole dihydrochloride monohydrate by weight of the blend; b. about 30% sodium carboxymethylcellulose by weight of the blend; c. about 13% crosslinked acrylic acid polymer by weight of the blend; d. about 21% silicified microcrystalline cellulose by weight of the blend; e. about 0.75% magnesium stearate by weight of the blend; and f. about 0.5% colloidal silicon dioxide by weight of the blend.

181. The method of claim 137, wherein the blend consists essentially of:a. about 40% to about 46% dexpramipexole dihydrochloride monohydrate by weight of the blend; b. about 10% to about 20% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend; c. about 38% to about 46% silicified microcrystalline cellulose by weight of the blend; d. about 0.25% to about 0.75% magnesium stearate by weight of the blend; and e. about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

182. The method of claim 181, wherein the blend consists essentially of: a. about 43% dexpramipexole dihydrochloride monohydrate by weight of the blend; b. about 15% hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose by weight of the blend; c. about 42% silicified microcrystalline cellulose by weight of the blend; d. about 0.5% magnesium stearate by weight of the blend; and e. about 0.5% colloidal silicon dioxide by weight of the blend.

183. The method of claim 137, wherein the blend consists essentially of: a. about 40% to about 46% dexpramipexole dihydrochloride monohydrate by weight of the blend; b. about 24% to about 32% sodium carboxymethylcellulose by weight of the blend; c. about 25% to about 34% silicified microcrystalline cellulose by weight of the blend; d. about 0.25% to about 0.75% magnesium stearate by weight of the blend; and e. about 0.25% to about 0.75% colloidal silicon dioxide by weight of the blend.

184. The method of claim 183, wherein the blend consists essentially of: a. about 43% dexpramipexole dihydrochloride monohydrate by weight of the blend; b. about 28% sodium carboxymethylcellulose by weight of the blend; c. about 29% silicified microcrystalline cellulose by weight of the blend; d. about 0.5% magnesium stearate by weight of the blend; and e. about 0.5% colloidal silicon dioxide by weight of the blend.

185. The method of any one of claims 137 to 184, wherein preparing the blend comprises: mixing the densified granules with the glidant thereby providing a mixture of the densified granules and the glidant; andmixing the mixture of the densified granules and the glidant with the lubricant thereby providing the blend.

186. The method of any one of claims 102 to 185, wherein preparing the pre-blend comprises: mixing dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more polymers and a microcrystalline cellulose thereby providing a mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more polymers and the microcrystalline cellulose; and mixing the mixture of dexpramipexole, or a pharmaceutically acceptable salt thereof, the one or more polymers and the microcrystalline cellulose with magnesium stearate thereby providing the pre-blend.

187. The method of claim 186, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

188. The method of any one of claims 102 to 187, wherein the pre-blend further comprises a microcrystalline cellulose, magnesium stearate, or a combination thereof.

189. The method of claim 188, wherein the pre-blend further comprises a microcrystalline cellulose and magnesium stearate.

190. The method of claim 188 or 189, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

191. The method of any one of claims 102 to 190, wherein the densified granules are prepared by dry granulation.

192. The method of any one of claims 102 to 190, wherein the densified granules are prepared by roller compaction.

193. A mixture comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, constituting about 30% to about 50% of dexpramipexole dihydrochloride monohydrate equivalent by weight of the mixture and about 5% to about 60% of one or more polymers by weight of the mixture.

194. The mixture of claim 193, wherein the one or more polymers are anionic polymers.

195. The mixture of claim 194, wherein the one or more anionic polymers constitute about 25% to about 50% by weight of the mixture.

196. The mixture of claim 194, wherein the one or more anionic polymers constitute about 28% to about 48% by weight of the mixture.

197. The mixture of claim 196, wherein the one or more anionic polymers constitute about 28% by weight of the mixture.

198. The mixture of claim 196, wherein the one or more anionic polymers constitute about 40% to about 48% by weight of the mixture.

199. The mixture of claim 198, wherein the one or more anionic polymers constitute about 40% by weight of the mixture.

200. The mixture of claim 198, wherein the one or more anionic polymers constitute about 43% by weight of the mixture.

201. The mixture of claim 198, wherein the one or more anionic polymers constitute about 48% by weight of the mixture.

202. The mixture of any one of claims 193 to 201, wherein the pharmaceutically acceptable salt of dexpramipexole is a methane sulfonic acid salt, sulfuric acid salt, tartaric acid salt, p- toluene sulfonic acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, malic acid salt, citric acid salt, succinic acid salt, or any combination thereof.

203. The mixture of any one of claims 193 to 201, wherein the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride or a hydrate thereof.

204. The mixture of claim 203, wherein the pharmaceutically acceptable salt of dexpramipexole is dexpramipexole dihydrochloride monohydrate.

205. The mixture of any one of claims 194 to 204, wherein the one or more anionic polymers are selected from carboxymethylcellulose, an acrylic acid polymer, a methacrylic acid polymer, a methacrylic acid copolymer, alignate, carrageenan, xanthan gum, or arabic gum.

206. The mixture of any one of claims 194 to 205, wherein the one or more anionic polymers are selected from carboxymethylcellulose and an acrylic acid polymer.

207. The mixture of claim 205 or 206, wherein carboxymethylcellulose is sodium carboxymethylcellulose.

208. The mixture of any one of claims 205 to 207, wherein the acrylic acid polymer is a crosslinked acrylic acid polymer.

209. The mixture of any one of claims 194 to 208, comprising a first anionic polymer and a second anionic polymer, wherein the first anionic polymer is carboxymethylcellulose and the second anionic polymer is an acrylic acid polymer.

210. The mixture of claim 209, wherein the acrylic acid polymer is a crosslinked acrylic acid polymer.

211. The mixture of claim 209 or 210, wherein carboxymethylcellulose is sodium carboxymethylcellulose.

212. The mixture of any one of claims 209 to 211, wherein carboxymethylcellulose constitutes about 27% to about 34% of sodium carboxymethylcellulose equivalent by weight of the mixture and the acrylic acid polymer constitutes about 11% to about 15% by weight of the mixture.

213. The mixture of 212, wherein carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the mixture and the acrylic acid polymer constitutes about 12% by weight of the mixture.

214. The mixture of claim 212, wherein carboxymethylcellulose constitutes about 30% of sodium carboxymethylcellulose equivalent by weight of the mixture and the acrylic acid polymer constitutes about 13% by weight of the mixture.

215. The mixture of claim 212, wherein carboxymethylcellulose constitutes about 33% of sodium carboxymethylcellulose equivalent by weight of the mixture and the acrylic acid polymer constitutes about 14% by weight of the mixture.

216. The mixture of claim 193, comprising one anionic polymer and wherein the anionic polymer is carboxymethylcellulose.

217. The mixture of claim 216, wherein carboxymethylcellulose is sodium carboxymethylcellulose.

218. The mixture of any one of claims 216 to 217, wherein carboxymethylcellulose constitutes about 27% to about 29% of sodium carboxymethylcellulose equivalent by weight of the mixture.

219. The mixture of claim 218, wherein carboxymethylcellulose constitutes about 28% of sodium carboxymethylcellulose equivalent by weight of the mixture.

220. The mixture of claim 193, wherein the one or more polymers are netural polymers.

221. The mixture of claim 220, wherein the one or more neutral polymers are hydroxypropyl methylcellulose or silicified hydroxypropyl methylcellulose.

222. The mixture of claim 220 or 221, wherein the one or more neutral polymers constitute about 5% to about 25% by weight of the mixture.

223. The mixture of claim 222, wherein the one or more neutral polymers constitute about 15% by weight of the mixture.

224. The mixture of claim 193, consisting essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, and two anionic polymers.

225. The mixture of claim 193, consisting essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one anionic polymer.

226. The mixture of claim 193, consisting essentially of dexpramipexole, or a pharmaceutically acceptable salt thereof, and one neutral polymer.

227. The mixture of any one of claims 193 to 226, further comprising a microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide, or any combination thereof.

228. The mixture of any one of claims 193 to 227, wherein dexpramipexole, or the pharmaceutically acceptable salt thereof, has a chiral purity for dexpramipexole, or the pharmaceutically salt thereof, of 99.96% or more.

229. The mixture of any one of claims 193 to 228, comprising 0.02% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the mixture.

230. The mixture of claim 229, comprising 0.015% or less pramipexole, or a pharmaceutically acceptable salt thereof, by weight of the mixture.

231. A sustained release pharmaceutical composition comprising the mixture according to any one of claims 193 to 230.

232. The composition of claim 231, comprising dexpramipexole, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg to about 500 mg of dexpramipexole dihydrochloride equivalent.

233. The composition of claim 232, wherein the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 300 mg of dexpramipexole dihydrochloride equivalent.

234. The composition of claim 232, wherein the amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 376 mg of dexpramipexole dihydrochloride equivalent.

235. The composition of any one of claims 231 to 234, wherein the weight of the composition is about 1500 mg or less.

236. The composition of claim 235, wherein the weight of the composition is about 1300 mg or less.

237. The composition of claim 236, wherein the weight of the composition is about 1000 mg or less.

238. The composition of any one of claims 231 to 238, wherein the composition is an orally deliverable capsule.

239. The composition of claim 238, wherein the capsule comprises the mixture enclosed in one or more beads.

240. The composition of any one of claims 231 to 239, wherein the composition is an orally deliverable tablet.

241. A method of treating or preventing asthma in a human subject in need thereof, the method comprising orally administering to the human subject the composition of any one of claims 231 to 240.

242. The method of claim 241, wherein the asthma is eosinophilic asthma.

243. A method of treating or preventing chronic obstructive pulmonary disease in a human subject in need thereof, the method comprising orally administering to the human subject the composition of any one of claims 231 to 240.

244. A method of treating or preventing an eosinophilic disorder in a human subject in need thereof, the method comprising orally administering to the human subject the composition of any one of claims 231 to 240.

245. The method of claim 245, wherein the eosinophilic disorder is selected from the group consisting of hypereosinophilic syndrome, chronic rhinosinusitis with nasal polyps, nasal polyposis, atopic dermatitis, eosinophilic granulomatosis with polyangiitis, eosinophilic gastroenteritis, eosinophilic esophagitis, and any combination thereof.

246. The method of any one of claims 241 to 245, wherein the composition is administered once daily.

247. The composition of any one of claims 231 to 240 for use as a medicament.

248. The composition of any one of claims 231 to 240 for use in a method of any one of claims 241 to 246.

249. Use of the composition of any one of claims 231 to 240 in the manufacture of a medicament for a method of any one of claims 240 to 246.

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