WO2022132978A1

WO2022132978A1 - Modified release solid oral dosage form for once daily administration of monomethyl fumarate

Info

Publication number: WO2022132978A1
Application number: PCT/US2021/063632
Authority: WO
Inventors: Chandrashekar Giliyar; JR. Kenneth William UTECHT; Sarah Jane OLSON; Basawaraj Chickmath; Blake William JOHNSON
Original assignee: Upsher-Smith Laboratories, Llc
Priority date: 2020-12-18
Filing date: 2021-12-15
Publication date: 2022-06-23

Abstract

This disclosure describes a dosage form formulated for once daily oral administration that includes monomethyl fumarate (MMF). In some embodiments, the dosage form may preferably be a solid dosage form. In some embodiments, the dosage form may be a tablet including, for example, a press-coated tablet. In some embodiments, the dosage form may include a first portion wherein the first portion includes a first amount of monomethyl fumarate, and a second portion, wherein the second portion includes a second amount of monomethyl fumarate.

Description

MODIFIED RELEASE SOLID ORAL DOSAGE FORM FOR ONCE DAILY ADMINISTRATION OF MONOMETHYL FUMARATE

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/127,454 filed 18 December 2020, the disclosure of which is incorporated by reference herein in its entirety.

BACKGROUND

Fumarates including monomethyl fumarate (MMF) and dimethyl fumarate (DMF) are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis.

SUMMARY OF THE INVENTION

This disclosure describes a dosage form that includes monomethyl fumarate (MMF) that is formulated for once daily oral administration and methods of using that dosage form.

In one aspect, this disclosure describes a dosage form that includes 150 mg to 500 mg of monomethyl fumarate formulated for once daily administration.

In some embodiments, once daily oral administration of the dosage form to a subject provides a pharmacokinetic parameter selected from: a plasma monomethyl fumarate Cmax of 0.4 mg/L to 4.3 mg/L; a plasma monomethyl fumarate AUCo-24h of 1.8 h*mg/L to 14.9 h*mg/L; or a plasma monomethyl fumarate elimination half-life (ti/2) of 0.9 hours to 2.3 hours; or any combination thereof.

In some embodiments, the dosage form includes a press-coated tablet, the press-coated tablet including a first portion and a second portion, wherein the first portion comprises a first amount of monomethyl fumarate and the second portion comprises a second amount of monomethyl fumarate, and wherein a ratio of the first amount of monomethyl fumarate to the second amount of monomethyl fumarate is in a range of 1 :0.5 to 1 :2. After administration to a subject, the first portion releases the first amount of monomethyl fumarate within a first period of time and the second portion releases the second amount of monomethyl fumarate within a second period of time. The first period of time is in a range of 0.5 hours to 12 hours post-administration and the second period of time begins at least 6 hours post-administration. In some embodiments, the press-coated tablet has a first axis (X-Y) in a range of 9 mm to 22 mm and a second axis (A-B) in a range of 5 mm to 8 mm, wherein the first axis is orthogonal to the second axis. In some embodiments, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of 0.1 N hydrochloric acid as dissolution medium, maintained at a temperature of 37°C, the dosage form releases less than 10 % w/w of the monomethyl fumarate present in the dosage form within 2 hours after the start of the test.

In some embodiments, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of USP Simulated Gastric Fluid pH 1.2 as dissolution medium, maintained at a temperature of 37°C, at least 10 % w/w of the monomethyl fumarate present in the dosage form is released within 2 hours after the start of the test.

In some embodiments, the dosage form comprises a first portion and a second portion, wherein the first portion comprises a first amount of monomethyl fumarate and the second portion comprises a second amount of monomethyl fumarate. In some embodiments, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 6.0 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, at least 70 % w/w of the first amount of monomethyl fumarate is released within 6 hours after the start of the test. In some embodiments, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of 0.1 N hydrochloric acid as dissolution medium, maintained at a temperature of 37 °C, and wherein no more than 10 % w/w of the monomethyl fumarate present in the dosage form is released within 2 hours after the start of the test. At the end of 2 hours, if the tablet sinker with its contents is further tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of pH 6.0 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, substantially all of the first amount of monomethyl fumarate is released within 6 hours after the start of the test in pH 6.0 phosphate buffer as dissolution medium. Or, alternatively, at the end of 2 hours, if the tablet sinker with its contents is further tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of pH 6.5 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, substantially all of the first amount of monomethyl fumarate is released within 6 hours after the start of the test in pH 6.5 phosphate buffer as dissolution medium. Or, alternatively, at the end of 2 hours, if the tablet sinker with its contents is further tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of pH 7.5 phosphate buffer as dissolution medium, maintained at a temperature of 37°C, substantially all monomethyl fumarate in the dosage form is released within 6 hours after the start of the test in pH 7.5 phosphate buffer as dissolution medium.

In some embodiments, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 6.8 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, 30 % w/w to 90 % w/w of the monomethyl fumarate present in the dosage form is released within 14 hours after the start of the test.

In some embodiments, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 6.5 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, 30 % w/w to 80 % w/w of the monomethyl fumarate present in the dosage form is released within 14 hours after the start of the test.

In some embodiments, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 7.5 phosphate buffer dissolution medium, maintained at a temperature of 37 °C, at least 80 % w/w of the monomethyl fumarate present in the dosage form is released within 6 hours after the start of the test.

In some embodiments, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form releases monomethyl fumarate as follows: no more than 10 % w/w of the monomethyl fumarate present in the dosage form is released within 2 hours after the start of the test when 900 mL of 0.1 N hydrochloric acid, maintained at a temperature of 37 °C, is used as dissolution medium, and/or 30 % w/w to 70 % w/w of the monomethyl fumarate present in the dosage form is released within 6 hours after the start of the test when 900 mL of pH 6.0 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution medium.

In some embodiments, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form releases monomethyl fumarate as follows: no more than 10 % w/w of the monomethyl fumarate present in the dosage form is released within 2 hours after the start of the test when 900 mL of 0.1 N hydrochloric acid, maintained at a temperature of 37 °C, is used as dissolution medium, and/or 30 % w/w to 70 % w/w of the monomethyl fumarate present in the dosage form is released within 6 hours after the start of the test when 900 mL of pH 6.5 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution medium.

In some embodiments, upon oral administration to a subject, the dosage form provides at least two pharmacokinetic parameters selected from: a plasma monomethyl fumarate Cmax of 0.4 mg/L to 4.3 mg/L; a plasma monomethyl fumarate AUCo-24h of 1.8 h*mg/L to 14.9 h*mg/L; and a plasma monomethyl fumarate elimination half-life (ti/2) of 0.9 hours to 2.3 hours. In addition, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form releases monomethyl fumarate as follows: (a) no more than 10 % w/w of the monomethyl fumarate present in the dosage form is released within 2 hours after the start of the test when 900 mL of 0.1 N hydrochloric acid, maintained at a temperature of 37 °C is used as dissolution medium, and (b) substantially all monomethyl fumarate in the dosage form is released within 6 hours after the start of the test when 900 mL of pH 7.5 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution media; wherein the tablet sinker with its contents at the end of 2 hours in step (a) is used in step (b).

In another aspect, this disclosure describes a dosage form including 150 mg to 500 mg of monomethyl fumarate and a means for achieving, upon once daily administration to a subject, a plasma monomethyl fumarate Cmax of 0.4 mg/L to 4.3 mg/L; a plasma monomethyl fumarate AUCo-24h of 1.8 h*mg/L to 14.9 h*mg/L; or a plasma monomethyl fumarate elimination half-life (ti/2) of 0.9 hours to 2.3 hours; or any combination thereof.

In another aspect, this disclosure describes a method for treating or reducing the symptoms of multiple sclerosis or psoriasis in a subject that includes once daily administration to the subject of a dosage form including, for example, a press-coated tablet, as described herein.

In another aspect, this disclosure describes a method of treating multiple sclerosis or psoriasis that includes administering to a subject in need thereof a dosage form including, for example, a press-coated tablet, as described herein.

As used herein, AUC(O-T) is the area under the curve of a graph of the concentration of an active agent (typically plasma concentration) vs. time (T), measured from time 0 to T. AUC(O-T) is also used to define the exposure to the drug over a defined period of time. AUC(O-T) is typically reported herein for a time period measured from 0 to 24 hours (AUC0-24 or AUCo-24h) or for a time period measured from 0 to 12 hours (AUC0-12 or AUCo- ).

As used herein, Cmax is the measured concentration of an active agent (for example, MMF) in the plasma of a subject at the point of maximum concentration. As used herein, Tmax is the time to reach maximum plasma concentration (Cmax). As used herein, t1/2 is the plasma elimination half-life and represents the amount of time required for the plasma concentration of an active agent (for example, MMF) to decrease to half of its starting dose in the body. As used herein, kel is the elimination rate constant for an active agent (for example, MMF), and is estimated using the relationship: t1/2 = (0.693/kel). Unless otherwise specified, the pharmacokinetic profiles and characteristic parameters thereof including AUC_(0-τ), C_max, T_max, t_1/2 and k_el are based on a pharmacokinetic evaluation performed upon inistration of a single (that is, unit) dose to a human subject. In some

embodiments, a single dose may include a single dosage form (for example, a single tablet) or multiple dosage forms (for example, multiple tablets) administered at the same dosing time. As used herein D(n) is the diameter wherein (n*100)% of the particles in a sample are smaller, on a volume basis. For example, D(0.9) is the diameter of a sphere at which 90 % of the particles are smaller on a volume basis. The volume diameter of drug particles in a sample may preferably be determined using a laser diffraction technique. An exemplary laser diffraction instruments for determining the volume diameter of a particle (including, for example, a drug particle) using laser diffraction is a MALVERN MASTERSIZER® 2000. The particle size distribution of aggregated particles (including, for example, granulated particles including drug particles alone or in combination with other inactive particles) in a sample may preferably be determined using standard sieves or mesh sizes (for example, according to ASTM E11-20). D(0.1), D(0.5) and D(0.9) together represent volume-weighted particle size distribution obtained, for example, by laser diffraction measurements. D(0.5), also written as D50 % or Dv50, is the maximum particle diameter below which 50 % of the sample volume exists and is also referred to as the median particle size by volume. As used herein, “molecular weight” refers to the sum of the atomic masses of all atoms in a molecule, based on a scale in which the atomic masses of hydrogen, carbon, nitrogen, and oxygen are 1, 12, 14, and 16, respectively. The term “substantially” as used here has the same meaning as “significantly,” and can be understood to modify the term that follows by at least about 95 %, at least about 98 %, or at least about 99 %. The term “substantially free” of a particular compound means that the composition contains less than 1 wt-% of the recited compound. The words “preferred” and “preferably” refer to embodiments of the invention that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful and is not intended to exclude other embodiments from the scope of the invention.

The terms “comprises” and variations thereof do not have a limiting meaning where these terms appear in the description and claims. Such terms will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements.

By “consisting of’ is meant including, and limited to, whatever follows the phrase “consisting of.” Thus, the phrase “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present. By “consisting essentially of’ is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of’ indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they materially affect the activity or action of the listed elements.

Unless otherwise specified, “a,” “an,” “the,” and “at least one” are used interchangeably and mean one or more than one. As used herein, the term “or” is generally employed in its usual sense including “and/or” unless the content clearly dictates otherwise. The term “and/or” means one or all of the listed elements or a combination of any two or more of the listed elements.

Any reference to standard methods (for example, United States Pharmacopoeia/National Formulary (USP/NF), ASTM, etc.} refer to the most recent available version of the method at the time of filing of this disclosure unless otherwise indicated.

Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (for example, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.}. Herein, “up to” a number (for example, up to 50) includes the number (for example, 50). The term “in the range” or “within a range” (and similar statements) includes the endpoints of the stated range.

For any method disclosed herein that includes discrete steps, the steps may be conducted in any feasible order. And, as appropriate, any combination of two or more steps may be conducted simultaneously. All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified.

Reference throughout this specification to “one embodiment,” “an embodiment,” “certain embodiments,” or “some embodiments,” etc., means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” As one of ordinary skill in the art would understand, the exact boundary of “about” will depend on the component of the composition. Illustratively, the use of the term “about” indicates that values slightly outside the cited values, that is, plus or minus 0.1% to 10 %, which are also effective and safe. Thus, compositions slightly outside the cited ranges are also encompassed by the scope of the present claims. As used herein in connection with a measured quantity in the Examples, the term “about” refers to that variation in the measured quantity as would be expected by the skilled artisan making the measurement and exercising a level of care commensurate with the objective of the measurement and the accuracy of the measuring equipment used. Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

As used herein, “substantially all” means at least 90 % or, more preferably, at least 95%, and most preferably, at least 98%.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. All numerical values, however, inherently contain a range necessarily resulting from the standard deviation found in their respective testing measurements. The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1, 2, and 3 show in vitro dissolution profiles as described in Example 3 A.

FIGS. 4, 5, and 6 show exemplary release profiles from once-daily MMF tablet dosage forms at various ratios of MMF in the first and second portions as described in Example 3B.

FIG. 7 shows an illustration of the A-B and X-Y axes of an exemplary once-daily MMF tablet dosage form. When the tablet includes an optional ellipsoid core, the core may have a longest axis x’-y’.

FIG. 8 shows an illustration of an exemplary press-coated once-daily MMF tablet according to one embodiment of the present invention.

FIGS. 9A and 9B show an exemplary manufacturing process for a press-coated once-daily MMF tablet according to one embodiment of the present invention.

FIG. 10 shows the in vitro dissolution profile from a coated press-coated once-daily MMF tablet prepared in accordance with one embodiment of the present invention.

FIG. 11 shows the in vitro dissolution profile from a press-coated once-daily MMF tablet prepared in accordance with one embodiment of the present invention.

DETAILED DESCRIPTION

This disclosure describes a dosage form formulated for once daily oral administration that includes monomethyl fumarate (MMF) and methods of using that dosage form.

Tecfidera and Bafiertam

TECFIDERA® is a hard gelatin capsule dosage form including dimethyl fumarate (DMF) indicated for the treatment of patients with relapsing forms of multiple sclerosis. DMF is a prodrug of monomethyl fumarate (MMF). The product label for TECFIDERA directs that a starting dose of 120 mg of DMF be administered twice a day (total 240 mg DMF per day), orally, for 7 days, then after 7 days a maintenance dose of 240 mg of DMF be administered twice a day (total 480 mg DMF per day), orally. TECFIDERA is offered in two strengths - 120 mg DMF per capsule and 240 mg DMF per capsule.

BAFIERTAM® is a soft gelatin capsule including MMF indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsingremitting disease, and active secondary progressive disease, in adults. The product label BAFIERTAM directs that a starting dose of 95 mg of MMF be administered twice a day (total 190 mg MMF per day), orally, for 7 days, then after 7 days a maintenance dose of 190 mg of MMF (administered as two 95 mg capsules) be administered twice a day (total 380 mg MMF per day), orally. BAFIERTAM is offered in a single strength: 95 mg MMF per capsule. Additionally, BAFIERTAM requires refrigerated storage (2 °C-8 °C) until the bottle is opened for use. Once the bottle is opened, BAFIERTAM may be stored at room temperature for not more than 3 months.

The twice-daily dosing scheme of both TECFIDERA and BAFIERTAM has been identified as one of the main barriers of patient adherence to treatment. Specifically, administering multiple dosage units at each dosing time per day poses even more significant challenges to patient compliance to treatment with MMF. A once daily administration of MMF would, therefore, be advantageous.

Dosage Form

In some embodiments, the dosage form may preferably be a solid dosage form. In some embodiments, the solid dosage form may be a tablet. In some embodiments, the solid dosage form may be a capsule.

Exemplary tablets include a modified-release tablet, a delayed-release tablet, a sustained release matrix tablet, a press-coated tablet, a multiple-layered tablet, or a timed-release tablet, or any combination thereof. In some embodiments, the solid dosage form may preferably be a press- coated tablet. In some embodiments, the press-coated tablet may include a tablet-in-tablet.

In embodiments where the dosage form includes a tablet, the tablet may preferably be a modified-release tablet. Exemplary modified release tablets include a delayed-release tablet; a controlled release tablet; an extended-release tablet; a sustained release tablet; a matrix tablet; an osmotic-controlled release tablet; a coated tablet including, for example, a press-coated tablet; a multiple-layered tablet; a timed-release tablet; etc. Combinations of these tablets are also envisioned. In some embodiments, the dosage form may preferably be a coated tablet. In some embodiments, the solid dosage form may include a tablet having multiple coatings. The tablet may include a first portion and a second portion, where the second portion forms a core and the first portion is disposed (e.g., completely surrounds) the core. Each of the first and second portions may include MMF. The core may be coated with a core coat. The core may further be surrounded by a barrier layer disposed between the core and the core coat. The tablet may be coated with a tablet coat. The core coat, the tablet coat, or both may include an enteric coating or a delayed release coating. In some embodiments, the tablet is coated with an enteric coating. In some embodiments, the core is coated with a delayed release coating. In some embodiments, one or more coat layers includes MMF.

In some embodiments, the tablet may preferably be a press-coated tablet. In some embodiments, the press-coated tablet includes a tablet-in-tablet. The tablet-in-tablet may include a core. The core may be coated with a core coat. The core may include a barrier layer disposed between the core and the core coat. The press-coated tablet may be coated with a tablet coat. The core coat, the tablet coat, or both may include an enteric coating or a delayed release coating. In some embodiments, the tablet is coated with an enteric coating. In some embodiments, the core is coated with a delayed release coating.

In some embodiments, the dosage form is preferably room temperature stable for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the dosage form is preferably room temperature stable for up to 12 months, up to 24 months, or up to 3 years. In some embodiments, the dosage form is preferably room temperature stable throughout an expected shelf-life of the tablet.

In some embodiments, the dosage form is preferably an oral dosage form.

In some embodiments, the dosage form is preferably a unit dosage form. In some embodiments, a single (that is, unit) dose may include a single dosage form (for example, a single tablet) or multiple dosage forms (for example, multiple tablets). In some embodiments, the dosage form includes 150 mg to 500 mg of monomethyl fumarate.

In some embodiments, the dosage form includes 150 mg to 250 mg of monomethyl fumarate. For example, in an exemplary embodiment, the dosage form includes 175 mg to 225 mg of monomethyl fumarate. In another exemplary embodiment, the dosage form includes 190 mg of monomethyl fumarate. In some embodiments, the dosage form includes 300 mg to 500 mg of monomethyl fumarate. For example, in an exemplary embodiment, the dosage form includes 350 mg to 450 mg of monomethyl fumarate. In another exemplary embodiment, the dosage form includes 380 mg of monomethyl fumarate.

In some embodiments, the dosage form may include multiple portions (for example, a first portion, a second portion, a third portion, etc.}. For example, the dosage form may include a first portion and a second portion, wherein the first portion comprises a first amount of MMF and the second portion comprises a second amount of MMF. In some embodiments, the dosage form may include a third portion. The third portion may include a third amount of MMF.

Exemplary amounts of monomethyl fumarate in a first portion (for example, an outer portion) and a second portion (for example, a core portion) are shown in Table 3A - Table 3H.

In some embodiments when the dosage form includes multiple portions, when the dosage the first portion includes at least 50 mg MMF, at least 75 mg MMF, at least 100 mg MMF, at least 125 mg MMF, at least 150 mg MMF, at least 175 mg MMF, at least 200 mg MMF, at least 225 mg MMF, at least 250 mg MMF, at least 275 mg MMF, at least 300 mg MMF, or at least 325 mg MMF. In some embodiments, the first portion includes up to 50 mg MMF, up to 75 mg MMF, up to 100 mg MMF, up to 125 mg MMF, up to 150 mg MMF, up to 175 mg MMF, up to 200 mg MMF, up to 225 mg MMF, up to 250 mg MMF, up to 275 mg MMF, up to 300 mg MMF, up to 325 mg MMF, or up to 350 mg MMF. Exemplary ranges for the amount of MMF in the first portion include 50 mg to 350 mg, 50 mg to 175 g, 50 mg to 200 g, 50 mg to 225 mg, 75 mg to 250 mg, 75 mg to 300 mg, 75 mg to 325 mg, and 100 mg to 350 mg.

In some embodiments when the dosage form includes multiple portions, the second portion includes at least 47 mg MMF, at least 50 mg MMF, at least 75 mg MMF, at least 100 mg MMF, at least 125 mg MMF, at least 150 mg MMF, at least 175 mg MMF, at least 200 mg MMF, at least 225 mg MMF, at least 250 mg MMF, at least 275 mg MMF, at least 300 mg MMF, or at least 325 mg MMF. In some embodiments, the second portion includes up to 50 mg MMF, up to 75 mg MMF, up to 100 mg MMF, up to 125 mg MMF, up to 150 mg MMF, up to 175 mg MMF, up to 200 mg MMF, up to 225 mg MMF, up to 250 mg MMF, up to 275 mg MMF, up to 300 mg MMF, up to 325 mg MMF, or up to 350 mg MMF. Exemplary ranges for the amount of MMF in the second portion include 47 mg to 350 mg, 47 mg to 175 mg, 50 mg to 175 mg, 50 mg to 200 mg, 50 mg to 225 mg, 75 mg to 250 mg, 75 mg to 300 mg, 75 mg to 325 mg, and 100 mg to 350 mg. In some embodiments, when the MMF of the dosage form includes particles, the particles have a particle size distribution wherein D(0.9) is 250 µm or less, 225 µm or less, 200 µm or less, 175 µm or less, 150 µm or less, 125 µm or less, 100 µm or less, 80 µm or less, 70 µm or less, 50 µm or less, 40 µm or less, 20 µm or less. In some embodiments, when the MMF of the dosage includes particles, the particles have a particle size distribution wherein: D_(0.5) is 125 µm or less, 115 µm or less, 100 µm or less, 90 µm or less, 80 µm or less, 60 µm or less, 50 µm or less, 40 µm or less, 30 µm or less, 25 µm or less, 15 µm or less, or 10 µm or less. In some embodiment the D(0.5) is between 50 µm and 90 µm; between 30 µm and 60 µm; between 20 µm and 50 µm; between 15 µm and 30 µm; between 10 µm and 25 µm, or between 1 µm and 15 µm In some embodiments, when the MMF of the dosage form includes particles, the particles have a particle size distribution wherein: D(0.1) is 25 µm or less, 15 µm or less, 10 µm or less, 5 µm or less, or 1 µm or less. For example, in an exemplary embodiment, the particle size distribution of MMF may include a D(0.9) 175 µm or less and a D(0.5) in a range of 50 µm to125 µm. In another exemplary embodiment, the particle size distribution of MMF may include a D_(0.9) 175 µm or less and a D_(0.5) in a range of 30 µm and 100 µm. In yet another exemplary embodiment, the particle size distribution of MMF may include a D(0.9) 150 µm or less and a D(0.5) in a range of 20 µm to 80 µm. In a further exemplary embodiment, the particle size distribution of MMF may include a D_(0.9) 125 µm or less and a D_(0.5) in a range of10 µm and 80 µm. In another exemplary embodiment, the particle size distribution of MMF may include a D(0.9) 100 µm or less and a D(0.5) in a range of 10 µm and 70 µm. In yet another exemplary embodiment, the particle size distribution of MMF may include a D_(0.9) 90 µm or less and a D_(0.5) in a range of 5 µm to 50 µm. In a further exemplary embodiment, the particle size distribution of MMF may include a D(0.9) 70 µm or less and a D(0.5) in a range of 3 µm and 30 µm. In an additional exemplary embodiment, the particle size distribution of MMF may include a D_(0.9) 50 µm or less and a D_(0.5) in a range of 1 µm and 20 µm. Pharmacokinetic Profile In some embodiments, the dosage form may be characterized by its pharmacokinetic profile including, for example, C_max, T_max, AUC_0-12h and/or AUC_0-24h. In some embodiments, including, for example, when the dosage form includes 150 mg to 500 mg of MMF, the dosage form may be characterized by a plasma MMF Cmax in a range of 0.4 mg/L to 4.3 mg/L. In some embodiments, including, for example, when the dosage form includes 150 mg to 500 mg of MMF, the dosage form may be characterized by a plasma MMF AUC0-24h of 1.8 h*mg/L to 14.9 h*mg/L. In some embodiments, including, for example, when the dosage form includes 150 mg to 500 mg of MMF, the dosage form may be characterized by a plasma MMF elimination half-life (t_1/2) of 0.9 hours to 2.3 hours. Any combination of these pharmacokinetic parameters is also envisioned. For example, in some embodiments, dosage form may be characterized by a combination of at least two of: a plasma MMF Cmax in a range of 0.4 mg/L to 4.3 mg/L; a plasma MMF AUC0-24h of 1.8 h*mg/L to 14.9 h*mg/L; and a plasma MMF elimination half-life (t_1/2) of 0.9 hours to 2.3 hours. In some embodiments, dosage form may be characterized by a combination of all three of: a plasma MMF Cmax in a range of 0.4 mg/L to 4.3 mg/L; a plasma MMF AUC0-24h of 1.8 h*mg/L to 14.9 h*mg/L; and a plasma MMF elimination half-life (t_1/2) of 0.9 hours to 2.3 hours. In some embodiments, oral administration of a single dose of the dosage form to a subject under fed conditions may provide a plasma MMF Cmax in a range of 80 % to 125 % of a corresponding C_max obtained when a single dose of the dosage form is orally administered to a subject under fasting conditions. Additionally or alternatively, oral administration of a single dose of the dosage form to a subject under fed conditions may provide a plasma MMF AUC0-24h in a range of 80 % to 125% of a corresponding AUC_0-24h obtained when such dose is orally administered to a subject under fasting conditions. For example, oral administration of a single dose of the dosage form to a subject under fed conditions may provide a plasma MMF Cmax in a range of 80 % to 125 % of a corresponding Cmax obtained when a single dose of the dosage form is orally administered to a subject under fasting conditions and a plasma MMF AUC_0-24h in a range of 80 % to 125 % of a corresponding AUC0-24h obtained when such dose is orally administered to a subject under fasting conditions. In some embodiments, including, for example, when the dosage form includes 150 mg to 250 mg of MMF, oral administration of a single dose of the dosage form to a subject may provide a plasma MMF Cmax in a range of 0.4 mg/L to 2.1 mg/L and/or a plasma MMF AUC0-24h in a range of 1.8 h*mg/L to 7.4 h*mg/L. As described in Example 1 (see, for example, Table 2F), when the dosage form includes 150 mg to 250 mg of MMF, Cmax is expected to be in a range of 0.4 mg/L to 2.1 mg/L and AUC0-24h is expected to be in a range of 1.8 h*mg/L to 7.4 h*mg/L. In some embodiments, including, for example, when the dosage form includes 300 mg to 500 mg of MMF, oral administration of a single dose of the dosage form to a subject may provide a plasma MMF Cmax in a range of 0.8 mg/L to 4.3 mg/L and/or a plasma MMF AUC0 – 24h in a range of 3.7 h*mg/L to 14.9 h*mg/L. As described in Example 1 (see, for example, Table 2F), when the dosage form includes 300 mg to 500 mg of MMF, C_max is expected to be in a range of 0.8 mg/L to 4.3 mg/L and AUC0-24h is expected to be in a range of 3.7 h*mg/L to 14.9 h*mg/L. In vitro Dissolution Profile In some embodiments, the dosage form may be characterized by its dissolution profile. A profile is characterized by the test conditions selected. Thus, the dissolution profile can be generated at a pre-selected apparatus type, shaft speed, temperature, volume, and pH of the dispersion media. Several dissolution profiles may be obtained. For example, a first dissolution profile may be measured at a pH level approximating that of the stomach (e.g., pH 1.2); a second dissolution profile may be measured at a pH level approximating that of the pH of the region from the duodenum to around the middle of small intestine (e.g., a pH in a range of 6.0 to 6.8, or a pH in a range of 6.5 to 6.8); additionally or alternatively, a dissolution profile may be measured at a pH level of the distal end of small intestine (e.g., a pH in a range of 7.0 to 8.0, or a pH 7.5). With respect to characterizing the dissolution profile using in vitro methods, well- established methods are available, especially methods described by official monographs including, for example, United States Pharmacopeia (USP) or the European Pharmacopoeia. A person skilled in the art will know which method to choose and how to select the specific conditions to carry out the in vitro test. A suitable dissolution test for tablets is, for example, described in the United States Pharmacopoeia (USP) <711> using a USP Apparatus-II (Paddle). In some embodiments, the dosage form may be placed in a tablet sinker. In some embodiments, the apparatus may be operated at a stirring speed in a range of 50 rpm to 120 rpm including, for example, 100 rpm. The dissolution medium is maintained at 37 °C ± 0.5 °C during the test, as indicated by the standard. Any suitable amount of dissolution buffer may be used. When the dissolution buffer includes hydrochloric acid or USP Simulated Gastric Fluid, a useful amount of dissolution buffer may be in a range of 500 mL to 1000 mL, including, for example, 900 mL. When the dissolution buffer includes a phosphate buffer, a useful amount of dissolution buffer may be 900 mL. In some embodiments, 900 mL of dissolution buffer may be preferred. In some embodiments, 0.1 N hydrochloric acid is employed as the dissolution medium. In some embodiments, USP Simulated Gastric Fluid pH 1.2 is employed as the dissolution medium. The USP Simulated Gastric Fluid pH 1.2 may include or may not include pepsin. In some embodiments, the phosphate buffer is employed as the dissolution medium. In some embodiments, the phosphate buffer is a pH 6.0 phosphate buffer, a pH 6.5 phosphate buffer, a pH 6.8 phosphate buffer, or a pH 7.5 phosphate buffer. In some embodiments, the phosphate buffer may be prepared as described in the United States Pharmacopoeia (USP). The dosage form may be tested in the dissolution medium for any suitable period of time. Exemplary periods of time include 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, and 24 hours. For example, the dosage form may be exposed to the dissolution medium for a single period of 2 hours or 6 hours. Or the dosage form may be exposed to a first dissolution medium for 2 hours and then a second dissolution medium for an additional period of time. In some embodiments, 0.1 N hydrochloric acid or USP Simulated Gastric Fluid pH 1.2 is employed as the dissolution medium during the first 2 hours of a test and then a phosphate buffer is employed as the dissolution medium for the remaining test period. The USP Simulated Gastric Fluid pH 1.2 may include or may not include pepsin. For example, in an exemplary embodiment, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of 0.1 N hydrochloric acid as dissolution medium, maintained at a temperature of 37 °C, the dosage form releases no more than 10 % w/w of the MMF present in the dosage form within 2 hours after the start of the test or less than 10 % w/w of the MMF present in the dosage form within 2 hours after the start of the test. In some embodiments, the dosage form releases less than 5% w/w of the MMF present in the dosage form within 2 hours after the start of the test. Exemplary release profiles showing such low MMF release during the first 2 hours in 0.1 N hydrochloric acid as dissolution media are shown in FIG.4 – FIG.6. In another exemplary embodiment, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of USP Simulated Gastric Fluid pH 1.2 as dissolution medium, maintained at a temperature of 37 °C, at least 10 % w/w of the MMF present in the dosage form is released within 2 hours after the start of the test. In some embodiments, the dosage form releases less than 5% w/w of the MMF present in the dosage form within 2 hours after the start of the test. The USP Simulated Gastric Fluid pH 1.2 may include or may not include pepsin. In yet another exemplary embodiment, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 6.8 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, 30 % w/w to 90 % w/w of the MMF present in the dosage form is released within 14 hours after the start of the test. In some embodiments, 30 % w/w to 80 % w/w of the MMF present in the dosage form is released within 14 hours after the start of the test. In some embodiments, 30 % w/w to 70 % w/w of the MMF present in the dosage form is released within 6 hours after the start of the test. In a further exemplary embodiment, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 6.5 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, 30 % w/w to 80 % w/w of the MMF present in the dosage form is released within 14 hours after the start of the test. In some embodiments, 30 % w/w to 70 % w/w of the MMF present in the dosage form is released within 14 hours after the start of the test. In some embodiments, 30 % w/w to 70 % w/w of the MMF present in the dosage form is released within 6 hours after the start of the test. In another exemplary embodiment, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 6.0 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, 30 % w/w to 70 % w/w of the MMF present in the dosage form is released within 14 hours after the start of the test. In some embodiments, 30 % w/w to 70 % w/w of the MMF present in the dosage form is released within 6 hours after the start of the test. In another exemplary embodiment, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 7.5 phosphate buffer dissolution medium, maintained at a temperature of 37 °C, at least 80 % w/w of the MMF present in the dosage form is released within 6 hours after the start of the test. In some embodiments, substantially all the MMF is released within 2 hours, within 3 hours, within 4 hours, within 5 hours, or within 6 hours after the start of the test. Exemplary ranges for the total amount of MMF released within 6 hours or within 14 hours when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a phosphate buffer (e.g., having a pH 6.0, pH 6.5, pH 6.8, or pH 7.5) used as dissolution medium are shown in Table 1. Table 1. pH of phosphate buffer % w/w of TOTAL MMF present in the dosage form released i l i i within 14 hours within 6 hours

In some embodiments, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form releases no more than 10 % w/w of the MMF present in the dosage form within 2 hours after the start of the test when 900 mL of 0.1 N hydrochloric acid, maintained at a temperature of 37 °C, is used as dissolution medium. At the end of 2 hours, if the dosage form is further tested using 900 mL of pH 6.0 phosphate buffer, maintained at a temperature of 37 °C, as dissolution medium, the dosage form releases 30 % w/w to 70 % w/w of the MMF present in the dosage form within 6 hours after the start of the test in pH 6.0 phosphate buffer as dissolution medium. In some embodiments, 30 % w/w to 60 % w/w of the MMF present in the dosage form is released within 6 hours after the start of the test in pH 6.0 phosphate buffer as dissolution medium. In some embodiments, 30 % w/w to 55% w/w of the MMF present in the dosage form is released within 6 hours after the start of the test in pH 6.0 phosphate buffer as dissolution medium. Exemplary release profiles showing low MMF release (for example, up to 10 % w/w/) during the first 2 hours in 0.1 N hydrochloric acid as dissolution media followed by release of up to 70 % MMF in pH 6 dissolution medium during the following 6 hours are shown in FIG.4 – FIG.6. These profiles contrast with the dissolution profiles for the capsules and tablets described in Example 3A which exhibited release of greater than 80 % of the MMF (FIG.2) or greater than 90 % of the MMF (FIG.1 and FIG.3) within 8 hours after the start of the test. In some embodiments, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form releases no more than 10 % w/w of the MMF present in the dosage form within 2 hours after the start of the test when 900 mL of 0.1 N hydrochloric acid, maintained at a temperature of 37 °C, is used as dissolution medium. At the end of 2 hours, if the dosage form is further tested, the dosage form releases 30 % w/w to 70 % w/w of the MMF present in the dosage form within 6 hours after the start of the test when 900 mL of pH 6.5 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution medium. In some embodiments, 30 % w/w to 60 % w/w of the MMF present in the dosage form is released within 6 hours after the start of the test in pH 6.5 phosphate buffer as dissolution medium. In some embodiments, 30 % w/w to 55% w/w of the MMF present in the dosage form is released within 6 hours after the start of the test in pH 6.5 phosphate buffer as dissolution medium. Exemplary release profiles showing low MMF release (for example, up to 10 % w/w/) during the first 2 hours in 0.1 N hydrochloric acid as dissolution media followed by release of up to 70 % MMF in pH 6.5 dissolution medium during the following 6 hours are shown in FIG.4 – FIG.6. These profiles contrast with the dissolution profiles for the capsules and tablets described in Example 3A which exhibited release of greater than 80 % of the MMF (FIG.2) or greater than 90 % of the MMF (FIG.1 and FIG.3) within 8 hours after the start of the test. In some embodiments, when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form releases no more than 10 % w/w of the MMF present within 2 hours after the start of the test when 900 mL of 0.1 N hydrochloric acid, maintained at a temperature of 37 °C is used as dissolution medium. Additionally, if at the end of 2 hours, the tablet sinker with its contents is further tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of pH 7.5 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, substantially all MMF in the dosage form is released within 6 hours after the start of the test in pH 7.5 phosphate buffer as dissolution medium. In some embodiments, the dosage form to be tested may include both a first portion and a second portion, wherein the first portion comprises a first amount of MMF and the second portion comprises a second amount of MMF. Exemplary amounts of MMF in a first portion (for example, an outer portion) and a second portion (for example, a core portion) are shown in Table 3A – Table 3H. In an exemplary embodiment when such a dosage form having both a first and a second portion is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of pH 6.0 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, at least 70 % w/w of the first amount of MMF is released within 6 hours after the start of the test. In some embodiments, substantially all of the first amount of MMF is released within 6 hours after the start of the test. In some embodiments, substantially all of the first amount of MMF is released within 4 hours after the start of the test. In some embodiments, substantially all of the first amount of MMF is released within 2 hours after the start of the test. In another exemplary embodiment when such a dosage form having both a first portion and a second portion is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of 0.1 N hydrochloric acid as dissolution medium, maintained at a temperature of 37 °C, no more than 10 % w/w of the MMF present in the dosage form is released within 2 hours after the start of the test. Additionally, if at the end of 2 hours, the tablet sinker with its contents is further tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of pH 6.0 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, substantially all of the first amount of MMF is released within 6 hours after the start of the test in pH 6.0 phosphate buffer as dissolution medium. Alternatively, if at the end of 2 hours, the tablet sinker with its contents is further tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of pH 7.5 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, substantially all MMF in the dosage form is released within 6 hours after the start of the test in pH 7.5 phosphate buffer as dissolution medium. Tablet Composition and Geometry In some embodiments, the dosage form preferably includes a tablet. In some embodiments, the tablet is preferably a press-coated tablet. In some embodiments, the tablet is a tablet-in-tablet. Tablet Composition In some embodiments, the press-coated tablet may include MMF in a range of 150 mg to 500 mg. In some embodiments, the press-coated tablet may include MMF in a range of 150 mg to 250 mg or in a range of 175 mg to 225 mg. In some embodiments, the press-coated tablet may include 190 mg MMF. In some embodiments, the press-coated tablet may include MMF in a range of 300 mg to 480 mg or in a range of 350 mg to 450 mg. In some embodiments, the press-coated tablet may include 380 mg MMF. In some embodiments, the press-coated tablet may be formulated for once daily oral administration. In some embodiments, the press-coated tablet includes a first portion and a second portion, wherein the first portion includes a first amount of MMF and the second portion includes a second amount of MMF. For example, the second portion may include a core, and the first portion may be disposed around the core. Additionally or alternatively, the second portion may include a compressed tablet, a bead, or a pellet. In some embodiments, the second portion may include a compressed tablet that forms a core of the press-coated tablet. The core may be coated with a core coat. The core may further be surrounded by a barrier layer disposed between the core and the core coat. The tablet may be coated with a tablet coat. The core coat, the tablet coat, or both may include an enteric coating or a delayed release coating. In some embodiments, the tablet is coated with an enteric coating. In some embodiments, the core is coated with a delayed release coating. In some embodiments, a ratio of the first amount of MMF to the second amount of MMF may be in a range of 1:0.5 to 1:2. In some embodiments, a ratio of the first amount of MMF to the second amount of MMF may be 1:1. In some embodiments, after administration to a subject, the first portion may release the first amount of MMF within a first period of time and the second portion may release the second amount of MMF within a second period of time. In some embodiments, the first portion may include an additional component such as a release modifier, a stabilizer, a disintegrant, a process aid, a coloring agent, or a filler, or any combination thereof. In some embodiments, the first period of time may overlap with the range of time it takes for the tablet to traverse the stomach and for the first amount of MMF to be released in the small intestine. In some embodiments, the first period of time may be the time it takes for the tablet to traverse the stomach and for the first amount of MMF to be released in the small intestine. In some embodiments, the first period of time may be in a range of 0.5 hours to 12 hours post- administration, including for example, is in a range of 0.5 hours to 4 hours post-administration, in a range of 0.5 hours to 5 hours post-administration, in a range of 0.5 hours to 6 hours post- administration, or in a range of 0.5 hours to 8 hours post-administration. In some embodiments, the second period of time may begin at a time after the tablet has traversed the stomach and the small intestine, that is, when the tablet enters the terminal portion of the small intestine. In some embodiments, the second period of time may begin at least 6 hours post-administration. In some embodiments, the second period of time may be in a range of 6 hours to 24 hours post-administration, including, for example, in a range of 6 hours to 18 hours post- administration, in a range of 6 hours to 12 hours post-administration, in a range of 6 hours to 10 hours post-administration, or in a range of 10 hours to 14 hours post-administration. In some embodiments, the second portion may include an additional component such as a release modifier, a stabilizer, a disintegrant, a process aid, a coloring agent, or a filler, or any combination thereof. The additional component may be admixed with the second amount of MMF or it may surround the second amount of MMF, or both. For example, if the additional component is a release modifier, the release modifier may be admixed with the second amount of MMF, may surround a core of the second amount of MMF, or some release modifier may be admixed with the second amount of MMF and some release modifier may surround a core of the second amount of MMF admixed with release modifier. In some embodiments, the second amount of MMF may be homogenously mixed throughout the core. In some embodiments, the second amount of MMF may be non-homogenously distributed in the core. That is, certain portions within the core include MMF and other portions are free or substantially free of MMF. In another exemplary embodiment, the second amount of MMF may be homogenously mixed with a first release modifier, and a second release modifier may coat the mixture. At least in some embodiments, the coat (e.g., core coat, tablet coat, or both) is free of MMF. In some embodiments, the press-coated tablet may further include a third portion. The third portion may include a third amount of MMF. The third portion may include a release modifier, a stabilizer, a disintegrant, a process aid, a coloring agent, or a filler, or any combination thereof. In an exemplary embodiment, the second portion may form a core including the third portion, wherein the third portion includes mini-tablets or beads including MMF, wherein the mini-tablets or beads are disposed within the core. In some embodiments including mini-tablets or beads disposed within the core, different sizes of mini-tablets or beads or mini-tablets or beads having different coatings may be disposed within the core. Exemplary release modifiers include, for example, pH-independent polymers, pH-dependent polymers, pH-responsive polymers, hydrogel polymers, impermeable polymers, hydroxypropyl cellulose, hypromellose, ethyl cellulose, methylcellulose, methacrylate copolymer, cellulose acetate phthalate, hypromellose acetate succinate, shellac, monoglycerides, diglycerides, triglycerides, polyvinyl alcohol, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, glyceryl monostearate, glyceryl distearate, glyceryl behenate, stearic acid, magnesium aluminum silicate (for example, VEEGUM®), wax, hydrogenated vegetable oil, xanthan gum, gelatin, and paraffin, and any combination thereof. Exemplary pH-responsive polymers include methacrylate copolymers such as EUDRAGIT® polymer grades L, L-55, L100, S, S-100, F, R, RL-100, RS-100, and NE, and combinations thereof. Exemplary types of stabilizers include an antioxidant, a surfactant (including, for example, a hydrophilic surfactant and a lipophilic surfactant), an emulsifier, a buffer, and a pH modifier, and any combination thereof. Exemplary stabilizers include ascorbic acid, tocopherol, tocopherol acetate, sorbic acid, propyl gallate, sodium edetate, EDTA, sodium thiosulphate, gallic acid, sodium lauryl sulphate, polysorbate 20, polysorbate 80, polyoxyl castor oil, polyoxyl hydrogenated castor oil, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, tocopheryl polyethylene glycol succinate (TPGS), lactic acid, phosphate buffer, sodium acetate, sodium bicarbonate, acetic acid, sodium hydroxide, maleic acid, tartaric acid, succinic acid, sodium lactate, sodium benzoate, sodium methyl paraben, and sodium propyl paraben, and combinations thereof. Exemplary disintegrants include sodium starch glycollate, croscarmellose, hydroxypropyl cellulose (low viscosity), and crospovidone, and combinations thereof. Exemplary fillers include microcrystalline cellulose, lactose, starch, dicalcium phosphate, tricalcium phosphate, sucrose, sorbitol, gelatin, and mannitol, and any combination thereof. Exemplary types of process aids include absorbents, acids, adjuvants, anticaking agents, antitacking agents, antifoamers, anticoagulants, antimicrobials, antioxidants, antiphlogistics, astringents, antiseptics, bases, binders, bufferants, chelating agents, sequestrants, celluloses, coagulants, colorants, dyes, pigments, complexing agents, crystal growth regulators, denaturants, desiccants, drying agents, dehydrating agents, diluents, disintegrants, dispersants, emulsifiers, encapsulants, enzymes, extenders, flavor masking agents, flavorants, fragrances, gelling agents, glidants hardeners, stiffening agents, humectants, lubricants, moisturizers, pH control agents, plasticizers, soothing agents, demulcents, retarding agents, spreading agents, stabilizers, suspending agents, sweeteners, thickening agents, surfactants, opacifiers, polymers, preservatives, rheology control agents, softeners, solubilizers, solvents tonicifiers, viscosity modulators, and UV absorbers, and combinations thereof. Exemplary process aids include magnesium stearate, silicon dioxide, stearic acid, sodium lauryl sulphate, polyethylene glycol, castor oil, lecithin, and talc, and combinations thereof. In some embodiments, a release modifier, stabilizer, disintegrant, process aid, coloring agent, filler, or any combination thereof may have more than one function. For example, a process aid may also act as a stabilizer. In another example, a stabilizer may also act as a component that facilitates bioavailability. In some embodiments, the press-coated tablet includes at least one coating. The coating may encompass (that is, completely surround) the first portion, the second portion, or both. In some embodiments, a coating preferably encompasses at least the first portion. If any additional component is present (including, for example, a third portion), the coating may encompass the additional component. If a third portion is present, either or both of the second portion and the third portion may have a coating. Without wishing to be bound by theory, it is believed that a coating encompassing at least the first portion is preferred because the coating may prevent release (for example, in the stomach) of the first portion, the second portion, and, if present, the third portion, preventing the MMF therein from causing severe gastric irritation. The coating may include a delayed-release polymer. Exemplary delayed-release polymers include a methacrylate copolymer, cellulose acetate phthalate, ethyl cellulose, hypromellose acetate succinate, hypromellose phthalate, and shellac, and any combination thereof. If a coating is present around both the first portion and the second portion, each coating may be the same or different. If a coating is present around both a second portion and a third portion, each coating may be the same or different. For example, a coating around the second portion may include a methacrylate copolymer and the third portion may be uncoated. Or a coating around a first portion may include shellac, a coating around a second portion may include a methacrylate copolymer, and a coating around a third portion may include a cellulose acetate phthalate. Largest Dimension In some embodiments, the tablet may preferably be less than 22 mm in its largest dimension or even more preferably less than 20 mm in its largest dimension. Without wishing to be bound by theory, it is believed that these dimensions may make the tablet easier to swallow than the capsules available on the market at the time of the invention and will allow for once daily administration, thereby reduce pill burden to the patients and significantly increase patient compliance. The capsule dosage form on the market at the time of the invention would have to be significantly larger than a tablet (for example at least 23 mm or 24 mm long (also referred as 24 Oblong capsule) to accommodate total MMF daily dose in a single unit dosage form. Using a tablet form, however, allows for further concentration of the MMF, meaning, in some embodiments, the tablets may be less than 22 mm in or even more preferably less than 20 mm in the largest dimension. The tablet may be any suitable shape including, for example a cylindrical shape. In some embodiments, the tablet may preferably have a cylindrical shape. As used herein, a cylindrical shape refers to any geometrical shape having the same cross section area throughout the length of the geometrical shape. The cross section of a cylinder within the meaning of this specification may have any two-dimensional shape. For example, the cross section may be circular, ovular, rectangular, triangular, angular, or star shaped. When the tablet has a cylindrical shape, the tablet may have two main dimensions: diameter and height (also referred as thickness). For example, the diameter may be a first length along a first axis of the tablet and the thickness or height of the tablet may provide a second length along a second axis. In some embodiments when the tablet has a cylindrical shape, the tablet may be a cuboid in shape, and the length along the first axis equals the length along second axis. In some embodiments when the tablet has a cylindrical shape, the top and the bottom surfaces of the cylinder may have a slight or deep convexity, to provide a dome-shape appearance. In some embodiments the tablet may be at least 5 mm in one dimension, at least 5.5 mm in one dimension, or at least 6 mm in one dimension. In some embodiments the tablet may be up to 6 mm in one dimension, up to 7 mm in one dimension, or up to 8 mm in one dimension. For example, when the tablet has a first axis (X-Y) having a first length and a second axis (A-B) having second length (see FIG.7), if the first axis is the largest dimension, the second axis may have a dimension in a range of 5 mm to 8 mm. In some embodiments, the tablet may be at least 8 mm in its largest dimension, at least 9 mm in its largest dimension, at least 10 mm in its largest dimension, at least 12 mm in its largest dimension, at least 14 mm in its largest dimension, at least 16 mm in its largest dimension, or at least 18 mm in its largest dimension. In some embodiments, the tablet may be up to 18 mm in its largest dimension, up to 20 mm in its largest dimension, or up to 22 mm in its largest dimension. For example, when the tablet has a first axis (X-Y) having a first length and a second axis (A-B) having second length (see FIG.7), if the first axis is the largest dimension, the first axis may have a dimension in a range of 9 mm to 22 mm. In some embodiments, the ratio of the A-B axis to X-Y axis may be in a range of 1:1.2 to 1:4, in a range of 1:1.7 to 1:3.8, or in a range of 1:1.8 to 1:3.5. Exemplary geometries for the tablet are described in Example 4 and Table 5A – Table 5Q. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 1.2 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5A. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 1.35 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5B. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 1.5 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5C. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 1.7 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5D. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 1.85 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5E. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 2 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5F. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 2.2 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5G. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 2.35 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5H. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 2.5 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5I. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 2.65 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5J. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 2.8 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5K. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 3 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5L. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 3.2 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5M. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 3.35 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5N. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 3.6 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5O. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 3.8 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5P. In some embodiments, the tablet may have a first axis (X-Y) having a length at least 4 times the length of a second axis (A-B) (see FIG.7). Exemplary dimensions for tablets having this geometry are described in Table 5Q. In some embodiments, the geometries described in Table 5A – Table 5D may be preferred, the geometries described in Table 5E – Table 5K may be even more preferred, and the geometries described in Table 5L – Table 5Q may be most preferred. In some embodiments, the tablet may include a core. When the tablet includes a core, the core may be any suitable shape such as round, cylindrical, ellipsoid, oblong, caplet, star-shaped, or polygonal (including, for example, triangular, square, pentagonal, hexagonal, etc.). In some embodiments, the tablet includes an ellipsoid core, as shown in an exemplary embodiment in FIG.7. When the tablet includes a core, the first axis (X-Y) of the press-coated tablet may be at least 1.1 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, or at least 10 times longer than the longest axis (x’-y’) of the core. Additionally or alternatively, the first axis (X-Y) of the press-coated tablet may be up to 1.2 times, up to 1.5 times, up to 2 times, up to 3 times, up to 4 times, up to 5 times, up to 6 times, up to 7, up to 8 times, up to 9 times, or up to 10 times longer than the longest axis (x’-y’) of the core. When the tablet includes a core, the ratio of the first, longest axis (X-Y) of the press-coated tablet to the longest axis (x’-y’) of the core may be in a range of 1:0.1 to 1:0.9, in a range of 1:0.2 to 1:0.8; in a range of 1:0.3 to 1:0.8; in a range of 1:0.4 to 1:0.8; in a range of 1:0.5 to 1:0.8, in a range of 1:0.2 to 1:0.8, or in a range of 1:0.3 to 1:0.7. Methods of Use In another aspect, this disclosure describes a method of using a dosage form as described herein. In some embodiments, the dosage form may be used or indicated for treating or reducing the symptoms of multiple sclerosis or psoriasis in a subject (including, for example, a human). In some embodiments, the dosage form may be used or indicated for the treatment of a subject (including, for example, a human) with relapsing forms of multiple sclerosis. In some embodiments, the dosage form may be used or indicated for the treatment of relapsing forms of multiple sclerosis (MS), including, for example, clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. In some embodiments, the dosage form may be used or indicated for treatment of an adult subject (including, for example, a human). In some embodiments, a method of using the dosage form may include administering a dosage form that includes 150 mg to 250 mg of MMF once a day for at least 3 days, at least 5 days, or at least 7 days. In some embodiments, a method of using the dosage form may include administering a dosage form that includes 150 mg to 250 mg of MMF once a day for up to 7 days, up to 9 days, up to 11 days, up to 13 days, up to 14 days, or up to 15 days. For example, in an exemplary embodiment, the dosage form that includes 150 mg to 250 mg of MMF may be administered for 7 to 14 days. In another exemplary embodiment, the dosage form that includes 150 mg to 250 mg of MMF may be administered for 7 days. In some embodiments, a method of using the dosage form may include administering a dosage form that includes 300 mg to 500 mg of MMF once a day. In some embodiments, a method of using the dosage form may include administering a dosage form that includes 150 mg to 250 mg of MMF once a day (including, for example, for 7 to 14 days) and then administering a dosage form that includes 300 mg to 500 mg of MMF once a day. It can further be envisioned to administer a dosage form that includes 300 mg to 500 mg of MMF once a day, multiple doses of a dosage form that includes 150 mg to 250 mg of MMF may be taken at the same time (that is, once a day). The invention is defined in the claims. However, below there is provided a non-exhaustive listing of non-limiting exemplary aspects. Any one or more of the features of these aspects may be combined with any one or more features of another example, embodiment, or aspect described herein. Exemplary PK Aspects A1. A dosage form formulated for once daily oral administration comprising 150 mg to 500 mg of MMF, wherein once daily oral administration of the dosage form to a subject provides a pharmacokinetic parameter selected from: a plasma MMF Cmax of 0.4 mg/L to 4.3 mg/L; a plasma MMF AUC_{0 – 24h} of 1.8 h*mg/L to 14.9 h*mg/L; a plasma MMF elimination half-life (t_1/2) of 0.9 hours to 2.3 hours; and any combination thereof. A2. The dosage form of Aspect A1, wherein once daily oral administration of the dosage form to a subject provides at least two pharmacokinetic parameters selected from: a plasma MMF C_max of 0.4 mg/L to 4.3 mg/L; a plasma MMF AUC_{0 – 24h} of 1.8 h*mg/L to 14.9 h*mg/L; and a plasma MMF elimination half-life (t1/2) of 0.9 hours to 2.3 hours. A3. The dosage form of Aspect A1 or A2, wherein oral administration of a single dose of the dosage form to a subject under fed conditions provides a plasma MMF C_max in a range of 80 % to 125% of a corresponding C_max obtained when a single dose of the dosage form is orally administered to a subject under fasting conditions, and a plasma MMF AUC0 – 24h in a range of 80 % to 125% of a corresponding AUC_{0 – 24h} obtained when a single dose of the dosage form is orally administered to a subject under fasting conditions. A4. The dosage form of any one of Aspect A1 to A3, the dosage form comprising 150 mg to 250 mg of MMF, providing a plasma MMF C_max in a range of 0.4 mg/L to 2.1 mg/L, and a plasma MMF AUC_{0 – 24h} in a range of 1.8 h*mg/L to 7.4 h*mg/L. A5. The dosage form of any one of Aspect A1 to A4, the dosage form comprising 190 mg of MMF. A6. The dosage form of Aspect A1, the dosage form comprising 300 mg to 500 mg of MMF, providing a plasma MMF Cmax in a range of 0.8 mg/L to 4.3 mg/L, or a plasma MMF AUC0 – 24h in a range of 3.7 h*mg/L to 14.9 h*mg/L, or both. A7. The dosage form of Aspect A6, the dosage form comprising 380 mg of MMF. A8. The dosage form of any one of Aspects Al to A7, wherein the dosage form comprises a solid dosage form.

A9. The dosage form of Aspect A8, wherein the solid dosage form is a tablet selected from a modified-release tablet, a delayed-release tablet, a sustained release matrix tablet, a press-coated tablet, a multiple-layered tablet, a timed-release tablet, and any combination thereof.

A10. The dosage form of any one of Aspects Al to A9, wherein the dosage form comprises a press-coated tablet.

Al l. The dosage form of Aspect A10, wherein the press-coated tablet comprises a tablet-in- tablet.

A12. A method of treating multiple sclerosis or psoriasis comprising administering to a subject in need thereof a dosage form of any one of Aspects Al to Al 1.

Exemplary Composition of Matter Aspects

Bl. A dosage form comprising 150 mg to 500 mg of MMF formulated for once daily administration.

B2. The dosage form of Aspect Bl, wherein the dosage form comprises a modified release tablet.

B3. The dosage form of Aspect B2, wherein the modified release tablet is selected from the group consisting of a delayed-release tablet, a controlled release tablet, an extended release tablet, a sustained release tablet, a matrix tablet, an osmotic-controlled release tablet, a press-coated tablet, a multiple-layered tablet, timed-release tablet and any combination thereof.

B4. The dosage form of any one of Aspects Bl to B3, wherein the dosage form comprises a press-coated tablet.

B5. The dosage form of Aspect B4, wherein the press-coated tablet comprises a tablet-in- tablet.

B6. A press-coated tablet comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, the press-coated tablet comprising a first portion and a second portion, wherein the first portion comprises a first amount of MMF and the second portion comprises a second amount of MMF, wherein a ratio of the first amount of MMF to the second amount of MMF is in a range of 1 :0.5 to 1 :2; wherein after administration to a subject, the first portion releases the first amount of MMF within a first period of time and the second portion releases the second amount of MMF within a second period of time, wherein the first period of time is in a range of 0.5 hours to 12 hours post-administration, and wherein the second period of time begins at least 6 hours postadministration.

B7. The press-coated tablet of Aspect B6, wherein the first period of time is in a range of 0.5 hours to 4 hours post-administration, in a range of 0.5 hours to 5 hours post-administration, in a range of 0.5 hours to 6 hours post-administration, or in a range of 0.5 hours to 8 hours postadministration.

B8. The press-coated tablet of Aspect B6 or B7, wherein the second period of time is in a range of 6 hours to 24 hours post-administration, in a range of 6 hours to 18 hours postadministration, in a range of 6 hours to 12 hours post-administration, in a range of 6 hours to 10 hours post-administration.

B9. The press-coated tablet of any one of Aspects B6 to B8, wherein the second portion comprises a core and the first portion is disposed around the core.

B10. The press-coated tablet of any one of Aspects B6 to B9, wherein the second portion comprises a compressed tablet, a bead, or a pellet.

Bl 1. The press-coated tablet of Aspect B10, wherein the second portion comprises a compressed tablet.

B12. The press-coated tablet of any one of Aspects B6 to Bl 1, wherein press-coated tablet comprises a tablet-in-tablet.

B13. The press-coated tablet of any one of Aspects B6 to Bl 2, wherein the second portion comprises at least one component selected from a release modifier, a stabilizer, a disintegrant, a filler, and any combination thereof.

B14. The press-coated tablet of Aspect B13, wherein the second portion comprises a release modifier, and the release modifier comprises hydroxypropyl cellulose, hypromellose, ethyl cellulose, methylcellulose, methacrylate copolymer, cellulose acetate phthalate, hypromellose acetate succinate, shellac, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, glyceryl monostearate, glyceryl distearate, glyceryl behenate, stearic acid, wax, hydrogenated vegetable oil, xanthan gum, gelatin, paraffin, or any combination thereof.

B15. The press-coated tablet of Aspect B13 or B14, wherein the second portion comprises a release modifier admixed with the second amount of MMF.

Bl 6. The press-coated tablet of any one of Aspects B13 to B15, wherein the second portion comprises a release modifier surrounding a core comprising the second amount of MMF. Bl 7. The press-coated tablet of any one of Aspects B6 to Bl 6, wherein the second portion comprises a stabilizer, and the stabilizer comprises an antioxidant, a surfactant, a buffer, a pH modifier, or any combination thereof.

Bl 8. The press-coated tablet of any one of Aspects B6 to Bl 7, wherein the second portion comprises a disintegrant, and the disintegrant comprises sodium starch glycollate, croscarmellose, hydroxypropyl cellulose (low viscosity), crospovidone, or any combination thereof.

Bl 9. The press-coated tablet of any one of Aspects B6 to Bl 8, wherein the second portion comprises a filler, wherein the filler comprises microcrystalline cellulose, lactose, starch, dicalcium phosphate, sucrose, mannitol, or any combination thereof.

B20. The press-coated tablet of any one of Aspects B6 to Bl 9, wherein press-coated tablet comprises a third portion.

B21. The press-coated tablet of Aspect B20, wherein the third portion comprises at least one component selected from a release modifier, a stabilizer, a disintegrant, a filler, and any combination thereof.

B22. The press-coated tablet of Aspect B21, wherein the third portion comprises a release modifier, and the release modifier comprises hydroxypropyl cellulose, hypromellose, ethyl cellulose, methylcellulose, methacrylate copolymer, cellulose acetate phthalate, hypromellose acetate succinate, shellac, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, glyceryl monostearate, glyceryl distearate, glyceryl behenate, stearic acid, wax, hydrogenated vegetable oil, xanthan gum, gelatin, paraffin, or any combination thereof.

B23. The press-coated tablet of any one of Aspects B21 to B22, wherein the third portion comprises a stabilizer, and the stabilizer comprises an antioxidant, a surfactant, a buffer, a pH modifier, or any combination thereof.

B24. The press-coated tablet of any one of Aspects B21 to B23, wherein the third portion comprises a disintegrant, and the disintegrant comprises sodium starch glycollate, croscarmellose, hydroxypropyl cellulose (low viscosity), crospovidone, or any combination thereof.

B25. The press-coated tablet of any one of Aspects B21 to B24, wherein the third portion comprises a filler, wherein the filler comprises microcrystalline cellulose, lactose, starch, dicalcium phosphate, sucrose, mannitol, or any combination thereof.

B26. The press-coated tablet of any one of Aspects B6 to B25, the press-coated tablet further comprising at least one coating comprising a delayed-release polymer selected from a methacrylate copolymer, cellulose acetate phthalate, hypromellose acetate succinate, shellac, and any combination thereof.

B27. The press-coated tablet of Aspect B26, wherein at least one coating encompasses the second portion.

B28. The press-coated tablet of Aspect B26 or B27, wherein at least one coating encompasses the first portion.

B29. The press-coated tablet of any one of Aspects B6 to B29, wherein the press-coated tablet is less than 22 mm in its largest dimension.

B30. The press-coated tablet of any one of Aspects B6 to B29, wherein the ratio of the first amount of MMF to the second amount of MMF is 1 : 1.

B31. The press-coated tablet of any one of Aspects B6 to B30, wherein the first amount of MMF and the second amount of MMF comprise a total amount MMF in a range of 150 mg to 250 mg.

B32. The press-coated tablet of any one of Aspects B6 to B30, wherein the first amount of MMF and the second amount of MMF comprise a total amount MMF in a range of 175 mg to 225 mg.

B33. The press-coated tablet of any one of Aspects B6 to B30, wherein the first amount of MMF and the second amount of MMF comprise a total amount MMF of 190 mg.

B34. The press-coated tablet any one of Aspects B6 to B30, wherein the first amount of MMF and the second amount of MMF comprise a total amount MMF in a range of 300 mg to 480 mg.

B35. The press-coated tablet of any one of Aspects B6 to B30, wherein the first amount of MMF and the second amount of MMF comprise a total amount MMF in a range of 350 mg to 450 mg MMF.

B36. The press-coated tablet of any one of Aspects B6 to B30, wherein the first amount of MMF and the second amount of MMF comprise a total amount MMF of 380 mg.

B37. The press-coated tablet of any one of Aspects B6 to B36, wherein the first amount of MMF comprises at least 50 mg MMF, at least 75 mg MMF, at least 100 mg MMF, at least 125 mg MMF, at least 150 mg MMF, at least 175 mg MMF, at least 200 mg MMF, at least 225 mg MMF, at least 250 mg MMF, at least 275 mg MMF, at least 300 mg MMF, or at least 325 mg MMF; or wherein the first amount of MMF comprises up to 50 mg MMF, up to 75 mg MMF, up to 100 mg MMF, up to 125 mg MMF, up to 150 mg MMF, up to 175 mg MMF, up to 200 mg MMF, up to 225 mg MMF, up to 250m g MMF, up to 275 mg MMF, up to 300 mg MMF, up to 325 mg MMF, or up to 350 mg MMF; or both.

B38. The press-coated tablet of any one of Aspects B6 to B38, wherein the second amount of MMF comprises at least 47 mg MMF, at least 50 mg MMF, at least 75 mg MMF, at least 100 mg MMF, at least 125 mg MMF, at least 150 mg MMF, at least 175 mg MMF, at least 200 mg MMF, at least 225 mg MMF, at least 250 mg MMF, at least 275 mg MMF, at least 300 mg MMF, or at least 325 mg MMF; or wherein the second amount of MMF comprises up to 50 mg MMF, up to 75 mg MMF, up to 100 mg MMF, up to 125 mg MMF, up to 150 mg MMF, up to 175 mg MMF, up to 200 mg MMF, up to 225 mg MMF, up to 250 mg MMF, up to 275 mg MMF, up to 300 mg MMF, up to 325 mg MMF, or up to 350 mg MMF; or both.

B39. The press-coated tablet of any one of Aspects B6 to B38, wherein the first portion, the second portion, or both the first and second portions comprise at least one component selected from diluent, filler, binder, disintegrating agent, glidant, lubricant, drug release modifying agent, osmotic agent, stabilizing agent, pH modifying agent, pH buffering agent, hydrogel, dispersing agent, emulsifying agent, enzyme, gelling agent, gum, effervescent agent, surfactant, solubilizing agent, ant-static agent, and adhesive agent, drug permeability enhancing agent, viscosity enhancing agent, lipophilic agent, hydrophilic agent, moisture adsorbing agent, pore-forming agent, wicking agent, drying agent, coloring agent, triglyceride, oil, wax, and any combination thereof.

B40. The press-coated tablet of any one of Aspects B6 to B39, wherein second portion comprises 40 wt-% to 95 wt-% of MMF, from 3 wt-% to 60 wt% of one or more diluents, fillers, and binders, 10 wt-% or less of one or more disintegrating agents, 5 wt-% or less of one or more stabilizers, 3 wt-% or less of one or more glidants, and 2 wt-% or less of one or more process aids.

B41. The press-coated tablet of any one of Aspects B6 to B39, wherein first portion comprises 30 wt-% to 75 wt-% of MMF, from 15 wt-% to 75 wt% of one or more diluents, fillers, and binders, 10 wt-% or less of one or more disintegrating agents, 5 wt-% or less of one or more stabilizers, 3 wt-% or less of one or more glidants, and 2 wt-% or less of one or more process aids.

B42. The press-coated tablet of Aspect B40 or B41, wherein the one or more diluents, fillers, and binders comprise microcrystalline cellulose, silicified microcrystalline cellulose, lactose, dicalcium phosphate, starch, pregelatinized starch, crospovidone, povidone, mannitol, sucrose, hypromellose, hydroxypropyl cellulose (HPC), gelatin, or a combination thereof. B43. The press-coated tablet of Aspect B40 or B41, wherein the one or more disintegrating agents comprise carmellose, croscarmellose, sodium starch glycollate, sodium lauryl sulphate, povidone, alginates, or a combination thereof.

B44. The press-coated tablet of Aspect B40 or B41, wherein the one or more stabilizers comprise pH modifiers, buffering agent, antioxidants, surfactants, viscosity enhancers, solubilizing agents, or a combination thereof.

B45. The press-coated tablet of Aspect B40 or B41, wherein the one or more glidants comprise colloidal silicon dioxide, talc, or a combination thereof.

B46. The press-coated tablet of Aspect B40 or B41, wherein the one or more process aids comprise lubricant, glidant, anti-static agents, colloidal silicon dioxide, talc, magnesium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, paraffins, lecithin, or a combination thereof.

B47. The press-coated tablet of any one of Aspects B6 to B46, wherein the first portion, the second portion, or both the first and second portions are prepared using MMF particles having a particle size D(1.0) of 200 pm or less. The MMF particles may have a particle size distribution of D(0.1) is 25 pm or less, D(0.5) is 60 pm or less and D(0.9) is 150 pm or less. The MMF particles may have a particle size distribution of D (0.1) is 15 pm or less, D(0.5) is 40 pm or less and D(0.9) is 100 pm or less.

B48. The press-coated tablet of any one of Aspects B6 to B47, wherein the first portion, the second portion, or both the first and second portions are coated with a coating system comprising a coating polymer independently selected from ethyl cellulose, methyl cellulose, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phthalates, hypromellose phthalate, hypromellose acetate succinate, polymethacrylate, polyvinyl acetate, polyethylene oxide, polyvinyl pyrrolidone, shellac, gelatin, wax, and combinations thereof. In some embodiments, the first portion, the second portion, or both the first and second portions are coated with a coating polymer comprising poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1 : 2 : 1; poly(ethyl acrylate, methyl methacrylate) 2 : 1; poly(methacrylic acid, methyl methacrylate) 1 : 1; poly(methacrylic acid, ethyl acrylate) 1 : 1; poly(methacrylic acid, methyl methacrylate) 1 : 2; poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7: 3: 1; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.2; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1, or a combination thereof. In some embodiments, the first portion, the second portion, or both the first and second portions are coated with a coating polymer comprising poly(methacrylic acid, ethyl acrylate) 1 : 1 copolymer. In some embodiments, the first portion, the second portion, or both the first and second portions are coated with an enteric coating.

B49. The press-coated tablet of Aspect B48, wherein the coating system further comprises 5 wt-% to 30 wt-% of a plasticizer, optionally up to 30 wt-% of a pore former, up to 60 wt-% of a coating process aid, each measured by weight of the coating polymer, and up to 90 wt-% of a solvent or diluent, by weight of the coating system. The plasticizer may comprise dibutyl phthalate, diethyl phthalate, triethyl citrate, acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, dibutyl sebacate, polyethylene glycols, castor oil, or a combination thereof. The optional pore former may comprise polyethylene glycol, povidone, hypromellose, HPC, mannitol, sucrose, or a combination thereof. The coating process aid may comprise talc, colloidal silicon dioxide, sodium lauryl sulphate, lecithin, glyceryl dibehenate, stearic acid, magnesium stearate or a combination thereof. The solvent or diluent for preparing the coating system may comprise ethanol, water, isopropyl alcohol (IP A) methanol, acetone, methylene chloride, ethanol -water, IPA-water, or a combination thereof.

B50. The press-coated tablet of any one of Aspects B6 to B49, wherein the first portion has a weight of 100 mg to 750 mg and comprises 75 mg to 225 mg MMF, the second portion has a weight of 80 mg to 375 mg and comprises from 75 mg to 225 mg of MMF. The second portion may be coated with a coating that weighs from 2 % to 30 % or from 2 % to 20 % of the weight of the second portion. The first portion may be coated with a coating that weighs, in terms of total solids, from 1 % to 15 % or from 1 % to 8 % of the total weight of the press-coated tablet. The press- coated tablet may comprise a total amount of MMF of 180 mg to 200 mg, 185 mg to 195 mg, from 188 mg to 192 mg, or 190 mg. Each of the first and second portions may comprise from 90 mg to 100 mg of MMF, or about 95 mg of MMF.

B51. The press-coated tablet of any one of Aspects B6 to B50, wherein the second portion is a delayed-release coated core comprising from 30 wt-% to 70 wt-%, or from 40 wt-% to 60 wt-%, from 45 wt-% to 55 wt-%, or about 50 wt-% of the total MMF in the press-coated tablet, the balance of the MMF being in the first portion. The press-coated tablet may comprise an enteric coating applied over the first portion.

B52. The press-coated tablet of Aspect B51, wherein the core comprises about 190 mg MMF and is coated with a delayed-release coating system having a total solids from about 5 % to about 12% of the weight of the core. The first portion comprises about 190 mg MMF and has a total weight of about 380 mg. The first portion is covered by an enteric coating system. The delayed- release coated core is disposed within the first portion, which are pressed together and coated with an enteric coating system, providing an enteric coated press-coated once-daily MMF tablet.

B53. The press-coated tablet of any one of Aspects B6 to B52, further comprising a barrier layer in between the delayed-release coat and the core. The optional barrier layer may comprise an inert polymer selected from hypromellose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, gelatin or a combination thereof.

Exemplary Dissolution Profile Aspects

Cl. A dosage form comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of 0.1 N hydrochloric acid as dissolution medium, maintained at a temperature of 37 °C, the dosage form releases less than 10 % w/w of the MMF present in the dosage form within 2 hours after the start of the test.

C2. The dosage form of Aspect Cl, wherein the dosage form releases less than 5% w/w of the MMF present in the dosage form within 2 hours after the start of the test.

C3. A dosage form comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of USP Simulated Gastric Fluid pH 1.2 as dissolution medium, maintained at a temperature of 37 °C, at least 10 % w/w of the MMF present in the dosage form is released within 2 hours after the start of the test.

C4. The dosage form of Aspect C3, wherein the dosage form releases less than 5% w/w of the MMF present in the dosage form within 2 hours after the start of the test.

C5. The dosage form of Aspect C3 or C4, wherein the USP Simulated Gastric Fluid does not comprise pepsin.

C6. A dosage form comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, wherein the dosage form comprises a first portion and a second portion, wherein the first portion comprises a first amount of MMF and the second portion comprises a second amount of MMF, and when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 6.0 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, at least 70 % w/w of the first amount of MMF is released within 6 hours after the start of the test. C7. The dosage form of Aspect C5, wherein substantially all of the first amount of MMF is released within 6 hours after the start of the test.

C8. The dosage form of Aspect C5, wherein substantially all of the first amount of MMF is released within 4 hours after the start of the test.

C9. The dosage form of Aspect C5, wherein substantially all of the first amount of MMF is released within 2 hours after the start of the test.

CIO. A dosage form comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 6.8 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, 30 % w/w to 90 % w/w of the MMF present in the dosage form is released within 14 hours after the start of the test.

Cl 1. The dosage form of Aspect CIO, wherein 30 % w/w to 80 % w/w of the MMF present in the dosage form is released within 14 hours after the start of the test.

C12. A dosage form comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 6.5 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, 30 % w/w to 80 % w/w of the MMF present in the dosage form is released within 14 hours after the start of the test.

C13. The dosage form of any one of Aspects CIO to Cl 2, wherein 30 % w/w to 70 % w/w of the MMF present in the dosage form is released within 6 hours after the start of the test.

C14. A dosage form comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 7.5 phosphate buffer dissolution medium, maintained at a temperature of 37 °C, at least 80 % w/w of the MMF present in the dosage form is released within 6 hours after the start of the test.

C15. The dosage form of Aspect C14, wherein substantially all the MMF is released within 4 hours after the start of the test.

C16. The dosage form of Aspect C14, wherein substantially all the MMF is released within 3 hours after the start of the test.

C17. The dosage form of Aspect C14, wherein substantially all the MMF is released within 2 hours after the start of the test. C18. A dosage form comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, wherein the dosage form comprises a first portion and a second portion, wherein the first portion comprises a first amount of MMF and the second portion comprises a second amount of MMF; wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of 0.1 N hydrochloric acid as dissolution medium, maintained at a temperature of 37 °C, no more than 10 % w/w of the MMF present in the dosage form is released within 2 hours after the start of the test; and wherein the tablet sinker with its contents at the end of 2 hours is either tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of pH 6.0 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, and wherein substantially all of the first amount of MMF is released within 6 hours after the start of the test in pH 6.0 phosphate buffer as dissolution medium; or tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of pH 7.5 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, and wherein substantially all MMF in the dosage form is released within 6 hours after the start of the test in pH 7.5 phosphate buffer as dissolution medium.

Cl 9. A dosage form comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form releases MMF as follows: no more than 10 % w/w of the MMF present in the dosage form is released within 2 hours after the start of the test when 900 mL of 0.1 N hydrochloric acid, maintained at a temperature of 37 °C, is used as dissolution medium, and/or

30 % w/w to 70 % w/w of the MMF present in the dosage form is released within 6 hours after the start of the test when 900 mL of pH 6.0 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution medium.

C20. The dosage form of Aspect C19, wherein 30 % w/w to 60 % w/w of the MMF present in the dosage form is released within 6 hours after the start of the test when 900 mL of pH 6.0 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution medium.

C21. The dosage form of Aspect C19 or C20, wherein 30 % w/w to 55% w/w of the MMF present in the dosage form is released within 6 hours after the start of the test when 900 mL of pH 6.0 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution medium. C22. A dosage form comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form releases MMF as follows: no more than 10 % w/w of the MMF present in the dosage form is released within 2 hours after the start of the test when 900 mL of 0.1 N hydrochloric acid, maintained at a temperature of 37 °C, is used as dissolution medium, and/or

30 % w/w to 70 % w/w of the MMF present in the dosage form is released within 6 hours after the start of the test when 900 mL of pH 6.5 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution medium.

C23. The dosage form of Aspect C22, wherein 30 % w/w to 60 % w/w of the MMF present in the dosage form is released within 6 hours after the start of the test when 900 mL of pH 6.5 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution medium.

C24. The dosage form of Aspect C22, wherein 30 % w/w to 55% w/w of the MMF present in the dosage form is released within 6 hours after the start of the test when 900 mL of pH 6.5 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution medium.

C25. A dosage form comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, wherein, upon oral administration to a subject, the dosage form provides at least two pharmacokinetic parameters selected from: a plasma MMF Cmax of 0.4 mg/L to 4.3 mg/L; a plasma MMF AUCo-24h of 1.8 h*mg/L to 14.9 h*mg/L; and a plasma MMF elimination half-life (ti/2) of 0.9 hours to 2.3 hours; and wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form releases MMF as follows:

(a) no more than 10 % w/w of the MMF present in the dosage form is released within 2 hours after the start of the test when 900 mL of 0.1 N hydrochloric acid, maintained at a temperature of 37 °C is used as dissolution medium, and (b) at least 80 % w/w/ MMF in the dosage form is released within 6 hours after the start of the test when 900 mL of pH 7.5 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution media, and further wherein the tablet sinker with its contents at the end of 2 hours in step (a) is used in step (b).

C26. A dosage form comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, wherein the dosage form comprises a first portion and a second portion, wherein the first portion comprises a first amount of MMF and the second portion comprises a second amount of MMF; wherein when the dosage form is placed in a tablet sinker and tested in multiple dissolution media conditions shown below, using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form exhibits MMF release profile described therein: a) in 900 mL of 0.1 N hydrochloric acid as dissolution medium, maintained at a temperature of 37 °C, no more than 10 % w/w of the MMF present in the dosage form is released within 2 hours after the start of the test, b) in 900 mL of pH 6.5 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, substantially all of the first amount of MMF is released within 6 hours after the start of the test in pH 6.5 phosphate buffer as dissolution medium, c) in 900 mL of pH 7.5 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, substantially all second amount of MMF is released within 8 hours after the start of the test in pH 7.5 phosphate buffer as dissolution medium. wherein, the tablet sinker with its contents at the end of 2 hours in (a) is transferred to dissolution medium (b), and subsequently, the tablet sinker with its contents at the end of 6 hours in (b) is transferred to dissolution medium (c).

C27. The dosage form of any one of Aspects C6 to C9 or C18 to C21, wherein the ratio of the first amount of MMF to the second amount of MMF is 1 : 1.

C28. The dosage form of any one of Aspects C6 to C27 having a release profile as shown in FIGURE 11.

C29. The press-coated tablet of any one of Aspects C6 to C9, C18 to C21, or C27, wherein the first amount of MMF and the second amount of MMF comprise a total amount MMF in a range of 150 mg to 250 mg. C30. The press-coated tablet of any one of Aspects C6 to C9, C18 to C21, or C27, wherein the first amount of MMF and the second amount of MMF comprise a total amount MMF in a range of 175 mg to 225 mg.

C31. The press-coated tablet of any one of Aspects C6 to C9, C18 to C21, or C27, wherein the first amount of MMF and the second amount of MMF comprise a total amount MMF of 190 mg.

C32. The press-coated tablet of any one of Aspects C6 to C9, C18 to C21, or C27, wherein the first amount of MMF and the second amount of MMF comprise a total amount MMF in a range of 300 mg to 480 mg.

C33. The press-coated tablet of any one of Aspects C6 to C9, C18 to C21, or C27, wherein the first amount of MMF and the second amount of MMF comprise a total amount MMF in a range of 350 mg to 450 mg MMF.

C34. The press-coated tablet of any one of Aspects C6 to C9, C18 to C21, or C27, wherein the first amount of MMF and the second amount of MMF comprise a total amount MMF of 380 mg.

C35. The press-coated tablet of any one of Aspects C6 to C9, C18 to C21, or C27 to C34, wherein the first amount of MMF comprises at least 50 g MMF, at least 75 mg MMF, at least 100 mg MMF, at least 125 mg MMF, at least 150 mg MMF, at least 175 mg MMF, at least 200 mg MMF, at least 225 mg MMF, at least 250 mg MMF, at least 275 mg MMF, at least 300 mg MMF, or at least 325 mg MMF; or wherein the first amount of MMF comprises up to 50 mg MMF, up to 75 mg MMF, up to 100 mg MMF, up to 125 mg MMF, up to 150 mg MMF, up to 175 mg MMF, up to 200 mg MMF, up to 225 mg MMF, up to 250 mg MMF, up to 275 mg MMF, up to 300 mg MMF, up to 325 mg MMF, or up to 350 mg MMF; or both.

C36. The press-coated tablet of any one of Aspects C6 to C9, C18 to C21, or C27 to C35, wherein the second amount of MMF comprises at least 47 mg MMF, at least 50 mg MMF, at least 75 mg MMF, at least 100 mg MMF, at least 125 mg MMF, at least 150 mg MMF, at least 175 mg MMF, at least 200 mg MMF, at least 225 mg MMF, at least 250 mg MMF, at least 275 mg MMF, at least 300 mg MMF, or at least 325 mg MMF; or wherein the second amount of MMF comprises up to 50 mg MMF, up to 75 mg MMF, up to 100 mg MMF, up to 125 mg MMF, up to 150 mg MMF, up to 175 mg MMF, up to 200 mg MMF, up to 225 mg MMF, up to 250 mg MMF, up to 275 mg MMF, up to 300 mg MMF, up to 325 mg MMF, or up to 350 mg MMF; or both. Exemplary Press-coated Tablet Geometry Aspects

DI. A press-coated tablet comprising 150 mg to 500 mg of MMF formulated for once daily oral administration, the press-coated tablet comprising a first portion and a second portion, wherein the first portion comprises a first amount of MMF and the second portion comprises a second amount of MMF, and wherein the press-coated tablet has a first axis (X-Y) in a range of 9 mm to 22 mm and a second axis (A-B) in a range of 5 mm to 8 mm, wherein the first axis is orthogonal to the second axis.

D2. The press-coated tablet of Aspect DI, wherein the press-coated tablet comprises the press-coated tablet of any one of Aspects B6 to B38.

D3. The press-coated tablet of Aspect DI or D2, wherein the ratio of the A-B axis to X-Y axis is in a range of 1 : 1.2 to 1 :4.

D4. The press-coated tablet of Aspect DI or D2, wherein the ratio of the A-B axis to X-Y axis is in a range of 1 : 1.7 to 1 :3.8.

D5. The press-coated tablet of Aspect DI or D2, wherein the ratio of the A-B axis to X-Y axis is in a range of 1 : 1.8 and 1 :3.5.

Exemplary Means-Plus-Function Aspects

El. A dosage form comprising 150 mg to 500 mg of MMF and a means for achieving, upon once daily administration to a subject, a plasma MMF Cmax of 0.4 mg/L to 4.3 mg/L; a plasma MMF AUCo-24h of 1.8 h*mg/L to 14.9 h*mg/L; or a plasma MMF elimination half-life (ti/2) of 0.9 hours to 2.3 hours; or any combination thereof.

E2. The dosage form of Aspect El, wherein once daily oral administration of the dosage form to a subject provides at least two pharmacokinetic parameters selected from: a plasma MMF Cmax of 0.4 mg/L to 4.3 mg/L; a plasma MMF AUCo-24h of 1.8 h*mg/L to 14.9 h*mg/L; and a plasma MMF elimination half-life (ti/2) of 0.9 hours to 2.3 hours.

E3. The dosage form of Aspect El, the dosage form comprising 150 mg to 250 mg of MMF wherein once daily oral administration of the dosage form to a subject provides at least two pharmacokinetic parameters selected from: a plasma MMF Cmax of 0.4 mg/L to 2.1 mg/L; a plasma MMF AUCo-24h of 1.8 h*mg/L to 7.4 h*mg/L; and a plasma MMF elimination half-life (ti/2) of 0.9 hours to 2.3 hours.

E4. The dosage form of Aspect El, the dosage form comprising 300 mg to 500 mg of MMF wherein once daily oral administration of the dosage form to a subject provides at least two pharmacokinetic parameters selected from: a plasma MMF Cmax of 0.8 mg/L to 4.3 mg/L; a plasma MMF AUCo-24h of 3.7 h*mg/L to 14.9 h*mg/L; and a plasma MMF elimination half-life (ti/2) of 0.9 hours to 2.3 hours.

Exemplary Method of Use Aspects

FL A method for treating or reducing the symptoms of multiple sclerosis or psoriasis in a subject comprising once daily administration to the subject of the dosage form of any one of Aspects Al to Al 1, Bl to B3, or Cl to C34, or the press-coated tablet of any one of Aspects B4 to B38 or DI to D5.

F2. The method of Aspect Fl, wherein the multiple sclerosis comprises a relapsing form of multiple sclerosis.

F3. The method of Aspect Fl or F2, wherein the multiple sclerosis comprises clinically isolated syndrome.

F4. The method of any one of Aspects Fl to F3, wherein the multiple sclerosis comprises a relapsing-remitting multiple sclerosis.

F5. The method of any one of Aspects Fl to F4, wherein the multiple sclerosis comprises active secondary progressive multiple sclerosis.

F6. The method of any one of Aspects Fl to F5, wherein the subject is an adult.

F7. The method of any one of Aspects Fl to F6, wherein the method comprises administering a dosage form comprising 150 mg to 250 mg of MMF once a day for 7 days.

F8. The method of any one of Aspects Fl to F7, wherein the method comprises administering a dosage form comprising 300 mg to 500 mg of MMF once a day.

F9. The method of Aspect F8, wherein the dosage form comprising 300 mg to 500 mg of MMF is administered once a day after a dosage form comprising 150 mg to 250 mg of MMF has been administered once a day for 7 days. Exemplary Omnibus Aspects

G1. A composition as described herein.

G2. A method of using a composition as described herein.

G3. The method of G2, wherein the method comprises treating or reducing the symptoms of multiple sclerosis or psoriasis in a subject.

G4. The dosage form of any one of Aspects Al to Al 1, Bl to B 3, or Cl to C34, or the press- coated tablet of any one of Aspects B4 to B38 or DI to D5 for use in the treatment of multiple sclerosis or psoriasis.

G5. The method of preparing a press-coated once daily dosage form as described herein.

Exemplary Method of Making Aspects

Hl. A method of preparing a press-coated once daily dosage form comprising monomethyl fumarate, the method comprising: preparing a first formulation comprising monomethyl fumarate and one or more pharmaceutically inactive ingredients; preparing a second formulation comprising monomethyl fumarate and one or more pharmaceutically inactive ingredients; preparing a core from the second formulation; compressing the first formulation and core together so as to provide a press-coated tablet comprising the core and an outer portion, wherein the outer portion comprises a first amount of monomethyl fumarate and the core comprises a second amount of monomethyl fumarate; wherein the press-coated tablet comprises a total amount of monomethyl fumarate between 150 mg and 500 mg.

H2. The method of Aspect Hl further comprising coating the core with a core coating system.

H2A. The method of Aspect H2, wherein the core coating system provides a modified release coating or a delayed release coating.

H2B. The method of Aspect H2 or H2A, further comprising applying a barrier layer on the core prior to coating the core with the core coating system. The barrier layer may comprise at least one polymer selected from hypromellose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and gelatin.

H3. The method of Aspect Hl further comprising coating the press-coated tablet with a final tablet coating system. H3 A. The method of Aspect H3, wherein the final tablet coating system provides a modified release coating, a delayed release coating, or an enteric coating.

H4. The method of Aspect Hl, wherein the first formulation comprises from 40 wt-% to 95 wt-% of monomethyl fumarate and from 5 wt-% to 60 wt-% of the one or more excipients, by weight of the first formulation.

H5. The method of Aspect Hl, wherein the second formulation comprises from 30 wt-% to 75 wt-% of monomethyl fumarate and from 15 wt-% to 70 wt-% of the one or more excipients, by weight of the second formulation.

H6. The method of any one of Aspects H1-H5 wherein the first formulation and the second formulation independently comprise a blend, a granule, or a combination thereof.

The present invention is illustrated by the following examples. It is to be understood that the particular examples, materials, amounts, and procedures are to be interpreted broadly in accordance with the scope and spirit of the invention as set forth herein.

EXAMPLES

All reagents, starting materials, and solvents used in the following examples were purchased from commercial suppliers and were used without further purification unless otherwise indicated.

Example 1

This Example describes the properties of a once-daily monomethyl fumarate (MMF) tablet dosage form and the relationship of those properties to TECFIDERA® (a capsule containing 120 mg or 240 mg dimethyl fumarate intended to be taken twice daily) and BAFIERTAM® (a capsule containing 95 mg MMF intended to be taken twice daily).

Dimethyl fumarate (DMF) has a molecular weight of 140.12 g/mol. Monomethyl fumarate (MMF) has a molecular weight of 130.1 g/mol.

TECFIDERA Pharmacokinetics

Table 2 A shows a summary of pharmacokinetic parameters of MMF from two studies conducted in healthy volunteer and MS patients. (This data is available online at www.accessdata.fda.gov/drugsatfda_docs/nda/2013/2040630rigl sOOOClinPharmR.pdf) The dosing of TECFIDERA (DMF) and BAFIERTAM (MMF) was used to determine the equivalence of DMF and MMF.

The data of Table 2A was used to determine the half-life of a single dose of MMF in a fasted subject and in a fed subject (Table 2B). The data of Table 2A was also used to calculate the elimination rate constant (Kel) of a single dose in a fasted subject and in a fed subject (Table 2B) using the relationship half-life (ti/2) = 0.693/Kel.

The data of Table 2A were also used to calculate a low end (low range) and a high end (high range) for Tmax, the time at which the maximum plasma concentration of MMF is observed. Results are shown in Table 2C. No significant difference was observed between Tmax in subjects given a single dose or multiple doses of DMF, but food increased the Tmax of MMF by 278%.

The data of Table 2A were also used to calculate a low end (low range) and a high end (high range) for Cmax, the maximum plasma concentration of MMF (Table 2D), and for AUCo-24the area under the curve over 24 hours (Table 2E), for a once daily 380 mg dose of MMF and a once daily 190 mg dose of MMF.

Food increased AUC0-24 of MMF by about 24%. Food increased Cmax of MMF by about 12%. A linear increase in AUC0-24 versus dose administered was observed. These results indicated there was no significant effect by food on critical PK parameters.

Table 2 A. (prior art)

(Median values of Tmax are listed.)

CV = coefficient of variance

BAFIERTAM Pharmacokinetics

The BAFIERTAM (MMF 95 mg capsule) product insert reports the following information: Pharmacokinetics of monomethyl fumarate have previously been characterized after oral administration of its prodrug, dimethyl fumarate, as delay ed-release capsules, in healthy subjects and subjects with multiple sclerosis. After oral administration, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF). Additional pharmacokinetic data of monomethyl fumarate were obtained after oral administration of BAFIERTAM, the monomethyl fumarate delay ed-release capsules, in healthy subjects.

Absorption. Following oral administration of BAFIERTAM 190 mg (two 95 mg monomethyl fumarate delay ed-release capsules) under fasting conditions, the median Tmax of MMF is 4.03 hours; and the peak plasma concentration (Cmax) and overall exposure (AUC) of monomethyl fumarate are bioequivalent to those after oral administration of 240 mg dimethyl fumarate delayed-release capsule. A high-fat, high-calorie meal did not significantly affect the overall monomethyl fumarate plasma exposure (AUC), but decreased the Cmax of MMF by 20 %, with prolonged absorption. The median Tmax of MMF was delayed from approximately 4.0 hours to 11 hours by a high fat meal.

Bioequivalence between two dosage forms requires the ratio of means of the corresponding pharmacokinetic parameters such as Cmax and AUC of the dosage forms to be between 80 % and 125%. However, modified-release release dosage forms sometimes result in increased or decreased bioavailability of a drug. Thus, for once daily dosing, ranges of MMF included those having up to a 20 % increase in bioavailability or up to a 33% decrease in bioavailability. For a once daily dose to provide the same amount of MMF as a twice-daily dose of 95 mg of BAFIERTAM, it is expected that MMF in a range of 152 mg to 253 mg should be administered. For a once daily dose to provide the same amount of MMF as a twice-daily dose of 190 mg of BAFIERTAM, it is expected that MMF in a range of 304 mg to 505 mg should be administered.

As shown in Table 2F, MMF in a range of 150 mg to 250 mg is projected to have a Cmax in a range of 0.4 mg/L to 2.1 mg/L and an AUC0-24 in a range of 1.8 mg*h/L to 7.4 mg*h/L.

As shown in Table 2F, MMF in a range of 300 mg to 500 mg is projected to have a Cmax in a range of 0.8 mg/L to 4.3 mg/L and an AUC0-24 in a range of 3.7 mg*h/L to 14.9 mg*h/L.

As shown in Table 2F, both MMF in a range of 150 mg to 250 mg and in a range of 300 mg to 500 mg is projected to have an average elimination half-life (ti/2) in a range of 0.9 hours to 2.3 hours. Table 2B

* Elimination Rate Constant K_ei; 11/2 = 0.693/Kel

Food INCREASES Tmax of MMF by -278%

From the above data following a twice-daily (BID) and thrice-daily (TID) administration of TECFIDERA, the mean plasma MMF half-life is 1.3 hours and 1.39 hours, respectively. A similar MMF half-life is anticipated for the proposed once daily MMF Tablet comprising 150 mg - 500 mg MMF and the ranges estimated based on the %CV.

Example 2

This Example describes the projected MMF amounts in a press-coated tablet intended to be taken once daily. Exemplary amounts of MMF in a first portion (e.g., an outer portion) and a second portion (e.g., a core portion) are shown in Table 3A - Table 3H.

Example 3A - Comparative

This Example describes in vitro dissolution profiles of dimethyl fumarate (DMF) in a capsule as described in U.S. Publication No. 2009/0304790.

FIG. 1 shows an in vitro dissolution profile for a capsule prepared as described in Example 5 of U.S. Publication No. 2009/0304790, and in Table 4A. As described in Examples 5 and 15 of U.S. Publication No. 2009/0304790, micro-crystals were prepared as follows: a saturated solution of 50 g DMF in 300 ml 2-propanol was prepared at 60 °C and slowly cooled under permanent stirring. The precipitated crystals were filtered off and dried at 50 °C. The crystals were sieved and the 315- 710 pm fraction was used for a coating process in either a pan coater or a fluid-bed coater (MiniGlatt). A coating solution of 12 g ethyl cellulose and 3 g polyethylene glycol 400 in 500 g ethanol was sprayed at 60 °C onto the powder surface. After drying, the coated crystals were sieved through a 1.00 mm sieve. 156 mg of the microcrystals were filled in a hard-gelatin-capsule size 0. The capsules were enteric coated by dipping them into a solution of 5 % hydroxypropyl methylcellulose phthalate (HPMCP, Pharmacoat HP 50®) in acetone four times each capsule-side.

Table 4A

FIG. 2 shows an in vitro dissolution profile for a tablet (before an enteric coating was applied) prepared as described in Example 16 of U.S. Publication No. 2009/0304790, and in Table 4B. As described in Example 16 of U.S. Publication No. 2009/0304790, 50 g DMF was mixed with 12 g ethylcellulose and 3 g polyethyleneglycole 400 which was dissolved in 150 ml Ethanol 96%, passed through a 1.0 mm sieve, dried at 50 °C to 60 °C over 30 minutes and again passed through a sieve 1.0 mm. A placebo granulate was prepared as follows: Tablettose® and Avicel® 102 were mixed in equal shares and granulated with 2% povidone dissolved in water (q.s.), passed through a 1.0 mm sieve, dried at 50 °C to 60 °C over 30 minutes and again passed through a 1.0 mm sieve. 60 parts of the DMF-granulate and 38 parts of the placebo-granulate were mixed for 30 minutes in a Turbula Shaker Mixer. One-part Aerosil® 200 and one-part magnesium stearate were added and the blend was mixed again for 5 minutes. The blend was compressed to tablets with a diameter of 10 mm, a weight of about 260 mg and a hardness of about 50 N. Table 4B

FIG. 3 shows an in vitro dissolution profile for a tablet (before an enteric coating was applied) prepared as described in Example 17 of U.S. Publication No. 2009/0304790, reproduced below, and in Table 4C. As described in Example 17 of U.S. Publication No. 2009/0304790, 50 g DMF was mixed with 12 g Ethylcellulose and 3 g Polyethyleneglycol 400 which was dissolved in 150 ml Ethanol 96%, passed through a 1.0 mm sieve, dried at 50 °C to 60 °C over 30 minutes and again passed through a sieve 1.0 mm. A placebo granulate was prepared as follows: Tablettose® and Avicel® 102 were mixed in equal shares and granulated with 2% povidone dissolved in water (q.s.), passed through a 1.0 mm sieve, dried at 50 °C to 60 °C over 30 minutes and again passed through a 1.0 mm sieve. 60 parts of the DMF-granulate and 37 parts of the placebo-granulate were mixed for 30 minutes in a Turbula Shaker Mixer. One-part carboxymethylcellulose (e.g., Ac-Di- Sol®), one-part Aerosil® 200, and one-part magnesium stearate were added and the blend was mixed again for 5 minutes. The blend was compressed to tablets with a diameter of 10 mm, a weight of about 260 mg and a hardness of about 50 N.

Table 4C

Example 3B

This Example describes exemplary in vitro dissolution profiles of MMF in a press-coated tablet having a first portion (e.g., an outer portion) and a second portion (e.g., a core).

FIG. 4 shows an exemplary release profile when the MMF ratio in the first portion (e.g., an outer portion) and a second portion (e.g., a core) is 1 :2.

FIG. 5 shows an exemplary release profile when the MMF ratio in the first portion (e.g., an outer portion) and a second portion (e.g. , a core) is 1 : 1.

FIG. 6 shows an exemplary release profile when the MMF ratio in the first portion (e.g, an outer portion) and a second portion (e.g, a core) is 2: 1. Example 4

This Example describes exemplary tablet dimensions for MMF in a press-coated tablet intended to be taken once daily. Exemplary dimensions of different tablets are shown in Table 5A - Table 5Q. The axes A-B and X-Y are illustrated in FIG. 7.

Table 5A

Table 5B

Table 5C

Table 5D

Table 5E

Table 5F

Table 5G

Table 5H

Table 51

Table 5J

Table 5K

Table 5L

Table 5M

Table 5N

Table 50

Table 5P

Table 5Q

Example 5. Press-coated Once-daily MME Tablet

Turning now to FIG. 8, one embodiment of a dosage form of the present invention is shown. Press-coated once-daily MMF tablet 80 includes a core 82 disposed within an outer portion 86. The outer portion 86 comprises a first amount of MMF. The core 82 comprises a second amount of MMF. The core 82 can be optionally coated, partially or completely, with a core coat 84 positioned between the core 82 and the outer portion 86. The outer portion 86 can be optionally coated, partially or completely, with a final tablet coat 88, e.g., an enteric coating. With reference to FIGS. 9A-9B, in one embodiment a press-coated once-daily MMF tablet is manufactured in a process comprising the steps of:

(i) preparing the core, (ii) optionally coating the core,

(iii) preparing the outer portion blend, granule, or combination thereof,

(iv) compressing the core and outer portion to provide a tablet-in-tablet,

(v) optionally coating the tablet-in-tablet to provide a press-coated tablet. Example 6. Core Composition and Manufacturing Process

As discussed herein, a press-coated once-daily MMF tablet dosage form of the present invention can include a first portion, e.g., an outer portion, that has a first amount of MMF, and a second portion, e.g., a core, that has a second amount of MMF. In certain embodiments, the second portion includes a core having MMF as well as at least one pharmaceutically inactive ingredient. The at least one pharmaceutically inactive ingredient may include, but is not limited to, a diluent, filler, binder, disintegrating agent, glidant, lubricant, drug release modifying agent, osmotic agent, stabilizing agent, pH modifying agent, pH buffering agent, hydrogel, dispersing agent, emulsifying agent, enzyme, gelling agent, gum, effervescent agent, surfactant, solubilizing agent, anti-static agent, and adhesive agent, drug permeability enhancing agent, viscosity enhancing agent, lipophilic agent, hydrophilic agent, moisture adsorbing agent, pore-forming agent, wicking agent, drying agent, coloring agent, triglyceride, oil and/or wax.

The following tables provide representative examples of the composition of the core.

Table 6A-1: Core composition

Table 6A-2: Core compositions

In an embodiment, the core includes MMF particles 100 % of which are less than 200 pm in size. In another embodiment, the MMF particles have a particle size distribution as follows: D(0.1) is 25 pm or less, D(0.5) is 60 pm or less and D(0.9) is 150 pm or less. In yet another embodiment, the MMF particles have a particle size distribution as follows: D (0.1) is 15 pm or less, D(0.5) is or less 40 pm or less and D(0.9) is 100 pm or less. And in yet another embodiment, the MMF particles have a particle size distribution as follows: D(0.1) is 15 pm or less, D(0.5) is 30 pm or less and D(0.9) is 75 pm or less.

A core was prepared containing the second amount of MMF. The MMF particles used to prepare the core had a particle size distribution of D(0.1): 7 pm, D(0.5): 21 pm, and D(0.9): 51 pm. In particular, MMF, Microcrystalline cellulose and Croscarmellose sodium were passed through ASTM # 40 mesh and collected in a polythene bag and blended for about 5 minutes. Colloidal silicon dioxide, passed through ASTM # 20 mesh, was added to the blend, and mixed for about 3 minutes. Separately, magnesium stearate (lubricant) was passed through ASTM # 40 mesh and added to the blend and mixed for about two minutes to provide a final lubricated blend. The final lubricated blend was compressed into tablets using a standard concave tablet punch set fitted on manually operated Carver Press or a Single Station Compression machine (Minipress™ Mil, Riva S.A).

The core thickness and hardness were measured using Multitester Sotax MT50. The individual core weights (e.g., in milligram, mg), thickness (e.g., in millimeters, mm) and hardness (e.g., in kilopond (kp) or newtons (N)) were recorded for at least 3 randomly selected cores prepared from each formulation. The average of these respective measurements was also recorded.

The core breaking force, generally referred as tablet hardness, are calibrated in kiloponds (kp) or newtons (N). The relationship between these units of force is: 1 kp = 9.80 N (reference. United States Pharmacopeia, General Information <1217>, Tablet Breaking Force).

In one embodiment, the core hardness was adjusted to be between about 3 kP and about 20 kP, preferably between about 3 kP and about 15 kP, more preferably between 3 kP and 8 kP. In an embodiment, the target weight of the core (i.e., before the optional coating step) is between about 50 mg and about 835 mg, when the MMF amount in the core is between about 45 mg and about 335 mg.

In another embodiment, the target weight of the core (i.e., before the optional coating step) is between about 80 mg and about 375 mg, when the MMF amount in the core is between about 75 mg and about 225 mg.

Example 7 Core Coat, Coating System, and Manufacturing Process

As discussed herein, in certain embodiments the core is coated. This coating may encompass (that is, completely surround) the core

In one embodiment, the core coat (used herein interchangeably with the phrase core coating) is made from a coating system that includes at least one agent selected from the group comprising ethyl cellulose, methyl cellulose, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phthalates, hypromellose phthalate, hypromellose acetate succinate, polymethacrylate, polyvinyl acetate, polyethylene oxide, polyvinyl pyrrolidone, shellac, gelatin, and wax.

In another embodiment, the coating system comprises at least one polymethacrylate selected from poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1 : 2 : 1; poly(ethyl acrylate, methyl methacrylate) 2: 1; poly(methacrylic acid, methyl methacrylate) 1 : 1; poly(methacrylic acid, ethyl acrylate) 1 : 1; poly(methacrylic acid, methyl methacrylate) 1 : 2; poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7: 3: 1; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.2; and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1.

In yet another embodiment, the coating system comprises at least one polymethacrylate selected from poly(methacrylic acid, methyl methacrylate) 1 : 2; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1; poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7: 3: 1; and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.2.

In one embodiment, the core coat does not dissolve in an aqueous fluid having a pH of about 4 or less. In another embodiment, the core coat dissolves in an aqueous fluid having a pH of about 6 or higher. In yet another embodiment, the core coat dissolves in an aqueous fluid that has a pH of about 7 or higher. Table 7-1: Composition of Core Coating System

In one embodiment, the coating polymer of Table 7-1 comprises a combination of two or more types of polymers.

It is noted that any coating system ingredient can function in more than one way to aid in the processing and formation of the core coat. Further, it should also be noted that the solvent, diluent, and/or vehicle is substantially removed from the coating system upon application to the core to provide the core coat.

Commercially available ready-made coating systems may also be employed as the core coating system For example, the following polymethacrylates are commercially available as ready- made dispersions and solutions that can be used to prepare the core coating system: Eudragit NE 30 D, Eudragit NE 40 D, Eudragit L 12.5, Eudragit L 12.5 P, Eudragit L 30 D-55, Eudragit S 12.5, Eudragit S 12.5 P, Eudragit FS 30D, Eudragit RL 30 D, Eudragit RL 12.5, Eudragit RS 30 D, Eudragit RS 12.5; Acryl-EZE MP, Acryl-EZE, Kollicoat MAE 30 D. (Eudragit® is the Registered Trademark of Evonik Industries, Acryl-EZE® is the Trademark of Colorcon and Kollicoat® is the Trademark of BASF Fine Chemicals.)

In certain embodiments, the core coating system may also comprise an opacifying agent (e.g., titanium dioxide), colors, dyes, lakes, and/or flavoring agents.

Table 7-2: Composition of Delayed-release Core Coating Systems

The cores of Example 7 were coated with a coating system as described above using laboratory scale coating equipment. The following is a general description of the process used to prepare the coating system and to apply the prepared coating system onto a core.

The quantity of the ethyl alcohol was weighed into a stainless-steel container and the quantity of purified water was added to the alcohol under continuous stirring using a compressed air driven stirrer. Diethyl phthalate or triethyl citrate was added and polyethylene glycol also added to the alcohol-water mixture under continuous stirring. Poly(methacrylic acid, methyl methacrylate) 1 :2 (Eudragit SI 00) was then slowly added and the stirring continued until the polymer completely dissolved. Care was exercised to minimize foam formation throughout stirring process. Separately, talc was weighed and added slowly to the mixture under stirring. The mixture was stirred well to form a lump-free uniform suspension. The mixture was kept under continuous stirring throughout the coating process to prevent settling of the suspension.

The following is a brief description of the coating process. The cores were placed in a coating pan (Labcoat™ M5, O’Hara Technologies) and the equipment setup for the following processing parameters: Air Flow Rate: 100 cfm, Inlet Temperature: ~38 °C, Exhaust Temperature: ~30±2 °C, Atomization range: 8-10, Pattern Air Pressure range: 9 -18 psi, Pan speed range: 20-24 rpm

The cores were pre-heated until the target inlet and exhaust temperatures achieved. The initial group weight of about 10 cores (after pre-heat) was recorded. The cores were coated with the Eudragit S100 coating system (Table 7-2) at a spray rate ranging from about 6 g to 10 g per minute.

The cores are coated to achieve an average weight gain of about 2 % to about 30 %, about 4 % to about 25 %, about 6 % to about 25 %, about 8 % to about 25 %, about 10 % to about 25 %, about 12 % to about 25 %, about 5 % to about 20 %, about 6 % to about 20 %, about 7 % to about 20 %, about 8 % to about 20 %, about 5 % to about 15 %, or about 6 % to about 15 %, wherein the % weight gain is based on the total solids weight of coating system applied on the core. In one embodiment, the total solids weight of the coat includes the weights of all the coating system ingredients except the solvent, diluent and/or the vehicle which as discussed herein is substantially removed from the coating system during the coating process.

In other embodiments, the cores are coated to achieve an average weight gain of about 1 % to about 20 %, about 1.5 % to about 15 %, about 2 % to about 15 %, about 2.5 % to about 12 %, about 2.5 % to about 10 %, about 2.5 % to about 9 %, about 2.5 % to about 8 %, about 3 % to about 10 %, about 3 % to about 9 %, or about 3 % to about 8 %, by weight of the coating polymer(s) of the coating system. In one embodiment, the weight of the coating polymer in the coat includes the total dry weight(s) of the coating polymer(s) applied on the cores during coating process.

Example 8 Exemplary Cores

Table 8-1 shows the overall composition and characteristics of the coated cores comprising core formulation, IT-5 (Table 6A-2), and a delayed release coating system, DR-1 (Table 7-2).

A batch of cores (about 400) were prepared and compressed as previously described. A subbatch of at least 100 of these cores were coated with the DR -1 coating system to a total solids weight-gain (target) of about 5 % w/w. Another sub-batch of about 100 of these cores were coated with DR -1 coating system to a total solids weight-gain (target) of about 10 % w/w. The resulting total solids weight-gain estimates for these coated core sub-batches are shown in the Table 8-1 as formulations 8-1A and 8-1B, respectively.

Table 8-2 shows the overall composition and characteristics of the coated cores comprising core formulation, IT-6, and a delayed release coating system, DR-2. A batch of cores (about 750) were prepared and compressed as described. Three sub-batches (at least 120 cores per sub-batch) were separately coated with the DR -2 coating system to provide total solids weight-gain (target) of about 2.5 % w/w, about 3.5 % w/w, and about 7 %w/w. The resulting total solids weight-gain estimates for these sub-batches of the coated cores are shown in the Table as Formulations 8-2 A, 8- 2B and 8-2C, respectively.

Table 8-1: Composition of Delayed Release Coated Core

*substantially removed during coating process

Table 8-2: Overall Composition of Delayed Release Coated Core

* substantially removed during coating process

Example 9 Composition and Manufacturing Process for Outer Portion

As discussed herein, a once-daily MMF tablet dosage form of the present invention can include a first portion, e.g., an outer portion, that has a first amount of MMF, and a second portion, e.g., a core, that has a second amount of MMF. In one embodiment of the once-daily MMF tablet dosage form, the first portion is an outer portion that includes a first amount of MMF and at least one pharmaceutically inactive ingredient. Exemplary pharmaceutical inactive ingredients for the outer portion include, but is not limited to, diluent, filler, binder, disintegrating agent, glidant, lubricant, drug release modifying agent, osmotic agent, stabilizing agent, pH modifying agent, pH buffering agent, hydrogel, dispersing agent, emulsifying agent, surfactant, solubilizing agent, anti-static agent, and adhesive agent, drug permeability enhancing agent, viscosity enhancing agent, lipophilic agent, hydrophilic agent, moisture adsorbing agent, pore-forming agents, wicking agent, drying agent, coloring agent, triglyceride, oil and wax. A pharmaceutical inactive ingredient can function in more than one way to aid in the processing and compression of the once-daily MMF tablet dosage form. In one embodiment, the once-daily MMF tablet dosage form is a press-coated once-daily

MMF tablet having a first portion that comprises a dry powder blend, granules, or a combination thereof.

The following tables show exemplary composition of the outer portion.

Table 9-1: Composition of Outer Portion

The outer portion may optionally include a binder.

In an embodiment, the outer portion includes MMF particles, wherein 100 % of the MMF particles are less than 200 pm in size. In another embodiment, the MMF particles have a particle size distribution (as measured by Malvern MasterSizer 2000 or 3000, or an equivalent) as follows: D(0.1) is 25 pm or less, D(0.5) is 60 pm or less and D(0.9) is 150 pm or less.

In another embodiment, the MMF particles have a particle size distribution as follows: D (0.1) is 15 pm or less, D(0.5) is 40 pm or less and D(0.9) is 100 pm or less.

In another embodiment, the MMF particles have a particle size distribution as follows: D (0.1) is 15 pm or less, D(0.5) is 30 pm or less and D(0.9) is 75 pm or less.

In an embodiment, substantially all of the first amount of MMF is present in the first portion, e.g., in the outer portion.

In one embodiment, the outer portion is prepared by a blending process. MMF, microcrystalline cellulose (or Silicified microcrystalline cellulose) and croscarmellose sodium are passed through ASTM # 40 mesh and blended for about 5 minutes to provide a blend. Colloidal silicon dioxide is passed through ASTM # 40 mesh with the aid of a small portion of the blend and is added and further mixed for about 3 minutes. Magnesium stearate (lubricant) was passed through ASTM # 40 mesh and added and the blend was further mixed for about two minutes. The lubricated final drug blend for the outer portion is ready for use in compression.

A wet granulation process may also be employed to prepare the final drug blend for the outer portion. For instance, in an embodiment, MMF, and Microcrystalline cellulose (or silicified microcrystalline cellulose) are screened through ASTM # 40 mesh and placed in the bowl of a high shear granulator (PHARMX PX1, from Fluidair) and dry mixed for about 2 minutes. Purified water or a binder solution (e.g., polyvinyl pyrrolidone in water) is sprayed on the dry mix, under low shear, followed by a short rapid mixing action. The wet granulate obtained is dried in a fluid bed drier (Fluid Air, model 0002XP) to a get a loss-on-drying (LOD) value between about 0.5 % and about 2% w/w, as analyzed by moisture analyzer (Mettler Toledo HR83-P). The dried granules passed through a Quadro Comil (Quadro Engineering 1975) and then sifted through Sweco® sifter (e.g., fitted with ASTM #30 mesh) results in MMF granules. These granules are then blended with croscarmellose sodium and colloidal silicon dioxide for about 3 minutes, and lubricated with magnesium stearate for about 2 minutes, to obtain the final drug granules for the outer portion that are ready for compression.

In another embodiment, the outer portion may be prepared from a drug blend granulated by a roller-compaction process. Roller compaction is primarily used to “dry granulate” a powder material or a mixture of powders that exhibit poor flow characteristics and/or segregation potentials due to large differences in particle size distribution and/ or bulk densities of the individual powder component in the mixture. When roller compaction process is used, the desired MMF amount and microcrystalline cellulose (MCC) is dry mixed and slowly fed through the hopper of the roller compactor set-up (e.g., WP 120 Alexanderwerk) into the area between the two counter rotating rollers separated by a predetermined distance. The MMF-MCC blend gets compacted and rolls out as ribbons which can be milled using Quadro Comil to get the MMF granules of desired particle size distribution, having good powder-flow properties needed for tablet compression. Process parameters such as - Feed rate, roller speed, compaction pressure, roller design can be optimized to get consistent MMF-MCC ribbon characteristics that yield desired granule density and porosity. The granules are blended with the croscarmellose sodium and silicon dioxide, and lubricated with magnesium stearate to get the final drug blend ready for compression.

The target weight of the outer portion per press-coated tablet can range between about 60 mg and about 1,120 mg, when the MMF amount in the outer portion is between about 45 mg to about 335 mg.

In another embodiment, the target weight of the outer portion per press-coated tablet can range between about 100 mg and about 750 mg, when the MMF amount in the outer portion is between about 75 mg to about 225 mg. Example 10 Press-coated once-daily MME Tablets

This example describes the preparation of a press-coated once-daily MMF tablet comprising a coated core and outer portion OT-2 (Table 9-2).

All of the individual ingredient weights were estimated to prepare a total of 50 g of the formulation blend OT-2.

Except magnesium stearate, all the individual ingredients of the outer portion blend formulation were separately weighed, passed through ASTM mesh # 40 and collected together in polythene bag, and mixed for about 5 minutes. Then, the quantity of magnesium stearate was weighed, passed through ASTM mesh # 40, and mixed with the powder mixture in the polythene bag, for two minutes. The outer portion blend was ready and stored in tightly closed polythene bag until used in the preparation of the press-coated once-daily MMF tablet.

The single-station tablet press (Minipress® Model Mil, Riva) was fitted with round (0.3661” diameter) standard concave tablet tooling. Approximately half of the target total outer portion blend weight (see Table 9-2) was weighed and quantitatively transferred into the die-well created by lowering the lower punch. Using a forceps, one coated core (Example 8) was gently placed/ dropped over the blend contained in the die-well such that it was nearly evenly away from the die wall, i.e., the coated core was centered to the extent possible. The remaining quantity of the target outer portion blend was quantitatively transferred and manually compressed to obtain the press-coated tablet.

The press-coated tablet weight was noted, and thickness and hardness parameters were measured using Multitester Sotax (Model MT50).

In certain embodiments, the hardness of the press-coated once-daily MMF tablet is adjusted to be between about 4 and about 20 kP, preferably between about 5 and about 20 kP, more preferably between 8 and 20.

A fully automated tablet-in-tablet compression equipment (example: Kikusui Aquarius® model) can be used to manufacture the press-coated once-daily MMF tablets of the current invention.

Example 11 Final Tablet Coat, Coating System and Process of Application

An optional final tablet coating system can be applied to the outer portion to provide a press-coated once-daily MMF tablet according to the present invention. For example, the final tablet coating applied onto the outer portion of a press-coated once-daily MMF tablet can modify, delay, extend or sustain the release of the MMF contained in the tablet in vitro and/ or in vivo. In one embodiment, the coating applied to the outer portion is an enteric coating.

In certain embodiments, the final tablet coating causes the release of the first amount of MMF in an aqueous fluid having a pH of at least 4.5, for example, a pH of 5.5 or higher, a pH of 6 or higher, a pH of 6.8 or higher, or a pH of 7.4 or higher. In another embodiment, the final tablet coating does not dissolve in an aqueous fluid having a pH of 4 or less.

Exemplary final tablet coating systems include at least one ingredient selected from the group ethyl cellulose, methyl cellulose, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phthalates, Hypromellose phthalate, hypromellose acetate succinate, polymethacrylate, polyvinyl acetate, polyethylene oxide, polyvinyl pyrrolidone, shellac, gelatin, and wax.

In other embodiments, the final tablet coating system includes at least one polymer selected from poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1 : 2 : 1; poly(ethyl acrylate, methyl methacrylate) 2 : 1; poly(methacrylic acid, methyl methacrylate) 1 : 1; poly(methacrylic acid, ethyl acrylate) 1 : 1; poly(methacrylic acid, methyl methacrylate) 1 : 2; poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7: 3:1; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.2; and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1.

For example, the final tablet coating system is made of at least one polymer selected from poly(methacrylic acid, methyl methacrylate) 1 : 2; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1; poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7: 3:1; and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.2.

In another embodiment, the final tablet coating system includes poly(methacrylic acid, ethyl acrylate) 1 : 1 copolymer.

The final tablet coating system can also comprise a commercially available enteric coating system such, as but not limited to, the following: Acryl-EZE® (Colorcon); Acryl-EZE® MP (Colorcon); Eudragit® L 30 D-55 (Evonik); Eudragit® L 100-55 (Evonik); Eastacryl® 30D (Eastman Chemical); Kollicoat® MAE 30 D (BASF Fine Chemicals); Kollicoat® MAE 30 DP (BASF Fine Chemicals); and equivalents. The commercially available coating system employed provides equivalent properties as the above-discussed final tablet coating systems. For example, the following polymethacrylates, which are available as ready made dispersions and solutions, can be used to prepare the final tablet coating system: Eudragit NE 30 D, Eudragit NE 40 D, Eudragit L 12.5, Eudragit L 12.5 P, Eudragit L 30 D- 55, Eudragit S 12.5, Eudragit S 12.5 P, Eudragit FS 30D, Eudragit RL 30 D, Eudragit RL 12.5,

Eudragit RS 30 D, Eudragit RS 12.5; Acryl-EZE MP, Acryl-EZE, and Kollicoat MAE 30 D.

The final tablet coating system may also include an opacifying agent (e.g., titanium dioxide), color, dyes, lakes, and/or flavoring agent.

Table 11-1: Exemplary Final Tablet Coating System

*removed during coating process

An enteric coating system for the outer-portion of a press-coated once-daily MMF tablet was prepared as follows. Purified water was weighed in a stainless-steel container. Under gentle stirring, e.g., using a propeller-type blade mixer, tri ethyl citrate was added. Eudragit L30 D 55 was added to this solution. Sodium bicarbonate, if used, and talc were added and the mixture stirred continuously for about 45 minutes. Mixing was continued throughout the preparation of the enteric coating system to avoid settling of the suspension.

The following described certain features of the coating process. Press-coated once-daily MMF tablets were placed in a coating pan (Labcoat™ M5, O’Hara Technologies) and the equipment was setup for the following processing parameters: Air Flow Rate: 100 cfm, Inlet Temperature: 42±2 °C, Exhaust Temperature: ~32±2 °C, Atomization range: 16-21, Pattern Air Pressure range: 9 -18 psi, Pan speed range: 18-24 rpm.

The press-coated once-daily MMF tablets were pre-heated until the desired inlet and exhaust temperatures were achieved. The initial group weight of about 10 tablets (after pre-heat) was recorded. Two sub-batches of the press-coated once-daily MMF tablets (i.e., the outer portion of the press-coated once-daily MMF tablets) were enteric coated, viz., one sub-batch was coated with the Eudragit L30 D55 coating system 11-1 and the other sub-batch was coated with Eudragit L30 D55 coating system 11- 2 prepared as above, at a spray rate ranging from about 4 g - 6 g per minute.

The press-coated once-daily MMF tablets are coated to achieve an average weight gain of about 1 %, to about 15 %, about 2 % to about 10 %, about 3 % to about 10 %, about 2 % to about 8 %, about 2.5 % to about 8 %, about 2.5 % to about 7 %, about 3 % to about 12 %, about 2 % to about 8 %, about 2 % to about 7 %, about 2 % to about 6 %, about 3 % to about 7 %, or about 3 % to about 6 %, wherein the % weight gain is based on the total solids weight of final tablet coat system applied press-coated tablet. The total solids weight of the final tablet coat includes the weights of all the coating components except the solvent, diluent and/or the vehicle, which as discussed herein is substantially removed during the coating process.

In further embodiments, the press-coated once-daily MMF tablets are coated to achieve an average weight gain of about 1 % to about 8%, about 1.5 % to about 7 %, about 2 % to about 7 %, about 2 % to about 6 %, about 2.5 % to about 6%, about 2 % to about 5 % or about 2.5 % to about 5 %, by total weight of the coating polymer(s). In an embodiment, the weight of the coating polymer of the final tablet coat system includes the total dry weight(s) of the coating polymer(s) applied.

Example 12 Exemplary Enteric Coated Press-Coated Once-daily MME Tablets

This example describes overall compositions of exemplary enteric coated press-coated once- daily MMF tablets. Table 12-1 and Table 12-2 illustrate enteric coated press-coated once-daily MMF tablets 12- 1 and 12-2, respectively. Each comprises a delayed-release (DR) coated core, an outer portion comprising a blend formulation, and an enteric coating system applied to the outer portion.

The press-coated once-daily MMF tablet 12-1 comprises a total MMF amount of about 190 mg. This dosage form includes a delayed-release coated core having formulation 8- IB, which in turn comprises about 95 mg MMF. This dosage form includes about 200 mg of the outer portion formulation OT-2, which in turn comprises about 95 mg MMF. The outer portion is coated with enteric final coating system formulation 11-1.

The press-coated once-daily MMF tablet 12-2 includes a total MMF amount of about 190 mg. This dosage form includes a delayed-release coated core having formulation 8-2C, which in turn comprises about 95 mg MMF. This dosage form includes about 200 mg of outer portion formulation OT-2, which in turn comprises about 95 mg MMF. The outer portion is coated with enteric final coating system 11-1.

Table 12-1: Composition of Enteric Coated Press-coated Once-daily MMF Tablet,

Example 12-1.

Table 12-2: Composition of Enteric Coated Press-coated Once-daily MMF Tablet,

Example 12-1.

The press-coated once-daily MMF tablets of the current invention can comprise a higher total amount of MMF, e.g., greater than 190 mg, to suit the dosage regimen for treatment of relapsing forms of multiple sclerosis (MS).

For example, in certain embodiments the press-coated once-daily MMF tablet of the current invention include a total amount of MMF of about 360 mg to about 480 mg, about 380 mg to about 450 mg, or about 380 mg to about 430 mg. In addition, the once-daily MMF press-coated tablet include: a) a delayed-release coated core, wherein the core comprises about 30 % -70 %, about 40 % - 60 % about 45% - 55% or about 50 % by weight of the total amount of MMF, b) an outer portion which comprises an amount of MMF to meet the total amount of MMF in the press-coated once-daily MMF tablet, and c) an enteric coating system, wherein the core is disposed within the outer portion and the core and outer portion are compressed together so as to provide a press-coated tablet onto which is applied the enteric coating system so as to provide an enteric coated press-coated once-daily MMF tablet.

In a specific embodiment, the enteric coated press-coated once-daily MMF tablet comprises a total of about 380 mg MMF, wherein the tablet includes: a) one core made from formulation IT-7 comprising about 190 mg MMF, and wherein the core is coated with delayed-release coating system DR-1 or DR-2, to provide a total solids weight-gain from about 5% w/w to about 10 % w/w, b) about 380 mg of the outer portion blend formulation OT-4 which comprises about 190 mg MMF, c) and enteric coating system formulation 11-1 or 11-2, wherein the core is disposed within the outer portion and together the core and outer portion are compressed together so as to provide a press-coated tablet onto which is applied the enteric coating system so as to provide an enteric coated press-coated once-daily MMF tablet.

Example 13 In vitro Dissolution This example describes in vitro dissolution experiments carried out to determine the MMF release profiles from the delayed-release coated core and from an enteric coated press-coated once- daily MMF tablet of the current invention.

Evaluations were conducted by a multiple-stage in vitro dissolution test performed using an Agilent 708-DS Dissolution Apparatus with manual transfer from one medium to the next at each stage. At each pre-determined time point, about 2 mL of the dissolution medium was sampled using an Agilent 850-DS sampling station and filtered through a 10 pm polyethylene full-flow cannula filter (QLA FILO 10).

The MMF amount released was determined by analyzing the aliquots of the dissolution medium using high-performance liquid chromatography (HPLC). The cumulative MMF amount released at each time point was determined and the overall MMF release profile from the dosage form plotted as a function of time.

Table 13-A includes a brief summary of an example HPLC method employed to analyze the MMF amount released:

Table 13-A: HPLC method

The dissolution experiments use standard dissolution testing apparatus and methods according to United States Pharmacopoeia.

Certain in vitro dissolution experiment included multiple-media conditions as shown in Table 13-1 to determine the MMF release profiles from the delayed-release coated cores.

Table 13-1: In vitro Dissolution Experiment Conditions for DR-coated Cores

In another example, the in vitro dissolution experiment included multiple-media conditions as shown in Table 13-2 to determine the MMF release profiles from press-coated once-daily MMF tablets.

Table 13-2: In vitro Dissolution Experiment Conditions for Press-coated Tablets

The delayed-release coated cores indicated in Table-13-3, below, were evaluated for in vitro

MMF release profiles using the dissolution experiment conditions of Table 13-1.

Table-13-3: MME Release Profiles for Coated Cores

As shown in FIG. 10, by varying the delayed release coating weight gain in terms of % w/w of total delayed release polymer(s), the coated core can be designed to release MMF at pH 6.8 and pH 7.5, or only at pH 7.5. A combination of the polymer types can be used to achieve a desired MMF release pattern.

The enteric coated press-coated once-daily MMF tablets indicated in Table 13-4, below, were evaluated for in vitro MMF release profiles using the dissolution experimental conditions of Table 13-2.

Table 13-4: MMF Release Profiles of Enteric Coated Press-coated Once-daily MMF Tablets

As shown in FIG. 11, the in vitro MMF release profiles demonstrate that timed release of the first amount of MMF, i.e., MMF present in the outer portion, and the second amount of MMF, i.e., MMF present in the core, can be achieved. Accordingly, the enteric coated press-coated once-daily MMF tablets described herein can be used for once daily administration of MMF. By varying the first and second MMF amounts (in the outer portion and core, respectively), the total MMF amount delivered per day can be varied. Thus, different strengths of the MMF dosage form suitable for once daily administration can be manufactured.

The complete disclosure of all patents, patent applications, and publications, and electronically available material cited herein are incorporated by reference. In the event that any inconsistency exists between the disclosure of the present application and the disclosure(s) of any document incorporated herein by reference, the disclosure of the present application shall govern. The foregoing detailed description and examples have been given for clarity of understanding only. No unnecessary limitations are to be understood therefrom. The invention is not limited to the exact details shown and described, for variations obvious to one skilled in the art will be included within the invention defined by the claims.

Claims

What is claimed is:

1. A dosage form comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily administration.

2. A dosage form formulated for once daily oral administration comprising 150 mg to 500 mg of monomethyl fumarate, wherein once daily oral administration of the dosage form to a subject provides a pharmacokinetic parameter selected from: a plasma monomethyl fumarate Cmax of 0.4 mg/L to 4.3 mg/L; a plasma monomethyl fumarate AUCo-24h of 1.8 h*mg/L to 14.9 h*mg/L; a plasma monomethyl fumarate elimination half-life (ti/2) of 0.9 hours to 2.3 hours; and any combination thereof.

3. A press-coated tablet comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily oral administration, the press-coated tablet comprising a first portion and a second portion, wherein the first portion comprises a first amount of monomethyl fumarate and the second portion comprises a second amount of monomethyl fumarate, wherein a ratio of the first amount of monomethyl fumarate to the second amount of monomethyl fumarate is in a range of 1 :0.5 to 1 :2, wherein after administration of the press coated tablet to a subject, the first portion releases the first amount of monomethyl fumarate within a first period of time and the second portion releases the second amount of monomethyl fumarate within a second period of time, wherein the first period of time is in a range of 0.5 hours to 12 hours post-administration, and wherein the second period of time begins at least 6 hours post-administration.

4. A dosage form comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of 0.1 N hydrochloric acid as dissolution medium, maintained at a temperature of 37 °C, the dosage form releases less than 10 % w/w of the monomethyl fumarate present in the dosage form within 2 hours after start of the test.

5. A dosage form comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of USP Simulated Gastric Fluid pH 1.2 as dissolution medium, maintained at a temperature of 37 °C, at least 10 % w/w of the monomethyl fumarate present in the dosage form is released within 2 hours after start of the test.

6. A dosage form comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily oral administration, wherein the dosage form comprises a first portion and a second portion, wherein the first portion comprises a first amount of monomethyl fumarate and the second portion comprises a second amount of monomethyl fumarate, and when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 6.0 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, at least 70 % w/w of the first amount of monomethyl fumarate is released within 6 hours after start of the test.

7. A dosage form comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 6.8 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, 30 % w/w to 90 % w/w of the monomethyl fumarate present in the dosage form is released within 14 hours after start of the test.

8. A dosage form comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 6.5 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, 30 % w/w to 80 % w/w of the monomethyl fumarate present in the dosage form is released within 14 hours after start of the test.

9. A dosage form comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of a pH 7.5 phosphate buffer dissolution medium, maintained at a temperature of 37 °C, at least 80 % w/w of the monomethyl fumarate present in the dosage form is released within 6 hours after start of the test.

10. A dosage form comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily oral administration, wherein the dosage form comprises a first portion and a second portion, wherein the first portion comprises a first amount of monomethyl fumarate and the second portion comprises a second amount of monomethyl fumarate; wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of 0.1 N hydrochloric acid as dissolution medium, maintained at a temperature of 37 °C, no more than 10 % w/w of the monomethyl fumarate present in the dosage form is released within 2 hours after start of the test; and wherein the tablet sinker with its contents at 2 hours is either tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of pH 6.0 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, and wherein substantially all of the first amount of monomethyl fumarate is released within 6 hours after the start of the test in pH 6.0 phosphate buffer as dissolution medium; or tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm in 900 mL of pH 7.5 phosphate buffer as dissolution medium, maintained at a temperature of 37 °C, and wherein substantially all monomethyl fumarate in the dosage form is released within 6 hours after the start of the test in pH 7.5 phosphate buffer as dissolution medium.

11. A dosage form comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form releases monomethyl fumarate as follows: no more than 10 % w/w of the monomethyl fumarate present in the dosage form is released within 2 hours after start of the test when 900 mL of 0.1 N hydrochloric acid, maintained at a temperature of 37 °C, is used as dissolution medium, and/or

30 % w/w to 70 % w/w of the monomethyl fumarate present in the dosage form is released within 6 hours after start of the test when 900 mL of pH 6.0 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution medium.

12. A dosage form comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily oral administration, wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form releases monomethyl fumarate as follows: no more than 10 % w/w of the monomethyl fumarate present in the dosage form is released within 2 hours after start of the test when 900 mL of 0.1 N hydrochloric acid, maintained at a temperature of 37 °C, is used as dissolution medium, and/or

30 % w/w to 70 % w/w of the monomethyl fumarate present in the dosage form is released within 6 hours after start of the test when 900 mL of pH 6.5 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution medium.

13. A dosage form comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily oral administration, wherein, upon oral administration to a subject, the dosage form provides at least two pharmacokinetic parameters selected from: a plasma monomethyl fumarate Cmax of 0.4 mg/L to 4.3 mg/L; a plasma monomethyl fumarate AUCo-24h of 1.8 h*mg/L to 14.9 h*mg/L; and a plasma monomethyl fumarate elimination half-life (ti/2) of 0.9 hours to 2.3 hours; and wherein when the dosage form is placed in a tablet sinker and tested using USP Type-II (paddle) dissolution apparatus at a stirring rate of 100 rpm, the dosage form releases monomethyl fumarate as follows:

(a) no more than 10 % w/w of the monomethyl fumarate present in the dosage form is released within 2 hours after start of the test when 900 mL of 0.1 N hydrochloric acid, maintained at a temperature of 37 °C is used as dissolution medium, and

(b) substantially all monomethyl fumarate in the dosage form is released within 6 hours after the start of the test when 900 mL of pH 7.5 phosphate buffer, maintained at a temperature of 37 °C, is used as dissolution media, and further wherein the tablet sinker with its contents at 2 hours in step (a) is used in step (b).

14. A press-coated tablet comprising 150 mg to 500 mg of monomethyl fumarate formulated for once daily oral administration, the press-coated tablet comprising a first portion and a second portion, wherein the first portion comprises a first amount of monomethyl fumarate and the second portion comprises a second amount of monomethyl fumarate.

15. The press-coated tablet of claim 14, wherein the press-coated tablet has a first axis (X-Y) in a range of 9 mm to 22 mm and a second axis (A-B) in a range of 5 mm to 8 mm, wherein the first axis is orthogonal to the second axis.

16. The press-coated tablet of claim 14 or 15, wherein second portion comprises 40 wt-% to 95 wt-% of MMF, and optionally one or more of from 3 wt-% to 60 wt% of one or more diluents, fillers, and binders,

10 wt-% or less of one or more disintegrating agents,

5 wt-% or less of one or more stabilizers,

3 wt-% or less of one or more glidants, and

2 wt-% or less of one or more process aids, by weight of the second portion.

17. The press-coated tablet of any one of claims 14 to 16, wherein first portion comprises 30 wt- % to 75 wt-% of MMF, and optionally one or more of from 15 wt-% to 75 wt% of one or more diluents, fillers, and binders,

10 wt-% or less of one or more disintegrating agents,

5 wt-% or less of one or more stabilizers,

3 wt-% or less of one or more glidants, and

2 wt-% or less of one or more process aids by weight of the first portion.

18. The press-coated tablet of any one of claims 16 or 17, wherein the one or more diluents, fillers, and binders comprise microcrystalline cellulose, silicified microcrystalline cellulose, lactose, dicalcium phosphate, starch, pregelatinized starch, crospovidone, povidone, mannitol, sucrose, hypromellose, hydroxypropyl cellulose (HPC), gelatin, or a combination thereof.

19. The press-coated tablet of any one of claims 16 to 18, wherein the one or more disintegrating agents comprise carmellose, croscarmellose, sodium starch glycollate, sodium lauryl sulphate, povidone, alginates, or a combination thereof.

20. The press-coated tablet of any one of claims 14 to 19, wherein the first portion, the second portion, or both the first and second portions are prepared using MMF particles having a particle size D(1.0) of 200 pm or less.

21. The press-coated tablet of any one of claims 14 to 20, wherein the first portion, the second portion, or both the first and second portions are coated with a coating system comprising a coating polymer independently selected from ethyl cellulose, methyl cellulose, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phthalates, hypromellose phthalate, hypromellose acetate succinate, polymethacrylate, polyvinyl acetate, polyethylene oxide, polyvinyl pyrrolidone, shellac, gelatin, wax, and combinations thereof.

22. The press-coated tablet of 21, wherein the coating system forms an enteric coating or a delayed release coating, optionally wherein the first portion is coated with an enteric coating, further optionally wherein the second portion is coated with a delayed release coating.

23. The press-coated tablet of any one of claims 14 to 22, wherein the first portion has a weight of 100 mg to 750 mg and comprises 75 mg to 225 mg MMF, and the second portion has a weight of 80 mg to 375 mg and comprises from 75 mg to 225 mg of MMF.

24. The press-coated tablet of any one of claims 14 to 23, and wherein upon once daily administration to a subject, the press-coated tablet results in: a plasma monomethyl fumarate Cmax of 0.4 mg/L to 4.3 mg/L; a plasma monomethyl fumarate AUCo-24h of 1.8 h*mg/L to 14.9 h*mg/L; or a plasma monomethyl fumarate elimination half-life (ti/2) of 0.9 hours to 2.3 hours; or any combination thereof.

25. A dosage form comprising 150 mg to 500 mg of monomethyl fumarate and a means for achieving, upon once daily administration to a subject, a plasma monomethyl fumarate Cmax of 0.4 mg/L to 4.3 mg/L; a plasma monomethyl fumarate AUCo-24h of 1.8 h*mg/L to 14.9 h*mg/L; or a plasma monomethyl fumarate elimination half-life (ti/2) of 0.9 hours to 2.3 hours; or any combination thereof.

26. A method for treating or reducing symptoms of multiple sclerosis or psoriasis in a subject comprising once daily administration to the subject of the dosage form of any one of claims 1, 2, 4 to 13, or 15, or the press-coated tablet of claim 3 or 14 to 24.

27. A method of treating multiple sclerosis or psoriasis comprising administering to a subject in need thereof the dosage form of any one of claims 1, 2, 4 to 13, or 15, or the press-coated tablet of claim 3 or 14 to 24.

28. A composition as described herein.

29. A method of using a composition as described herein.