WO2017151184A1 - Formes posologiques d'ester de fumarate - Google Patents

Formes posologiques d'ester de fumarate Download PDF

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Publication number
WO2017151184A1
WO2017151184A1 PCT/US2016/048976 US2016048976W WO2017151184A1 WO 2017151184 A1 WO2017151184 A1 WO 2017151184A1 US 2016048976 W US2016048976 W US 2016048976W WO 2017151184 A1 WO2017151184 A1 WO 2017151184A1
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Prior art keywords
fae
fumarate
composition
weight
ester
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PCT/US2016/048976
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English (en)
Inventor
Jason M. VAUGHN
Justin R. Hughey
Tanesha ROBERTS
Tatyana Dyakonov
Sunil AGNIHOTRI
Aqeel A. Fatmi
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Banner Life Sciences Llc
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Publication of WO2017151184A1 publication Critical patent/WO2017151184A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells

Definitions

  • compositions comprising fumarate esters, methods for making the same, and methods for treating subjects in need thereof.
  • oral controlled release pharmaceutical compositions comprising fumarate esters suspended in liquid matrices are described.
  • One embodiment described herein is a pharmaceutical composition comprising fumarate esters suspended in a lipid or lipophilic liquid with enhanced bioavailability.
  • Fumaric acid esters are pharmacologically active substances used for treating hyperproliferative, inflammatory, or autoimmune disorders. They were first used to treat psoriasis and were licensed for this indication in Germany in 1995 as Fumaderm ® (Biogen pie, Inc., Cambridge, MA, USA). Fumaderm ® produces various undesirable side effects, including flushing, headaches, dizziness, eructation, nausea, vomiting, abdominal and intestinal cramps, and diarrhea. High concentrations of the drug released in the stomach are believed to be responsible for such side effects.
  • FAE Fumaric acid esters
  • fumarate esters e.g., alkyl or dialkyl fumarate esters such as dimethyl fumarate or monomethyl fumarate
  • Fumaderm ® produces various undesirable side effects, including flushing, headaches, dizziness, eructation, nausea, vomiting, abdominal and intestinal cramps, and diarrhea. High concentrations of the drug released in the stomach are believed to be responsible for such side effects.
  • DMF dimethyl fumarate
  • MMF monomethyl fumarate
  • the primary plasma metabolites of DMF are monomethyl fumarate, fumaric acid, citric acid, and glucose.
  • Monomethyl fumarate is further metabolized in the tricarboxylic acid cycle to carbon dioxide and water.
  • TECFIDERA ® Biogen pie, Inc.
  • TECFIDERA ® Biogen pie, Inc.
  • TECFIDERA ® Biogen pie, Inc.
  • TECFIDERA ® was intended to reduce the undesirable side effects by preventing release of DMF in the stomach.
  • the enterically coated DMF granules in TECFIDERA ® lack uniformity in shape and size, and the enteric coating may not be evenly distributed over the minitablets. This lack of homogeneity can diminish the enteric properties and affect the acid-resistance, dissolution, and release rates. In addition, the integrity of the acid-resistant coating fails when the coating cracks or flakes off. This leads to DMF release in the stomach and can cause flushing and the negative gastrointestinal side effects.
  • a subject's stomach content also affects delivery of DMF from TECFIDERA ® .
  • a meal was shown to decrease Cmax by 40% and delay Jmax from 2.0 hours to 5.5 hours; the AUC was unaffected.
  • WO 2006/037342 A reduction in the incidence of flushing by approximately 25% in the postprandial state was also observed.
  • TECFIDERA ® Prescribing Information 03/2013 Biogen pie Inc.
  • fumarate esters that: (1) provide enchanced bioavailability of the fumarate esters as compared to TECFIDERA ® or other solid dosage forms comprising granulated forms or minitablets; (2) prevent flushing and the undesirable GI side effects associated with oral administration of fumarate esters; (3) reduce or eliminate fumarate ester sublimation during manufacturing and storage; (4) increase the long-term stability of the pharmaceutical composition; and (5) provide a variety of different release profiles, dose strengths, dosage forms, and dosing regimens.
  • an oral pharmaceutical composition comprising a liquid suspension of solid particles of one or more fumarate esters comprising dimethyl fumarate, monomethyl fumarate, a pro-drug of monomethyl fumarate, or a combination thereof.
  • the oral pharmaceutical compositions have enhanced bioavailability and can be administered at lower doses of fumarate ester with equivalent clinical efficacy.
  • an oral pharmaceutical composition comprising a liquid suspension of one or more fumarate esters comprising dimethyl fumarate, monomethyl fumarate, a pro-drug thereof, or a combination thereof.
  • the liquid comprises a flowable, single-phase liquid.
  • the liquid comprises a non-aqueous liquid.
  • the liquid comprises a lipid or lipophilic liquid vehicle.
  • the composition comprises about 80 mg to about 230 mg of the fumarate ester.
  • the composition comprises about 90 mg to about 115 mg of the fumarate ester.
  • the composition comprises about 180 mg to about 220 mg of the fumarate ester.
  • the composition comprises about 180 mg to about 200 mg of the fumarate ester.
  • the liquid comprises a lipid vehicle, one or more solubility enhancing agents, and a neutralizing agent.
  • the one or more solubility enhancing agents comprise polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, or a combination thereof.
  • the liquid comprises mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lactic acid.
  • the weight ratio of the fumarate ester to non-aqueous liquid is about 1 : 1 to about 1 :8.
  • the weight ratio of the fumarate ester to non-aqueous liquid is about 1 :2.
  • the fumarate ester comprises about 10% to about 50% of the composition by weight.
  • the fumarate ester comprises about 20%) to about 40%> of the composition by weight.
  • the fumarate ester comprises about 30%> to about 40%> of the composition by weight.
  • the fumarate ester comprises about 35%> of the composition by weight.
  • the liquid comprises about 50%) to about 85%> of the composition by weight.
  • the liquid comprises about 60%) to about 70%> of the composition by weight.
  • the liquid comprises about 60%) of the composition by weight.
  • lactic acid comprises about 5%> of the composition by weight.
  • the composition comprises: about 30%> to about 40%> by weight of the one or more fumarate esters; about 55%> to about 65%> by weight of the liquid; and about 5% by weight of lactic acid.
  • the composition comprises about 90 mg to about 220 mg of one or more fumarate esters.
  • the composition comprises about 95 mg of one or more fumarate esters.
  • the composition comprises about 100 mg of one or more fumarate esters.
  • the composition comprises about 200 mg to about 220 mg of one or more fumarate esters.
  • the composition comprises about 200 mg of one or more fumarate esters.
  • the composition is encapsulated in a capsule. In another aspect, the composition is encapsulated in a soft capsule. In another aspect, the composition is encapsulated in an enterically coated soft capsule. In another aspect, the enteric coating comprises an acrylic polymer or copolymer. In another aspect, the composition is encapsulated in an enterically coated soft capsule shell comprising a subcoating. In another aspect, the subcoating comprises hydroxypropylmethylcellulose. In another aspect, the composition is encapsulated in an enterically coated soft capsule shell comprising a topcoating. In another aspect, the topcoating comprises polyvinyl alcohol. In another aspect, the fumarate ester is a prodrug to monomethyl fumarate. In another aspect, the fumarate ester is dimethyl fumarate. In another aspect, the fumarate ester is monomethyl fumarate.
  • an oral pharmaceutical composition comprising: about 12% to about 40% by weight of one or more fumarate esters; about 50% to about 80% by weight of mono- and di-glycerides; about 5% to about 15% by weight of polyoxyl 40 hydrogenated castor oil; about 1% to about 5% by weight of polyvinylpyrrolidone; and about 1% to about 5% by weight lactic acid.
  • the composition comprises: about 34% by weight one or more fumarate esters; about 48% by weight mono- and di-glycerides; about 10% by weight polyoxyl 40 hydrogenated castor oil; about 3% by weight polyvinylpyrrolidone; and about 5% by weight lactic acid.
  • the composition comprises about 80 mg to about 110 mg or about 160 mg to about 230 mg of the fumarate ester. In another aspect, the composition comprises about 90 mg to about 100 mg of the fumarate ester. In another aspect, the composition comprises about 180 mg to about 220 mg of the fumarate ester. In another aspect, the composition comprises about 190 mg to about 200 mg of the fumarate ester. In another aspect, the composition is encapsulated in a capsule shell. In another aspect, the composition is encapsulated in a capsule comprising one or more subcoatings, one or more enteric coatings, and one or more top coatings. In another aspect, the fumarate ester is a pro-drug of monomethyl fumarate.
  • the fumarate ester is dimethyl fumarate. In another aspect, the fumarate ester is monomethyl fumarate.
  • Another embodiment described herein is an oral pharmaceutical composition comprising a liquid suspension of one or more fumarate esters that is bioequivalent to a 240 mg dose of TECFIDERA® (dimethyl fumarate). In one aspect, the composition comprises about 190 mg to about 220 mg of the fumarate ester. In another aspect, bioequivalence is achieved by simultaneously administering two dosage forms, each comprising about 90 mg to about 100 mg of the fumarate ester. In another aspect, the composition comprises about 190 mg to about 200 mg of dimethyl fumarate, monomethyl fumarate, a pro-drug thereof, or a combination thereof. In another aspect, the composition comprises about 190 mg to about 200 mg of dimethyl fumarate or monomethyl fumarate.
  • Another embodiment described herein is a method of treating or reducing the symptoms of multiple sclerosis in a subject, the method comprising contacting peripheral blood mononuclear cells or monocytes of the subject with monomethyl fumarate by administering in an oral pharmaceutical composition comprising one or more fumarate esters in a liquid vehicle.
  • the composition comprises a liquid suspension of solid particles of dimethyl fumarate, monomethyl fumarate, pro-drugs thereof, or combinations thereof.
  • the liquid comprises a flowable, single-phase liquid.
  • the liquid comprises a non-aqueous liquid.
  • the liquid comprises a lipid or lipophilic liquid vehicle.
  • the composition comprises about 80 mg to about 1 15 mg or about 160 mg to about 230 mg of the fumarate ester. In another aspect, the composition comprises about 95 mg to about 100 mg of the fumarate ester. In another aspect, the composition comprises about 180 mg to about 220 mg of the fumarate ester. In another aspect, the composition comprises about 190 mg to about 200 mg of the fumarate ester.
  • the liquid comprises a lipid vehicle, one or more solubility enhancing agents, and a neutralizing agent. In another aspect, the one or more solubility enhancing agents comprise polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, or a combination thereof.
  • the liquid comprises mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lactic acid.
  • the weight ratio of the fumarate ester to non-aqueous liquid is about 1 : 1 to about 1 :8.
  • the composition comprises: about 30% to about 40% by weight of the one or more fumarate esters; about 55% to about 65% by weight of the liquid; and about 5% by weight of lactic acid.
  • the composition comprises: about 12% to about 40% by weight of the one or more fumarate esters; about 50%) to about 80%> by weight of mono- and di-glycerides; about 5%> to about 15%> by weight of polyoxyl 40 hydrogenated castor oil; about 1% to about 5% by weight of polyvinylpyrrolidone; and about 1% to about 5% by weight lactic acid.
  • the administration comprises: (a) administering two dosage froms simultaneously comprising about 80 mg to about 115 mg of fumarate ester twice per day (BID); (b) administering one dosage from comprising about 80 mg to about 1 15 mg of fumarate ester four times per day; or (c) administering one dosage from comprising about 160 to about 230 mg of fumarate ester twice per day (BID).
  • the administration comprises a total daily dosage of about 160 mg to about 440 mg of the fumarate ester.
  • the administration comprises a total daily dosage of about 160 mg, about 180 mg, about 190 mg, about 200 mg, about 220 mg, about 230 mg, about 360 mg, about 380 mg, about 400 mg, or about 440 mg of the fumarate ester.
  • the subject achieves a reduction of annualized relapse rate relative to baseline without substantially experiencing one or more of flushing, abdominal pain, diarrhea, or nausea.
  • the subject exhibits one or more pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Cmax ranging from about 1.87 mg/L to about 2.41 mg/L; (b) mean plasma monomethyl fumarate AUCo ⁇ ranging from about 1.99 h mg/L to about 2.43 h mg/L; or (c) a mean plasma monomethyl fumarate AUCoveraii ranging from about 3.2 h mg/L to about 11.2 h mg/L.
  • Another embodiment described herein is a method of treating multiple sclerosis or psoriasis comprising administering to a subject one or more dosage forms that cumulatively provide a daily dosage of a fumarate ester from about 360 mg to about 440 mg fumarate ester.
  • Another embodiment described herein is a method of treating multiple sclerosis or psoriasis comprising administering to a subject one or more dosage forms that cumulatively provide a daily dosage of a fumarate ester from about 160 mg to about 230 mg fumarate ester.
  • the administration is twice per day.
  • two dosage froms comprising between about 80 mg to about 115 mg of fumarate ester are simultaneously administered twice per day.
  • an oral pharmaceutical composition for activating a nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway comprising a liquid suspension of one or more fumarate esters comprising dimethyl fumarate, monomethyl fumarate, a pro-drug thereof, or a combination thereof.
  • Nrf2 nuclear factor-derived 2
  • Another embodiment described herein is a method for activating a nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway comprising administering a liquid suspension of solid particles of one or more fumarate esters comprising dimethyl fumarate, monomethyl fumarate, a pro-drug thereof, or a combination thereof.
  • Nrf2 nuclear factor
  • Another embodiment described herein is a method of manufacturing an oral pharmaceutical composition
  • a liquid suspension of solid particles of one or more fumarate esters comprising dimethyl fumarate, monomethyl fumarate, a pro-drug thereof, or a combination thereof.
  • compositions comprising a liquid suspension of solid particles of one or more fumarate esters comprising dimethyl fumarate, monomethyl fumarate, a pro-drug thereof, or a combination thereof, wherein the composition exhibits an in vitro dissolution rate comprising about 50% dissolution after about 30 minutes to about 50 minutes at pH 6.8.
  • Another embodiment described herein is an oral pharmaceutical composition providing a consistent fumarate ester release profile that reduces side effects comprising a liquid suspension of solid particles of one or more fumarate esters comprising dimethyl fumarate, monomethyl fumarate, a pro-drug thereof, or a combination thereof.
  • Another embodiment described herein is a method for providing a consistent fumarate ester release profile that reduces side effects comprising administering a liquid suspension of solid particles of one or more fumarate esters comprising dimethyl fumarate, monomethyl fumarate, a pro-drug thereof, or a combination thereof to a subject in need thereof.
  • Another embodiment described herein is a method for providing multiple sclerosis treatment to a subject in need thereof with increased subject compliance and optimal treatment outcome comprising administering a liquid suspension of solid particles of one or more fumarate esters comprising dimethyl fumarate, monomethyl fumarate, a pro-drug thereof, or a combination thereof to a subject in need thereof.
  • Another embodiment described herein is a method for providing multiple sclerosis treatment to a subject in need thereof with improved treatment outcome compared to 240 mg TECFIDERA ® (dimethyl fumarate) comprising administering a liquid suspension of solid particles of one or more fumarate esters comprising dimethyl fumarate, monomethyl fumarate, a pro-drug thereof, or a combination thereof to a subject in need thereof.
  • TECFIDERA ® dimethyl fumarate
  • Another embodiment described herein is a method for providing long-term multiple sclerosis treatment with optimal treatment outcome to a subject in need thereof comprising administering an oral pharmaceutical composition comprising a liquid suspension of solid particles of one or more fumarate esters comprising dimethyl fumarate, monom ethyl fumarate, a pro-drug thereof, or a combination thereof to a subject in need thereof.
  • an oral pharmaceutical dosage from comprising liquid composition comprising: about 12% to about 40% by weight of one or more fumarate esters; about 50% to about 80% by weight of mono- and di-glycerides; about 5% to about 15% by weight of polyoxyl 40 hydrogenated castor oil; about 1% to about 5% by weight of polyvinylpyrrolidone; and about 1% to about 5% by weight lactic acid; wherein the liquid composition is encapsulated in a capsule comprising one or more subcoatings, one or more enteric coatings, one or more top coatings, or a combination thereof.
  • the fumarate ester comprises from about 80 mg to about 440 mg of dimethyl fumarate, monomethyl fumarate, a prodrug of monomethyl fumarate, or a combination thereof.
  • one or more dosage forms, administered in a regimen is bioequivalent to 240 mg TECFIDERA ® (dimethyl fumarate) and has enhanced bioavailability.
  • compositions comprising one or more fumarate esters suspended in a lipid or lipophilic matrix.
  • the pharmaceutical composition is encapsulated in a soft capsule.
  • the oral soft capsules comprising controlled release matrix compositions prevent release of the fumarate ester active ingredient in the gastric environment, but release the active ingredient in the intestine in a controlled manner.
  • the compositions can be tailored to provide one or more release profiles, including immediate release, controlled release, delayed release, or extended release pharmacokinetics by the composition of the matrix fill.
  • the formulations described herein comprise solid micronized particles of fumarate esters suspended in a matrix.
  • the controlled release pharmaceutical composition comprising a matrix of fumarate esters reduce, ameliorate, or eliminate the undesirable gastrointestinal side effects observed with prior fumarate ester pharmaceuticals. Further, the formulations preclude or reduce sublimation of the fumarate ester during manufacturing and storage.
  • an oral pharmaceutical composition comprising a controlled release composition of one or more fumarate esters, including, but not limited to, dialkyl fumarates, alkyl fumarates, dimethyl fumarate (DMF), monomethyl fumarate (MMF), or combinations thereof.
  • the fumarate ester is DMF.
  • the fumarate ester is MMF.
  • the pharmaceutical composition comprises a controlled release pharmaceutical composition.
  • the pharmaceutical composition comprises a soft capsule shell encapsulating a matrix comprising one or more fumarate esters.
  • the matrix comprises a lipid or lipophilic vehicle, a neutralizing agent, and solid particles of fumarate esters.
  • the matrix comprises a lipid or lipophilic vehicle, a neutralizing agent, excipients, and solid particles of a fumarate ester.
  • the matrix comprises a lipid or lipophilic vehicle, a neutralizing agent, surfactants, and solid particles of a fumarate ester.
  • the lipid or lipophilic vehicle comprises polyvinylpyrrolidones, mono- and di-glycerides, and oils.
  • the surfactant can comprise polysorbate 80 or polyoxyl 40 hydrogenated castor oil.
  • the solid particles of fumarate ester comprise milled or micronized particles.
  • the milled or micronized particles of one or more fumarate esters comprise mean particle distribution sizes of about 20 ⁇ to about 300 ⁇ , including all integers within the specified range.
  • the solid particles of fumarate esters comprise mean particle distribution sizes of about 65 ⁇ to about 260 ⁇ , including all integers within the specified range.
  • the solid microparticles of fumarate esters have mean particle distribution sizes of less than 260 ⁇ .
  • the solid particles of fumarate esters have mean particle distribution sizes of about 100 ⁇ .
  • the neutralizing agent comprises an organic acid, ester, or salt.
  • the neutralizing agent comprises at least one of lactate, fumarate, caprylate, caprate, oleate, maleate, succinate, tartrate, citrate, glutamate, gluconate, or esters or salts thereof, or combinations thereof.
  • the matrix comprises a fumarate ester, a mixture of mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lactic acid.
  • the pharmaceutical composition comprises a matrix fill comprising about 10% to about 64% by weight of one or more fumarate esters (PSD: d90 ⁇ 100 ⁇ ); about 18% to about 70% by weight of a mixture of mono- and di-glycerides; at least about 1%) to about 10% by weight polyvinylpyrrolidone; at least about 1% to about 10% by weight polyoxyl 40 hydrogenated castor oil, and at least about 1% to about 5% by weight lactic acid.
  • PSD fumarate esters
  • the pharmaceutical composition comprises a matrix fill comprising about 29% by weight of one or more fumarate esters (PSD: d90 ⁇ 100 ⁇ ); about 54% by weight of a mixture of mono- and di-glycerides; about 3% by weight polyvinylpyrrolidone; about 10%) by weight polyoxyl 40 hydrogenated castor oil, and about 5% by weight lactic acid.
  • the composition has controlled release, delayed release, or extended release properties.
  • the composition comprises one or more FAEs in an amount of about 80 mg to about 460 mg.
  • the one or more FAEs comprise about 90 mg to about 110 mg.
  • the composition comprises one or more FAEs in an amount of about 170 mg to about 220 mg.
  • the composition comprises one or more FAEs in an amount of about 340 mg to about 440 mg. In one aspect, the composition comprises one or more FAEs in an amount of about 80 mg FAE, about 85 mg FAE, about 90 mg FAE, about 95 mg FAE, about 100 mg FAE, about 105 mg FAE, about 110 mg FAE, about 115 mg FAE, about 120 mg FAE, about 125 mg FAE, about 130 mg FAE, about 135 mg FAE, about 140 mg FAE, about 145 mg FAE, about 150 mg FAE, about 155 mg FAE, about 160 mg FAE, about 165 mg FAE, about 170 mg FAE, about 175 mg FAE, about 180 mg FAE, about 185 mg FAE, about 190 mg FAE, about 195 mg FAE, about 200 mg FAE, about 205 mg FAE, about 210 mg FAE, about 215 mg FAE, about 220 mg FAE, about 225 mg FAE, about 230 mg FAE, about 235 mg FAE,
  • the composition comprises one or more FAEs in an amount of about 0.5 mmol to about 4.0 mmol FAE. In one aspect, the composition comprises one or more FAEs in an amount of about 0.7 mmol to about 3.7 mmol FAE. In another aspect, the composition comprises DMF, MMF, or a combination thereof. In another aspect, the matrix comprises DMF. In another aspect, the composition comprises MMF. In another aspect, the composition further comprises one or more non-steroidal anti-inflammatory drugs (NSAIDS). In one aspect, the composition prevents sublimation of the fumarate ester during manufacturing. In another aspect, the composition prophylactically reduces the onset or ameliorates the symptoms of any flushing side effects.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • the composition reduces the onset or ameliorates the severity of any gastrointestinal side effects.
  • the composition is stable for at least 1 year at conditions comprising 25 °C and 60% relative humidity. In another aspect, the composition is stable for at least 2 years at conditions comprising 25 °C and 60%> relative humidity.
  • the soft capsule comprises and enteric soft capsule.
  • the soft capsule shell comprises one or more enteric, acid-insoluble polymers, a film- forming polymer, a plasticizer, an alkali-neutralizing agent, a solvent, and optionally, a coloring agent, a flavoring, or a pharmaceutical excipient.
  • the enteric soft capsule shell comprises about 20% to about 36%> by weight of at least one film-forming polymer; about 8%> to about 20% by weight of at least one enteric, acid-insoluble polymer; about 15% to about 20% by weight of at least one plasticizer; about 1%) to about 5% by weight of at least one alkali-neutralizing agent; about 20% to about 40% by weight of a solvent; optionally, about 1% to about 5% by weight of an opacifying agent; and optionally, about 0.05% to about 1% by weight of at least one coloring agent.
  • the soft capsule shell comprises about 30% of at least one film- forming polymer; about 10% by weight of at least one enteric, acid-insoluble polymer; about 20% by weight of at least one plasticizer; about 1% by weight of at least one alkali-neutralizing agent; about 37%) by weight of a solvent; and optionally, about 1.5% by weight of an opacifying agent; and optionally, at least one coloring agent.
  • the soft capsule shell comprises gelatin, acrylic methacrylate copolymers, glycerol, triethyl citrate, ammonia, water, and titanium dioxide.
  • Another embodiment described herein is a method for manufacturing an oral soft capsule shell encapsulating a matrix comprising a fumarate ester, the method comprising: (i) providing a matrix fill composition comprising any of the composition described herein; (ii) providing a soft capsule shell composition comprising any of the composition described herein; (iii) casting the soft capsule shell into films using heat-controlled drums or surfaces; and (iv) forming a soft capsule shell encapsulating the matrix fill composition using rotary die encapsulation technology.
  • the soft capsule matrix comprises one or more fumarate esters produced by said method.
  • Another embodiment described herein is a method for manufacturing an oral soft capsule shell encapsulating a matrix comprising a fumarate ester, the method comprising: (i) providing a matrix fill composition comprising: about 10% to about 64% by weight of one or more fumarate esters (PSD: d90 ⁇ 100 ⁇ ); about 18% to about 70% by weight of a mixture of mono- and di- glycerides; about 1% to about 10% by weight polyvinylpyrrolidone; about 2% to about 12% by weight polyoxyl 40 hydrogenated castor oil, and about 1% to about 5% by weight lactic acid; (ii) providing a soft capsule shell composition comprising: about 20% to about 36% by weight of at least one film-forming polymer; about 8% to about 20% by weight of at least one enteric, acid- insoluble polymer; about 15% to about 20% by weight of at least one plasticizer; about 1% to about 5% by weight of at least one alkali-neutralizing agent; about 20% to about 40% by weight of
  • a soft capsule comprising a shell encapsulating a fumarate ester matrix, wherein the matrix comprises: about 10% to about 64% by weight of one or more fumarate esters (PSD: d90 ⁇ 100 ⁇ ); about 18% to about 70% by weight of mono- and di-glycerides; at least about 1% to about 7% by weight of polyvinylpyrrolidone; at least about 2% to about 10%) by weight of polyoxyl 40 hydrogenated castor oil, and at least about 1% to about 5% by weight of lactic acid; and wherein the soft capsule shell comprises: about 20% to about 36% by weight of at least one film-forming polymer; about 8% to about 20% by weight of at least one enteric, acid-insoluble polymer; about 15% to about 20% by weight of at least one plasticizer; about 1%) to about 5% by weight of at least one alkali-neutralizing agent; about 20% to about 40% by weight of a solvent; optionally, about 1% to about 5% by weight of an
  • a soft capsule comprising a shell encapsulating a fumarate ester matrix, wherein the matrix comprises: about 29% by weight of one or more fumarate esters (PSD: d90 ⁇ 100 ⁇ ); about 54% by weight of a mixture of mono- and di-glycerides; about 3%) by weight polyvinylpyrrolidone; about 10% by weight polyoxyl 40 hydrogenated castor oil, and about 5% by weight lactic acid; and wherein the soft capsule shell comprises: about 30% by weight of at least one film-forming polymer; about 10% by weight of at least one enteric, acid- insoluble polymer; about 20% by weight of at least one plasticizer; about 1% by weight of at least one alkali-neutralizing agent; about 37% by weight of a solvent; optionally, about 1.5% by weight of an opacifying agent; and optionally, at least one coloring agent.
  • PSD fumarate esters
  • d90 ⁇ 100 ⁇ a mixture of mono- and di-glycerides
  • the composition comprises DMF, MMF, or a combination thereof.
  • the matrix comprises DMF.
  • the composition comprises MMF.
  • the soft capsule comprising a fumarate ester is resistant to dissolution at about pH 1.2 for at least about 2 hours.
  • the soft capsule comprising a fumarate ester begins dissolution at pH of about 6.8 within about 10 minutes.
  • the soft capsule has immediate release, controlled release, delayed release, or extended release properties.
  • the soft capsule comprising a fumarate ester reduces the onset or ameliorates the severity of any flushing or gastrointestinal side effects.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of multiple sclerosis or psoriasis, comprising administering to a subject in need thereof an oral pharmaceutical composition comprising a controlled release soft capsule shell and matrix comprising a fumarate ester.
  • the pharmaceutical composition comprises a controlled release soft capsule comprising a formulation of fumarate ester.
  • the pharmaceutical composition comprises a controlled release soft capsule comprising a formulation of fumarate ester.
  • the composition comprises DMF, MMF, or a combination thereof.
  • the matrix comprises DMF.
  • the composition comprises MMF.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising administering to a subject in need thereof an oral pharmaceutical composition comprising a controlled release formulation of a fumarate ester, wherein the subject achieves a reduction of annualized relapse rate relative to baseline without substantially experiencing one or more of flushing, abdominal pain, diarrhea, and nausea.
  • the pharmaceutical composition comprises any of the compositions described herein.
  • the composition comprises DMF, MMF, or a combination thereof.
  • the matrix comprises DMF.
  • the composition comprises MMF.
  • Another embodiment described herein is an oral pharmaceutical composition as described herein that is useful for treating neurodegenerative disorders.
  • the pharmaceutical composition is useful for treating multiple sclerosis or psoriasis.
  • subjects that are administered the oral pharmaceutical composition as described herein exhibit a mean plasma monomethyl fumarate Jmax of from about 1.5 hours to about 3.5 hours.
  • Another embodiment described herein is an oral pharmaceutical composition useful for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of general autoimmune or neurodegenerative disorders.
  • the composition comprises DMF, MMF, or a combination thereof.
  • the matrix comprises DMF.
  • the composition comprises MMF.
  • compositions comprises DMF, MMF, or a combination thereof.
  • the matrix comprises DMF.
  • composition comprises MMF.
  • an oral pharmaceutical composition comprising a controlled release composition comprising a formulation of a fumarate ester useful for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of general autoimmune or neurodegenerative disorders, including but not limited to, acute dermatitis, adrenal leukodystrophy, AGE-induced genome damage, Alexander's disease, alopecia areata (totalis and universalis), Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, angina pectoris, arthritis, asthma, autoimmune diseases, balo concentric sclerosis, Behcet's syndrome, bullous pemphigoid, Canavan disease, cardiac insufficiency including left ventricular insufficiency, central nervous system vasculitis, Charcot-Marie-Tooth disease, childhood ataxia with central nervous system hypomyelination, chronic active (lupoid) hepatitis, chronic dermatitis, chronic
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of general autoimmune or neurodegenerative disorders, including but not limited to, acute dermatitis, adrenal leukodystrophy, AGE-induced genome damage, Alexander's disease, alopecia areata (totalis and universalis), Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, angina pectoris, arthritis, asthma, autoimmune diseases, balo concentric sclerosis, Behcet's syndrome, bullous pemphigoid, Canavan disease, cardiac insufficiency including left ventricular insufficiency, central nervous system vasculitis, Charcot-Marie-Tooth disease, childhood ataxia with central nervous system hypomyelination, chronic active (lupoid) hepatitis, chronic dermatitis, chronic idiopathic peripheral neuropathy, chronic obstructive pulmonary disease, contact
  • the oral pharmaceutical composition comprises a soft capsule shell and matrix comprising a fumarate ester.
  • the pharmaceutical composition comprises a controlled release soft capsule comprising a formulation of a fumarate ester.
  • the pharmaceutical composition is an immediate release, delayed release, controlled release, or extended release formulation of a fumarate ester.
  • the composition comprises DMF, MMF, or a combination thereof.
  • the matrix comprises DMF.
  • the composition comprises MMF.
  • compositions comprising a controlled release formulation of a fumarate ester.
  • the composition is provided in a dosage form containing about 85 mg to about 110 mg of one or more fumarate esters, wherein subjects administered the dose form four times daily exhibit one or more pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 2.41 mg/L; or (b) a mean plasma monomethyl fumarate AUCoveraii ranging from about 3.2 h mg/L to about 11.2 h mg/L.
  • the composition in a dosage form containing about 120 mg to about 180 mg of one or more fumarate esters, wherein subjects administered the dose form exhibit one or more pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 2.41 mg/L; (b) a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 0.5 h mg/L to about 2.5 h mg/L; or (c) a mean AUCo ⁇ ranging from about 0.5 h mg/L to about 2.6 h mg/L.
  • pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 2.41 mg/L; (b) a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 0.5 h mg/L to about 2.5 h mg/L; or (c) a mean AUCo ⁇ ranging from about 0.5 h mg/L to about 2.6
  • the composition in a dosage form containing a total amount of about 170 mg to about 220 mg of one or more fumarate esters, wherein subjects administered the dose form twice-daily exhibit one or more pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Cmax ranging from about 1.0 mg/L to about 3.4 mg/L; (b) a mean plasma monomethyl fumarate AUCoveraii ranging from about 4.81 h mg/L to about 11.2 h mg/L.
  • the composition is provided in a dosage form containing about 170 mg to about 220 mg of one or more fumarate esters, wherein subjects administered the dose form exhibit one or more pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Cmax ranging from about 1.0 mg/L to about 3.4 mg/L; (b) a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 1.0 h mg/L to about 5.5 h mg/L; or (c) a mean AUCo ⁇ ranging from about 1.0 h mg/L to about 5.6 h mg/L.
  • the fumarate ester formulation is encapsulated in a soft capsule.
  • the composition comprises DMF, MMF, or a combination thereof.
  • the matrix comprises DMF.
  • the composition comprises MMF.
  • an oral pharmaceutical composition comprising total amount of about 85 mg to about 110 mg of one or more fumarate esters, wherein subjects administered the capsule exhibit one or more pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Jmax of from about 1.5 hours to about 3.5 hours; (b) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 2.41 mg/L; (c) a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 0.5 h mg/L to about 2.5 h mg/L; or (d) a mean AUCo ⁇ ranging from about 0.5 h mg/L to about 2.6 h mg/L.
  • the composition comprises about 170 mg to about 220 mg of one or more fumarate esters, wherein subjects administered the capsule exhibit one or more pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Jmax of from about 1.5 hours to about 3.5 hours; (b) a mean plasma monomethyl fumarate Cmax ranging from about 1.0 mg/L to about 3.4 mg/L; (c) a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 1.0 h mg/L to about 5.5 h mg/L; or (d) a mean AUCo ⁇ ranging from about 1.0 h mg/L to about 5.6 h mg/L.
  • the composition comprises DMF, MMF, or a combination thereof.
  • the matrix comprises DMF.
  • the composition comprises MMF.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising orally administering to a subject in need thereof a therapeutically effective amount of one or more fumarate esters comprising any of the compositions described herein and a therapeutically amount of one or more non-steroidal anti-inflammatory drugs effective to reduce flushing.
  • the one or more non-steroidal anti-inflammatory drug is aspirin, ibuprofen, naproxene, diclofenac, ketoprofen, celecoxib, or a combination thereof.
  • compositions comprising a delayed release, controlled release, or extended release formulation of a fumarate ester.
  • the composition is provided in one or more dosage forms containing about 80 mg to about 460 mg of one or more fumarate esters, wherein subjects administered the dose form once daily exhibit one or more pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 5.2 mg/L; or (b) a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 0.5 h mg/L to about 15.5 h mg/L.
  • the composition is provided in one or more dosage forms containing about 80 mg to about 460 mg of one or more fumarate esters, wherein subjects administered the dose form once daily exhibit one or more pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 5.2 mg/L, (b) a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 0.5 h mg/L to about 13.5 h mg/L, or (c) a mean AUCo ⁇ ranging from about 0.5 h mg/L to about 15.5 h mg/L.
  • pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 5.2 mg/L, (b) a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 0.5 h mg/L to about 13.5 h mg/L, or (c) a mean AUCo ⁇ ranging from about 0.5 h
  • the capsule contains a total amount of about 80 mg to about 460 mg of one or more fumarate esters, wherein subjects administered the one or more capsules exhibit one or more pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Jmax of from about 1.5 hours to about 10.5 hours; (b) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 5.2 mg/L; (c) a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 0.5 h mg/L to about 13.5 h mg/L; or (d) a mean AUCo ⁇ ranging from about 0.5h mg/L to about 15.5 h mg/L.
  • pharmacokinetic parameters comprising: (a) a mean plasma monomethyl fumarate Jmax of from about 1.5 hours to about 10.5 hours; (b) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 5.2 mg/L; (c) a mean plasma monomethyl fumarate
  • compositions as described herein for oral administration to a subject having multiple sclerosis containing one or more fumarate ester compounds, or pharmaceutically acceptable salts thereof that metabolize to monomethyl fumarate, wherein said administering the composition provides one or more of the following pharmacokinetic parameters: (a) a mean plasma monomethyl fumarate Jmax of from about 1.5 hours to about 3.5 hours; (b) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 3.4 mg/L; (c) a mean plasma monomethyl fumarate AUCoverall ranging from about 3.2 h mg/L to about 11.2 h mg/L; (d) a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 0.5 h mg/L to about 5.5 h mg/L; or (e) a mean AUCo ⁇ ranging from about 0.5 h mg/L to about 5.6 h mg/L.
  • pharmacokinetic parameters (a) a mean plasma monomethyl fumarate Jmax
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising administering to a subject in need thereof any one of the compositions of described herein, containing one or more fumarate ester compounds, or pharmaceutically acceptable salts thereof that metabolize to monomethyl fumarate, wherein said administering the composition provides one or more of the following pharmacokinetic parameters: (a) a mean plasma monomethyl fumarate Jmax of from about 1.5 hours to about 3.5 hours; (b) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 3.4 mg/L; (c) a mean plasma monomethyl fumarate AUCoveraii ranging from about 3.2 h mg/L to about 1 1.2 h mg/L; (d) a mean plasma monomethyl fumarate AUCo
  • compositions as described herein for oral administration to a subject having multiple sclerosis containing one or more fumarate ester compounds, or pharmaceutically acceptable salts thereof that metabolize to monomethyl fumarate, wherein said administering the composition provides one or more of the following pharmacokinetic parameters: (a) a mean plasma monomethyl fumarate Jmax of from about 1.5 hours to about 10.5 hours; (b) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 5.2 mg/L; (c) a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 0.5 h mg/L to about 13.5 h mg/L; or (d) a mean AUCo ⁇ ranging from about 0.5 h mg/L to about 15.5 h mg/L.
  • pharmacokinetic parameters (a) a mean plasma monomethyl fumarate Jmax of from about 1.5 hours to about 10.5 hours; (b) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising orally administering to a subject in need thereof any one of the compositions described herein comprising one or more fumarate ester compounds, or pharmaceutically acceptable salts thereof that metabolize to monomethyl fumarate, wherein said administering the composition provides one or more of the following pharmacokinetic parameters: (a) a mean plasma monomethyl fumarate Jmax of from about 1.5 hours to about 10.5 hours; (b) a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 5.2 mg/L; (c) a mean plasma monomethyl fumarate AUCoveraii ranging from about 0.5 h mg/L to about 15.2 h mg/L; (d) a mean plasma monomethyl fumarate AUCo ⁇
  • compositions comprising any one of the pharmaceutical compositions described herein for oral administration to a subject having multiple sclerosis, comprising a therapeutically effective amount of one or more fumarate esters, wherein the administration is sufficient to achieve a reduction of about 0.224 annualized relapse rate relative to baseline in the subject without substantially inducing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject.
  • the subject experiences one or more of flushing, abdominal pain, diarrhea, and nausea at a rate of less than about 10%.
  • the subject is a child. In one aspect, the child is over 9 years of age.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of multiple sclerosis, the method comprising the oral administration of a therapeutically effective amount of one or more fumarate esters comprising any one of the pharmaceutical compositions described herein, to a subject with multiple sclerosis, wherein the administration is sufficient to achieve a reduction of about 0.224 annualized relapse rate relative to baseline in the subject without substantially inducing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject.
  • the subject experiences one or more of flushing, abdominal pain, diarrhea, and nausea at a rate of less than about 10%.
  • the subject is a child. In one aspect, the child is over 9 years of age.
  • compositions comprising any one of the pharmaceutical compositions described herein for oral administration to a subject having multiple sclerosis, comprising a therapeutically effective amount of one or more fumarate esters, wherein the administration is sufficient to achieve a reduction of annualized relapse rate relative to baseline in the subject without substantially inducing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject.
  • the subject experiences one or more of flushing, abdominal pain, diarrhea, and nausea at a rate of less than about 10%.
  • the subject is a child. In one aspect, the child is over 9 years of age.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, the method comprising the oral administration of a therapeutically effective amount of one or more fumarate esters comprising any one of the pharmaceutical compositions described herein to a subject in need thereof, wherein the subject achieves a reduction annualized relapse rate relative to baseline without substantially experiencing one or more of flushing, abdominal pain, diarrhea, and nausea.
  • the subject experiences one or more of flushing, abdominal pain, diarrhea, and nausea at an incidence rate of less than about 10%.
  • the subject is a child. In one aspect, the child is over 9 years of age.
  • compositions comprising any one of the pharmaceutical compositions described herein, for oral administration to a subject having a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis, comprising a therapeutically effective amount of one or more fumarate esters, wherein the administration is sufficient to achieve a reduction of annualized relapse rate relative to baseline in the subject without substantially inducing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject; and wherein the administration does not require titration of the pharmaceutical composition.
  • the subject experiences one or more of flushing, abdominal pain, diarrhea, and nausea at an incidence rate of less than about 10%.
  • the subject is a child. In one aspect, the child is over 9 years of age.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis, the method comprising the oral administration of a therapeutically effective amount of one or more fumarate esters comprising any one of the pharmaceutical compositions described herein, to a subject in need thereof, wherein the administration is sufficient to achieve a reduction of annualized relapse rate relative to baseline in the subject without substantially inducing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject; and wherein the administration does not require titration of the pharmaceutical composition.
  • compositions comprising any of the pharmaceutical compositions described herein for oral administration to a subject having a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis, comprising a therapeutically effective amount of one or more fumarate esters, wherein the administration is sufficient to achieve a reduction of about 0.224 annualized relapse rate relative to baseline in the subject without substantially inducing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject and wherein the administration does not require titration of the pharmaceutical composition.
  • the subject experiences one or more of flushing, abdominal pain, diarrhea, and nausea at a rate of less than about 10%.
  • the subject is a child. In one aspect, the child is over 9 years of age.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis, the method comprising the oral administration of a therapeutically effective amount of one or more fumarate esters comprising any of the pharmaceutical compositions described herein to a subject in need thereof, wherein the administration is sufficient to achieve a reduction of about 0.224 annualized relapse rate relative to baseline in the subject without substantially inducing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject and wherein the administration does not require titration of the pharmaceutical composition.
  • the subject experiences one or more of flushing, abdominal pain, diarrhea, and nausea at an incidence rate of less than about 10%.
  • the subject is a child. In one aspect, the child is over 9 years of age.
  • compositions described herein are a pharmaceutical composition
  • a pharmaceutical composition comprising any one of the pharmaceutical compositions described herein, for oral administration to a subject having a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising a therapeutically effective amount of one or more fumarate esters, wherein the subject achieves a reduction of annualized relapse rate relative to baseline without substantially experiencing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject and wherein the administration does not require titration of the pharmaceutical composition.
  • a general autoimmune or neurodegenerative disorder including but not limited to multiple sclerosis or psoriasis
  • fumarate esters comprising a therapeutically effective amount of one or more fumarate esters
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, the method comprising the oral administration of a therapeutically effective amount of one or more fumarate esters comprising any one of the pharmaceutical compositions described herein, to a subject in need thereof, wherein the subject achieves a reduction of annualized relapse rate relative to baseline without substantially experiencing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject and wherein the administration does not require titration of the pharmaceutical composition.
  • compositions described herein for administration to a subject having a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising a therapeutically effective amount of one or more fumarate esters, wherein the pharmaceutical composition is stable at 25 °C and 60% RH for at least 1 year.
  • compositions described herein comprising any of the compositions described herein comprising a therapeutically effective amount of one or more fumarate esters for administration to a subject diagnosed with multiple sclerosis or psoriasis.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising orally administering to a subject in need thereof a therapeutically effective amount of one or more fumarate esters comprising any of the pharmaceutical compositions described herein.
  • compositions described herein for oral administration to a subject of less than 17 years of age having a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising a therapeutically effective amount of one or more fumarate esters.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a subject of less than 17 years of age having a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising orally administering to a subject in need thereof having an age less than 17 a therapeutically effective amount of one or more fumarate esters comprising any one of the pharmaceutical compositions described herein.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising orally administering to a subject in need thereof a therapeutically effective amount of a fumarate ester comprising any of the pharmaceutical compositions described herein and a therapeutically effective amount of a leukotriene receptor antagonist.
  • the leukotriene receptor antagonist comprises montelukast or zafirlukast.
  • compositions described herein are a pharmaceutical composition comprising a matrix fill comprising any of the compositions described herein.
  • the composition is shown in any of the tables described herein.
  • Another embodiment described herein is a pharmaceutical composition for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising a fumarate ester, wherein the pharmaceutical composition exhibits an in vitro dissolution rate (% dissolution per minute) at pH 6.8, as shown in any of the Drawings described herein.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising orally administering to a subject in need thereof a therapeutically effective amount of one or more fumarate esters comprising any of the pharmaceutical compositions described herein, wherein the composition exhibits an in vitro dissolution rate (% dissolution per minute) at pH 6.8, as shown in any of the Drawings described herein.
  • Another embodiment described herein is an oral pharmaceutical composition for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of general autoimmune or neurodegenerative disorders, including but not limited to multiple sclerosis or psoriasis, comprising one or more fumarate esters, wherein the pharmaceutical composition exhibits a plasma monomethyl fumarate Cmax of about 1321.3 ⁇ 618.9 ng/mL.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of general autoimmune or neurodegenerative disorders, including but not limited to multiple sclerosis or psoriasis, comprising orally administering to a subject in need thereof a therapeutically effective amount of one or more fumarate esters comprising any of the pharmaceutical compositions described herein, wherein the pharmaceutical composition exhibits a plasma monomethyl fumarate Cmax of about 1321.3 ⁇ 618.9 ng/mL.
  • Another embodiment described herein is an oral pharmaceutical composition for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of general autoimmune or neurodegenerative disorders, including but not limited to multiple sclerosis or psoriasis, comprising one or more fumarate esters, wherein the pharmaceutical composition exhibits a plasma monomethyl fumarate Cmax as shown herein in Drawing 15.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of general autoimmune or neurodegenerative disorders, including but not limited to multiple sclerosis or psoriasis, comprising orally administering to a subject in need thereof a therapeutically effective amount of one or more fumarate esters comprising any of the pharmaceutical compositions described herein, wherein the pharmaceutical composition exhibits a plasma monomethyl fumarate pharmacokinetic parameter as described herein.
  • Another embodiment described herein is an oral pharmaceutical composition for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, comprising one or more fumarate esters, wherein the pharmaceutical composition exhibits an in vitro dissolution rate at pH 6.8 comprising about 10% to about 80% dissolution after about 10 minutes to about 480 minutes.
  • Another embodiment described herein is a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of general autoimmune or neurodegenerative disorders, including but not limited to multiple sclerosis or psoriasis, comprising orally administering to a subject in need thereof a therapeutically effective amount of one or more fumarate esters comprising any of the pharmaceutical compositions described herein, wherein the pharmaceutical composition is administered without titration of the pharmaceutical composition and without substantially inducing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject.
  • Another embodiment described herein is an oral pharmaceutical composition for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of general autoimmune or neurodegenerative disorders, comprising one or more fumarate esters, wherein the pharmaceutical composition is administered without titration of the pharmaceutical composition and without substantially inducing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject.
  • an oral pharmaceutical composition comprising a controlled release soft capsule shell encapsulating a matrix comprising: about 10% to about 64% by weight of one or more fumarate esters (FAE; PSD: d90 ⁇ 100 ⁇ ); about 18% to about 70% by weight of a mixture of mono- and di-glycerides; about 3% by weight of polyvinylpyrrolidone; about 10%) by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • the matrix comprises about 13%> to about 16%>; about 27% to about 32%; about 34%), about 48%, or about 53% to about 64%, each by weight of one or more FAEs.
  • the mixture of mono- and di-glycerides is present in an amount of about 66% to about 69%; about 48% to about 55%; or about 18% to about 29%, each by weight.
  • the one or more FAEs comprise about 80 mg to about 460 mg FAE.
  • the matrix comprises about 80 mg to about 105 mg FAE, about 90 mg to about 110 mg FAE, about 95 mg to about 115 mg FAE, about 100 mg to about 120 mg FAE; about 180 mg to about 230 mg FAE; about 200 mg to about 230 mg FAE; about 270 mg to about 360 mg FAE; about 340 mg to about 440 mg FAE; or about 400 to about 460 mg FAE.
  • the matrix comprises about 90 mg to about 110 mg FAE. In another aspect, the matrix comprises about 180 mg to about 230 mg FAE. In another aspect, the matrix comprises about 200 mg to about 220 mg FAE. In another aspect, the matrix comprises about 214 mg FAE. In another aspect, the matrix comprises about 0.5 to about 3.5 mmol FAE. In another aspect, the matrix comprises about 0.6 to about 1.7 mmol FAE. In another aspect, the matrix comprises DMF, MMF, or a combination thereof. In another aspect, the matrix comprises DMF. In another aspect, the matrix comprises MMF.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of a composition comprising one or more fumarate esters in an amount of about 90 mg to about 110 mg FAE or about 170 mg to about 220 mg FAE, wherein the one or more doses comprise a controlled release pharmaceutical composition that releases the contents at a physiological pH of about pH 6.8.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of one or more fumarate esters comprising about 90 mg to about 110 mg FAE or about 170 mg to about 220 mg FAE wherein the FAE comprises dimethyl fumarate.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of one or more fumarate esters comprising about 90 mg to about 110 mg FAE or about 170 mg to about 220 mg FAE wherein the FAE comprises methyl hydrogen fumarate.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of one or more fumarate esters wherein methyl hydrogen fumarate activates a nuclear erythroid 2-related factor 2 (nuclear factor erythroid-derived 2-like 2; Nrf2) transcriptional pathway.
  • Nrf2 nuclear erythroid 2-related factor 2
  • the dose comprises an oral controlled release composition comprising: about 10% to about 64% by weight of one or more fumarate esters (FAE; PSD: d90 ⁇ 100 ⁇ ); about 18% to about 70% by weight of a mixture of mono- and di-glycerides; about 3% by weight of polyvinylpyrrolidone; about 10% by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • the dose comprises one or more FAEs in an amount of about 80 mg to about 460 mg.
  • the dose comprises one or more FAEs in an amount of about 85 mg to about 110 mg.
  • the dose comprises one or more FAEs in an amount of about 170 mg to about 220 mg.
  • a daily total dose comprises one or more FAEs in an amount of about 340 mg to about 440 mg.
  • the fumarate ester comprises MMF, DMF, or a combination thereof.
  • the matrix comprises DMF.
  • the fumarate ester comprises MMF.
  • an oral controlled release pharmaceutical composition comprising a soft capsule shell and a matrix, the matrix comprising about 10% to about 64% by weight of one or more FAEs (PSD: d90 ⁇ 100 ⁇ ); about 18% to about 70% by weight of a mixture of mono- and di-glycerides; about 1% to about 10% by weight polyvinylpyrrolidone; about 2% to about 10% by weight polyoxyl 40 hydrogenated castor oil, and about 1%) to about 5% by weight lactic acid.
  • FAEs PSD: d90 ⁇ 100 ⁇
  • the soft capsule shell is a soft capsule comprising about 30% by weight of gelatin; about 10% by weight of methylacrylic acid copolymer; about 18% by weight of glycerol; about 1 % by weight of tri ethyl citrate; about 1.5% by weight of ammonia; and about 37% by weight of water.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of an oral controlled release pharmaceutical composition comprising a soft capsule shell and a matrix, the matrix comprising about 10% to about 64% by weight of one or more fumarate esters (FAE; PSD: d90 ⁇ 100 ⁇ ); about 18%> to about 70% by weight of a mixture of mono- and di-glycerides; about 1%) to about 10%) by weight polyvinylpyrrolidone; about 2% to about 10%> by weight polyoxyl 40 hydrogenated castor oil, and about 1%> to about 5% by weight lactic acid.
  • FAE fumarate esters
  • an oral controlled release pharmaceutical composition comprising a soft capsule shell and a matrix, the matrix comprising about 34% by weight of FAE; about 48% by weight of a mixture of mono- and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5%) by weight of lactic acid.
  • the soft capsule shell is a soft capsule shell comprising about 30% by weight of gelatin; about 10% by weight of methylacrylic acid copolymer; about 18% by weight of glycerol; about 1% by weight of tri ethyl citrate; about 1.5% by weight of ammonia; and about 37% by weight of water.
  • Another embodiment described herein is method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of an oral controlled release pharmaceutical composition comprising a soft capsule shell and a matrix, the matrix comprising about 34% by weight of FAE; about 48% by weight of a mixture of mono- and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of an oral controlled release pharmaceutical composition comprising a soft capsule shell and a matrix, the matrix comprising about 34% by weight of DMF or MMF; about 48% by weight of a mixture of mono- and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • an oral controlled release pharmaceutical composition comprising a soft capsule shell and a matrix, the matrix comprising about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg, about 115 mg, about 120 mg, about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg of FAE; about 48% by weight of a mixture of mono- and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3%> by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • an oral controlled release pharmaceutical composition comprising a soft capsule shell and a matrix, the matrix comprising about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg, about 115 mg, about 120 mg, about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg of DMF or MMF; about 48%) by weight of a mixture of mono- and di-glycerides; about 10%> by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • Another embodiment described herein is an oral controlled release pharmaceutical composition dosage form comprising a daily total amount of FAE of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.
  • Another embodiment described herein is an oral controlled release pharmaceutical composition dosage form comprising a daily total amount of DMF or MMF of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.
  • Another embodiment described herein is an oral pharmaceutical composition providing a daily total amount of DMF or MMF of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg DMF or MMF; about 48% by weight of a mixture of mono- and di-glycerides; about 10%> by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of a pharmaceutical composition providing a daily total amount of FAE of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of a pharmaceutical composition providing a daily total amount of DMF or MMF of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.
  • an oral pharmaceutical composition comprising a controlled release soft capsule shell and matrix comprising: about 10% to about 64% of one or more fumarate esters (FAE; PSD: ⁇ 100 ⁇ ); about 18% to about 70% by weight of a mixture of mono- and di-glycerides; at least about 3% by weight of polyvinylpyrrolidone; at least about 10% by weight of polyoxyl 40 hydrogenated castor oil, and at least about 5% by weight of lactic acid.
  • the composition comprises one or more FAEs in an amount of about 13% to about 16% by weight; about 27% to about 32% by weight; or about 48% to about 64% by weight.
  • the composition comprises mono- and di-glycerides in an amount of about 66% to about 69% by weight; about 50% to about 55% by weight; or about 18% to about 29% by weight.
  • the composition comprises one or more FAEs in an amount of about 80 mg to about 460 mg FAE.
  • the composition comprises one or more FAEs in an amount of about 80 mg to about 100 mg FAE; about 90 mg to about 110 mg FAE, about 100 mg to about 120 mg FAE; about 180 mg to about 220 mg FAE; about 200 mg to about 230 mg FAE; or about 400 mg to about 460 mg FAE.
  • the composition comprises one or more FAEs in an amount of about 90 mg to about 110 mg FAE.
  • the composition comprises one or more FAEs in an amount of about 100 mg to about 120 mg FAE. In another aspect, the composition comprises one or more FAEs in an amount of about 200 mg to about 220 mg FAE. In another aspect, the composition comprises one or more FAEs in an amount of about 210 mg to about 220 mg FAE. In another aspect, the composition comprises one or more FAEs in an amount of about 214 mg FAE. In another aspect, the composition comprises one or more FAEs in an amount of about 1.5 to about 1.7 mmol FAE. In another aspect, the matrix comprises DMF, MMF, or a combination thereof. In another aspect, the matrix comprises DMF. In another aspect, the matrix comprises MMF.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of one or more fumarate esters in an amount of about 180 mg to about 220 mg FAE, wherein the one or more doses comprise a controlled release pharmaceutical composition that releases the contents at a physiological pH of about pH 6.8.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of one or more fumarate esters in an amount of about 180 mg to about 220 mg FAE, wherein the FAE comprises dimethyl fumarate.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subj ect in need thereof comprising orally administering to the subject one or more doses of one or more fumarate esters in an amount of about 180 mg to about 220 mg FAE, wherein the FAE comprises methyl hydrogen fumarate.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of one or more fumarate esters wherein methyl hydrogen fumarate activates a nuclear erythroid 2-related factor 2 (nuclear factor erythroid-derived 2-like 2; Nrf2) transcriptional pathway.
  • Nrf2 nuclear erythroid 2-related factor 2
  • the one or more doses of fumarate esters comprise an oral controlled release composition comprising: about 10% to about 64% by weight of one or more fumarate esters (FAE; PSD: ⁇ 100 ⁇ ); about 18% to about 70%) by weight of a mixture of mono- and di-glycerides; at least about 3% by weight polyvinylpyrrolidone; at least about 10%> by weight polyoxyl 40 hydrogenated castor oil, and at least about 5% by weight lactic acid.
  • the dose comprises one or more FAEs in an amount of about 80 mg to about 460 mg.
  • the dose comprises one or more FAEs in an amount of about 85 mg to about 110 mg.
  • the dose comprises one or more FAEs in an amount of about 170 mg to about 220 mg.
  • a daily total dose comprises one or more FAEs in an amount of about 340 mg to about 440 mg.
  • the FAE comprises MMF, DMF, or a combination thereof.
  • the FAE comprises DMF.
  • the FAE comprises MMF.
  • an oral controlled release pharmaceutical composition comprising a soft capsule and a matrix, the matrix comprising about 10%> to about 64%) by weight of one or more fumarate esters (FAE; PSD: d90 ⁇ 100 ⁇ ); about 18%> to about 70% by weight of a mixture of mono- and di-glycerides; about 1% to about 10% by weight polyvinylpyrrolidone; about 2% to about 10% by weight polyoxyl 40 hydrogenated castor oil, and about 1%) to about 5% by weight lactic acid.
  • the FAE is dimethyl fumarate.
  • the soft capsule is a soft capsule shell comprising about 30% by weight of gelatin; about 10% by weight of methylacrylic acid copolymer; about 18% by weight of glycerol; about 1 % by weight of tri ethyl citrate; about 1.5% by weight of ammonia; and about 37% by weight of water.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of an oral controlled release pharmaceutical composition comprising a soft capsule shell and a matrix, the matrix comprising about 10% to about 64% by weight of one or more fumarate esters (FAE; PSD: d90 ⁇ 100 ⁇ ); about 18% to about 70% by weight of a mixture of mono- and di-glycerides; about 1%) to about 10%) by weight polyvinylpyrrolidone; about 2% to about 10% by weight polyoxyl 40 hydrogenated castor oil, and about 1% to about 5% by weight lactic acid.
  • FAE fumarate esters
  • an oral controlled release pharmaceutical composition comprising a soft capsule shell and a matrix, the matrix comprising about 34% by weight of FAE; about 48% by weight of a mixture of mono- and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5%) by weight of lactic acid.
  • the FAE is dimethyl fumarate.
  • the soft capsule is a soft capsule comprising about 30% by weight of gelatin; about 10%) by weight of methylacrylic acid copolymer; about 18% by weight of glycerol; about 1 % by weight of tri ethyl citrate; about 1.5% by weight of ammonia; and about 37% by weight of water.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of an oral controlled release pharmaceutical composition comprising a soft capsule shell and a matrix, the matrix comprising about 34% by weight of FAE; about 48% by weight of a mixture of mono- and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of an oral controlled release pharmaceutical composition comprising a soft capsule shell and a matrix, the matrix comprising about 34% by weight of DMF or MMF; about 48% by weight of a mixture of mono- and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • an oral controlled release pharmaceutical composition comprising a soft capsule and a matrix, the matrix comprising about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg, about 115 mg, about 120 mg, about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg of FAE and about 48% by weight of a mixture of mono- and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • the soft capsule is a soft capsule comprising about 30% by weight of gelatin; about 10%) by weight of methylacrylic acid copolymer; about 18% by weight of glycerol; about 1 % by weight of tri ethyl citrate; about 1.5% by weight of ammonia; and about 37% by weight of water.
  • an oral controlled release pharmaceutical composition comprising a soft capsule and a matrix, the matrix comprising about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg, about 115 mg, about 120 mg, about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg of DMF or MMF and about 48% by weight of a mixture of mono- and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • the soft capsule is a soft capsule comprising about 30% by weight of gelatin; about 10%) by weight of methylacrylic acid copolymer; about 18% by weight of glycerol; about 1 % by weight of tri ethyl citrate; about 1.5% by weight of ammonia; and about 37% by weight of water.
  • Another embodiment described herein is an oral controlled release pharmaceutical composition dosage forms comprising a daily total amount of FAE of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.
  • Another embodiment described herein is an oral controlled release pharmaceutical composition dosage form comprising a daily total amount of DMF or MMF of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.
  • Another embodiment described herein is an oral pharmaceutical compositions providing a daily total amount of FAE of about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg FAE; about 48% by weight of a mixture of mono- and di-glycerides; about 10%> by weight of polyvinylpyrrolidone; about 3%) by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • Another embodiment described herein is an oral pharmaceutical compositions providing a daily total amount of DMF or MMF of about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg DMF or MMF; about 48%> by weight of a mixture of mono- and di-glycerides; about 10%> by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of a pharmaceutical composition providing a daily total amount of FAE of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.
  • the pharmaceutical composition comprises about 34% by weight of FAE; about 48%) by weight of a mixture of mono- and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • Another embodiment described herein is a method of treating multiple sclerosis in a subject in need thereof comprising orally administering to the subject one or more doses of a pharmaceutical composition providing a daily total amount of DMF or MMF of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.
  • the pharmaceutical composition comprises about 34% by weight of DMF or MMF; about 48% by weight of a mixture of mono- and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight of lactic acid.
  • Another embodiment described herein is an oral pharmaceutical composition for treating multiple sclerosis in a subject in need thereof comprising one or more fumarate esters comprising DMF, MMF, or a combination thereof.
  • Another embodiment described herein is an oral pharmaceutical composition for treating multiple sclerosis in a subject in need thereof comprising one or more fumarate esters comprising DMF.
  • Another embodiment described herein is an oral pharmaceutical composition for treating multiple sclerosis in a subject in need thereof comprising one or more fumarate esters comprising MMF.
  • Another embodiment described herein is any of the foregoing compositions or methods, wherein the fumarate ester comprises a therapeutically effective amount of DMF, MMF, or a combination thereof.
  • Another embodiment described herein is any of the foregoing compositions or methods, wherein the fumarate ester comprises a therapeutically effective amount of DMF.
  • Another embodiment described herein is any of the foregoing compositions or methods, wherein the fumarate ester comprises a therapeutically effective amount of MMF.
  • FIGURE 1 Scheme for manufacturing enteric soft capsules comprising a DMF matrix.
  • FIGURE 2 Dissolution of enteric soft capsules comprising two DMF formulations.
  • FIGURE 3 DMF enteric soft capsule stability.
  • FIGURE 4 DMF release in enteric soft capsules.
  • FIGURE 5 Surfactant affects DMF release rate.
  • FIGURE 6 Polyvinylpyrrolidone concentration affects DMF release rate.
  • FIGURE 7 DMF enteric soft capsules are amenable to controlled or extended release.
  • FIGURE 8 DMF particle size affects release rate.
  • FIGURE 9 Two-stage dissolution of application batches.
  • FIGURE 10 Two-stage dissolution of GMP batch compared to application batches.
  • FIGURE 1 1. Effects of Povidone K30 and PEG 600 on DMF release rate.
  • FIGURE 12 Two-stage dissolution of 120 mg DMF enteric soft capsule.
  • FIGURE 13 DMF enteric soft capsule stability at To and after 3- and 6-month conditions.
  • FIGURE 14 Two-stage dissolution of monomethyl fumarate enteric soft capsules.
  • FIGURE 15 Mean plasma concentration of MMF over time following dose administration.
  • FIGURE 16 Two-stage dissolution of dimethyl fumarate and monomethyl fumarate enteric soft capsules.
  • FIGURE 17 Release of monomethyl fumarate in soybean oil from enteric soft capsules under acidic conditions (pH 1.2).
  • FIGURE 18 Release of monomethyl fumarate in soybean and vegetable oil from enteric soft capsules under acidic conditions (pH 1.2).
  • FIGURE 19 Release of monomethyl fumarate in mono- and di-glycerides from enteric soft capsules under acidic conditions (pH 1.2).
  • FIGURE 20 Two-stage dissolution of monomethyl fumarate in soft capsules coated with an enteric coating.
  • FIGURE 21 Two-stage dissolution of monom ethyl fumarate in soft capsules and enteric soft capsules coated with an enteric coating.
  • FIGURE 22 Comparison of data from FIG. 21 with enteric soft capsule containing dimethyl fumarate.
  • FIGURE 23 Two-stage dissolution of monomethyl fumarate in a soft capsule and an enteric soft capsule coated with an enteric coating with and without precoating.
  • FIGURE 24 Mean plasma monomethyl fumarate concentrations for Test samples Tl, T2, T3, and the Reference as a function of time after dosing (see Examples 31-33). Panels A and B show the same data, with B having a logarithmic .y-axis.
  • FIGURE 24 Mean plasma monomethyl fumarate concentrations for Test samples T4, T5,
  • Panels A and B show the same data, with B having a logarithmic .y-axis.
  • Described herein are pharmaceutical compositions of fumarate esters, such as dimethyl fumarate, monomethyl fumarate, pro-drugs of monomethyl fumarate, other pharmacologically active fumarate esters, or combinations thereof.
  • compositions described herein provide compositions of fumarate esters, di-alkyl fumarates, mono-alkyl fumarates, such as dimethyl fumarate, monomethyl fumarate, or combinations thereof, and methods for preparation thereof. Also described herein are compositions and methods for manufacturing controlled, delayed, or extended release fumarate esters, dimethyl fumarate, monomethyl fumarate, or combinations thereof as capsule dosage forms.
  • the fumarate ester pharmaceutical composition is a liquid.
  • the liquid is a single-phase, flowable liquid.
  • the liquid can be lipid, lipophilic, hydrophilic, or combinations thereof.
  • the liquid is non-aqueous.
  • the liquid is aqueous.
  • the fumarate ester pharmaceutical composition is a liquid encapsulated within a soft capsule shell. In another embodiment described herein, the fumarate ester pharmaceutical composition is a liquid encapsulated within a hard capsule shell. In another embodiment, the soft capsule is a soft capsule or an enteric soft capsule coated with an enteric coating and one or more subcoatings or top coatings. In another embodiment described herein, the composition is encapsulated in a hard capsule or an enteric hard capsule. In another embodiment described herein, the composition is encapsulated in a hard capsule comprising an enteric coating and one or more subcoatings or top coatings.
  • the fumarate ester is in the form of solid microparticles of defined size within a composition comprising a lipid or lipophilic vehicle.
  • the lipid or lipophilic vehicle may comprise one or more hydrophilic polymers or species, but as described herein, the vehicle is considered a lipid or lipophilic vehicle.
  • the terms “fumarate ester” or “FAE” refers to any pharmacologically active mono- or di-alkyl fumarate ester, such as monomethyl fumarate, dimethyl fumarate, or other fumarate esters, acids, salts, pro-drugs of monomethyl fumarate, derivatives thereof, combinations or mixtures of any of the foregoing.
  • Fumarate ester as used herein also comprises prodrugs that are metabolized to monomethyl fumarate after administration to a subject.
  • active ingredient or “active pharmaceutical ingredient” as used herein refer to a pharmaceutical agent, active ingredient, compound, or substance, compositions, or mixtures thereof, that provide a pharmacological, often beneficial, effect.
  • dose denotes any form of the active ingredient formulation that contains an amount sufficient to produce a therapeutic effect with a single administration.
  • dose refers to the administering of a specific amount, number, and frequency of doses over a specified period of time, typically 1 day.
  • dosage form refers to any pharmaceutical composition described herein in a form that can be administered to a subject.
  • the dosage form used herein is for oral administration.
  • Exemplary dosage forms described herein include capsules, hard capsules, soft capsules, enteric soft capsules, coated soft capsules, suspensions, solutions emulsions, or the like.
  • soft capsule or “soft gel capsule” as used herein refers to a soft capsule comprising one or more film-forming polymers that is capable of encapsulating a liquid “matrix” or “fill” comprising pharmaceutically acceptable excipients and one or more active pharmaceutical ingredients.
  • soft capsule can encompass enteric soft capsules as described herein.
  • enteric soft capsule refers to a soft capsule comprising one or more enteric polymers in the shell or a soft capsule that has been coated with one or more enteric coatings that are applied to the external surface of the capsule as described herein.
  • the coated soft capsule may have one or more subcoatings applied prior to the application of the enteric coating.
  • matrix refers to a composition comprising one or more active pharmaceutical ingredients that is encapsulated within a capsule.
  • the matrix comprises a vehicle, one or more active pharmaceutical ingredients, and one or more pharmaceutically acceptable excipients.
  • the matrix is a liquid and comprises a lipid or lipophilic liquid comprising one or more fumarate esters.
  • active pharmaceutical ingredient load or “drug load” as used herein refers to the quantity (mass) of the active pharmaceutical ingredient comprised in a single soft capsule fill.
  • formulation refers to the drug in combination with pharmaceutically acceptable excipients. This term includes orally administrable formulations as well as formulations administrable by other means.
  • titration refers to the incremental increase in drug dosage to a level that provides the optimal therapeutic effect.
  • controlled release encompasses the terms “immediate release,” “modified release,” “sustained release,” “extended release,” and “delayed release.”
  • extended release or “sustained release” as used herein refers to a composition that releases an active ingredient according to a desired profile over an extended period under physiological conditions or in an in vitro test.
  • extended period it is meant a continuous period of time of at least about 1 hour; about 2 hours; about 4 hours; about 6 hours; about 8 hours; about 10 hours; about 12 hours; about 14 hours; about 16 hours; about 18 hours; about 20 hours about 24 hours; or even longer; specifically, over a period of about 18 hours under physiological conditions or in an in vitro assay.
  • modified release refers to a composition that releases an active ingredient at a slower rate than does an immediate release formulation under physiological conditions or in an in vitro test.
  • delayed release refers to a composition that releases an active ingredient after a period of time, for example minutes or hours, such that the active ingredient is not released initially.
  • a delayed release composition may provide, for example, the release of a drug or active ingredient from a dosage form, after a certain period, under physiological conditions or in an in vitro test.
  • mean “particle size distribution” (PSD) as used herein refers to the mean particle size from a statistical distribution of a range of particle sizes as described herein. The distribution may be a Gaussian, normal distribution, or a non-normal distribution.
  • d90 refers to the percentage (e.g., 90%, 50%, or 10%), respectively) of particle sizes that are less than a specified size, range, or distribution.
  • d90 ⁇ 90 ⁇ as specified means that 90% of the particle sizes within a distribution of particles are less than or equal to 90 ⁇ .
  • Cmax refers to the maximum observed blood (plasma, serum, or whole blood) concentration or the maximum blood concentration calculated or estimated from a concentration to time curve, and is expressed in units of mg/L or ng/mL, as applicable.
  • Cmin refers to the minimum observed blood (plasma, serum, or whole blood) concentration or the minimum blood concentration calculated or estimated from a concentration to time curve, and is expressed in units of mg/L or ng/mL, as applicable.
  • Cavg refers to the blood (plasma, serum, or whole blood) concentration of the drug within the dosing interval, is calculated as AUC/dosing interval, and is expressed in units of mg/L or ng/mL, as applicable.
  • Jmax refers to the time after administration at which Cmax occurs, and is expressed in units of hours (h) or minutes (min), as applicable.
  • AUCo ⁇ x refers to area under the blood (plasma, serum, or whole blood) concentration versus time curve from time zero to time tau ( ⁇ ) over a dosing interval at steady state, where tau is the length of the dosing interval, and is expressed in units of h mg/L or h- ng/mL, as applicable.
  • AUCo ⁇ i2 refers to the area under the concentration versus time curve from 0 to 12 hours.
  • AUCo ⁇ refers to the area under the blood (plasma, serum, or whole blood) concentration versus time curve from time 0 hours to infinity, and is expressed in units of h- mg/L or h- ng/mL, as applicable.
  • AUCoveraii refers to the combined area under the blood (plasma, serum, or whole blood) concentration versus time curve, and is expressed in units of h mg/L (or h - ng/mL) for at least one or more doses of the pharmaceutical compositions described herein.
  • the “AUCoveraii” refers to the combined area under the blood concentration versus time curve for at least two doses of the pharmaceutical compositions described herein.
  • bioequivalence or “bioequivalent” as used herein refer to a drug product or dosage form that has highly similar release and systemic absorption as compared to a reference drug.
  • ⁇ 505(j)(8)(B)(i)) provides that a drug is bioequivalent to a reference listed drug (RLD) if: "the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses . . . "
  • enhanced bioavailability refers to the increased proportion of an active pharmaceutical ingredient that enters the systemic circulation when introduced into the body as compared to a reference active pharmaceutical's bioavailability. Bioavailability can be determined by comparing the rate and extent of absorption of a test drug with a reference drug when administered at the same molar dose of the active therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses. Typical pharmacokinetic parameters can be used to demonstrate enhanced bioavailability compared to the reference.
  • treating refers to administering a therapy in an amount, manner, or mode effective (e.g., a therapeutic effect) to improve a condition, symptom, disorder, or parameter associated with a disorder, or a likelihood thereof.
  • prophylaxis refers to preventing or reducing the progression of a disorder, either to a statistically significant degree or to a degree detectable to one skilled in the art.
  • the pharmaceutical composition comprises a non-aqueous, single-phase, flowable liquid.
  • the pharmaceutical composition comprises a liquid comprising one or more lipid liquids, lipophilic liquids, hydrophilic liquids, or a combination thereof.
  • the pharmaceutical composition comprises a liquid comprising one or more lipid liquids, lipophilic liquids, or a combination thereof.
  • the pharmaceutical composition comprises a liquid comprising one or more lipophilic liquids, hydrophilic liquids, or a combination thereof.
  • the pharmaceutical composition comprises a liquid comprising one or more lipid liquids.
  • a controlled release pharmaceutical composition comprising one or more fumarate esters.
  • Another embodiment is a controlled release pharmaceutical composition comprising a soft capsule shell encapsulating a liquid matrix fill comprising one or more fumarate esters.
  • Another embodiment is a controlled release pharmaceutical composition comprising a hard capsule shell encapsulating a liquid matrix fill comprising one or more fumarate esters.
  • Another embodiment is a controlled release pharmaceutical composition
  • a capsule shell encapsulating a matrix fill comprising one or more fumarate esters, wherein the capsule shell comprises one or more subcoatings, coatings, or topcoatings.
  • Suitable coatings may be adherence coatings, enteric coatings, moisture barriers, air or gas barriers, polymer coatings, colorings, flavors, writings, or combinations thereof.
  • the pharmaceutical composition has controlled release properties.
  • the matrix fill provides controlled release properties.
  • controlled release matrix fills are described in International Patent Application Publication No. WO 2005/009409; U.S. Patent Application Publication No. US 2006/0115527; U.S. Patent Nos. 8,293,270; and 8,333,989, each of which is incorporated by reference herein for such teachings.
  • the matrix is configured to provide controlled release, extended release, sustained release, delayed release, or combinations thereof.
  • the matrix comprises a lipid or lipophilic vehicle that provides a suspension of fumarate ester microparticles having defined sizes.
  • a capsule comprising a lipid or lipophilic vehicle comprising suspension of one or more fumarate ester microparticles provides controlled release delivery of the fumarate ester.
  • the capsule is a soft capsule.
  • the capsule is a hard capsule.
  • the capsule is coated with one or more subcoatings, one or more enteric coatings, and one or more topcoating moisture barriers.
  • the fumarate ester particles described herein may be generated by any particle size reduction or particle growth methodology known to one having ordinary skill the art.
  • Exemplary and non-limiting methods may comprise a "top-down" reduction in particle size including mechanical micronization techniques, wherein a larger particle is crushed, bashed, or ground into a smaller particle through techniques, such as jet milling, ball milling, or high pressure homogenization; or particle engineering techniques such as cryogenic spraying or crystal engineering.
  • “bottom-up" processing may be used to build a suitable size of particles as described herein using dual solvent/anti- solvent rapid precipitation techniques.
  • fumarate ester particles of a specified size distribution are produce using a milling technique.
  • the pharmaceutical composition comprises liquid matrix fills for fumarate esters, such as dimethyl fumarate, monomethyl fumarate, prodrugs thereof, or derivatives thereof, based on lipids or lipophilic vehicles or hydrophilic vehicles.
  • liquid matrix fills for fumarate esters such as dimethyl fumarate, monomethyl fumarate, prodrugs thereof, or derivatives thereof, based on lipids or lipophilic vehicles or hydrophilic vehicles.
  • Some of the described matrices have a hydrophobic (lipophilic) surface in contact with the hydrophilic soft capsule shell to minimize any potential shell-fill interactions, such as when soft capsules are filled with hydrophilic vehicles.
  • liquid matrix fills comprising fumarate esters, such as dimethyl fumarate, monomethyl fumarate, prodrugs thereof, or derivatives thereof, in a controlled release soft capsule in the form of a suspension, where part or all of the fumarate ester is suspended within the matrix. Also provided are compositions and formulations where the fumarate ester is incorporated into a one-phase or two-phase matrix.
  • liquid matrix fills comprising fumarate esters or derivatives thereof, in a delayed release soft capsule in the form of a suspension, where part or all of the fumarate ester is suspended within the matrix.
  • methods for manufacturing liquid matrix fills comprising fumarate esters or derivatives thereof, in an extended release soft capsule in the form of a suspension, where part or all of the fumarate ester is suspended within the matrix are also described herein.
  • a controlled, delayed, or extended release capsule having a shell and a matrix fill
  • the matrix fill includes a lipid or lipophilic liquid vehicle comprising a suspension of solid particles of one or more fumarate esters such as dimethyl fumarate, monomethyl fumarate, prodrugs thereof, or derivatives thereof.
  • the lipid or lipophilic vehicle comprises an oil, a vegetable oil, fatty acid, fatty acid ester, or a combination thereof.
  • the matrix fill is a single phase lipid or lipophilic liquid at room temperature and prevents sublimation of the fumarate ester.
  • the lipid or lipophilic liquid vehicle comprises one or more oils, mono/diglycerides, polyoxyl hydrogenated castor oils, polyvinylpyrrolidones, or a combination thereof. In another embodiment, the lipid or lipophilic liquid vehicle comprises an oil. In another embodiment, the lipid or lipophilic vehicle comprises mono/diglycerides, polyoxyl hydrogenated castor oils, polyvinylpyrrolidones, or a combination thereof.
  • Exemplary lipid or lipophilic vehicles comprise mineral oil; light mineral oil; natural oils (e.g., vegetable, corn, canola, sunflower, soybean, olive, coconut, cocoa, peanut, almond, cottonseed, persic, sesame, squalane, castor, cod liver) hydrogenated vegetable oil; partially hydrogenated oils; beeswax; polyethoxylated beeswax; paraffin; normal waxes; medium chain medium chain monoglycerides, diglycerides and triglycerides; higher aliphatic alcohols; higher aliphatic acids; long chain fatty acids; saturated or unsaturated fatty acids; hydrogenated fatty acids; fatty acid glycerides; polyoxyethylated oleic glycerides; monoglycerides and diglycerides; mono-, bi- or tri-substituted glycerides; glycerol mono-oleate esters; glycerol mono-caprate; glyceryl monocapry
  • the liquid matrix comprises solid particles of fumarate ester suspended in a lipid or lipophilic vehicle of vegetable oil, fatty acid, fatty acid ester, or a combination thereof.
  • the lipid or lipophilic vehicle is a liquid at room temperature (e.g., 25 °C) or phisiological temperature (e.g., 37 °C).
  • the lipid or lipophilic vehicle is soybean oil.
  • the lipid or lipophilic vehicle comprises medium chain monoglycerides and diglycerides.
  • the matrix comprises a solvent or solubility enhancing agent.
  • Exemplary solvents or solubility enhancing agents useful for the matrix fills described herein include Capmul ® MCM, Cremophor ® RH 40, Captex ® 355, Croscarmellose, Crospovidone, Crospovidone CL, Crospovidone CL-F, Crospovidone CL-M, Imwitor ® 742, Kollidon ® CL, Kollidon ® CL-F, Kollidon ® CL-M, LabrafacTM Lipophile WL 1349, Labrafil ® M2125CS, Labrasol ® , Lutrol ® F 68, MaisineTM 35-1, mannitol, Miglyol ® 812, Pearlitol ® Flash, Peceol ® , polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 3350, Plurol ® Oleique CC 497, Povidone K 17, Povidone K 30, propylene glycol, or combinations thereof.
  • the lipid or lipophilic vehicle comprises medium chain mono- and diglycerides (e.g., Capmul ® MCM) and polyoxyl 40 hydrogenated castor oil (e.g., macrogolglycerol hydroxystearate; Cremophor ® RH 40).
  • medium chain mono- and diglycerides e.g., Capmul ® MCM
  • polyoxyl 40 hydrogenated castor oil e.g., macrogolglycerol hydroxystearate; Cremophor ® RH 40.
  • the matrix comprises a one or more hydrophilic solvents or suspension agents.
  • the matrix can polyvinylpyrrolidone, polyethylene glycols of molecular weight ranging from about 200 to about 8000 (MN, number average molecular weight), or combinations thereof.
  • the matrix comprises polyvinylpyrrolidone K30 (e.g., Povidone K30).
  • the matrix comprises polyethylene glycol 400 and poly polyvinylpyrrolidone K30.
  • the matrix fill comprises a release regulator such as a fatty acid salt, fatty acid ester, or fatty acid polyoxyethylene derivative.
  • the release regulator can also be a surfactant having a hydrophilic/lipophilic balance (HLB) value between about 2 and about 40.
  • HLB hydrophilic/lipophilic balance
  • the matrix comprises emulsifying or solubilizing agents such as acacia, cholesterol, diethanolamine, glyceryl monostearate, lanolin alcohols, lecithin, mono- and di-glycerides, monoethanolamines, oleic acids, oleyl alcohols, poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol diacetate, propylene glycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid, trolamine, emulsifying wax, or combinations thereof
  • the matrix comprises a neutralizing agent.
  • the neutralizing agent it thought to stabilize the fumarate ester in the matrix fill by preventing hydrolysis.
  • the neutralizing agent may stabilize soft capsule shells comprising enteric polymers such as acrylate methacrylate by forming salts with the methylacrylate moieties from the capsule shell.
  • the neutralizing agent comprises an organic acid, ester, or salt.
  • the neutralizing agent comprises at least one of lactate, fumarate, caprylate, caprate, oleate, maleate, succinate, tartrate, citrate, glutamate, gluconate, esters or salts thereof, or combinations thereof.
  • the neutralizing agent is lactic acid.
  • the matrix includes a hydrophilic internal phase and a lipid or lipophilic external phase.
  • the hydrophilic internal phase can comprise polypropylene glycol or polyethylene glycol of molecular weight ranging from about 200 to about 8000 (MN, number average molecular weight).
  • the internal phase comprises hydroalcoholic solutions of cellulose derivatives, polyacrylates, polyvinyl polymers, or combinations thereof.
  • the internal phase comprises polymers such as methylcellulose, hydroxypropylmethylcellulose, polymethylmethacrylate, or polyvinylpyrrolidone (PVP).
  • the internal phase of the matrix state is "fluid” or "structured.”
  • a “fluid” internal phase means a completely flowable liquid whose globules can aggregate to make a larger globule.
  • a “structured” internal phase means a solid, semisolid, or a gel whose shape is relatively stable and does not usually aggregate to form a large globule.
  • a structured internal phase can provide controlled drug release and stabilize the physical state of the matrix. Without being bound to any theory, the structured nature of the matrix impedes solvation or diffusion of the fumarate ester out of the matrix.
  • the external phase comprises a vegetable oil, hydrogenated vegetable oil, fatty acid, fatty acid ester, wax, or a combination thereof.
  • fumarate ester is dispersed in the internal phase as a suspension form.
  • the matrix fill is an emulsion type, where the fumarate ester is distributed in one or both of the external (lipophilic) and internal (hydrophilic) phases.
  • the external phase of the emulsion matrix fill comprises lipid or lipophilic vehicles similar to those described herein.
  • the fumarate ester can be dispersed in the internal phase as a solution or as a suspension.
  • an emulsion-type matrix may comprise a surfactant or combination of surfactants having HLB values ranging from about 2 to about 40, including all integers within the specified range.
  • the HLB range comprises from about 8 to about 20, including all integers within the specified range.
  • the pharmaceutical composition described herein comprises a soft capsule comprising a matrix comprising a lipid or lipophilic vehicle that provides a solution, suspension, or combination thereof of a fumarate ester.
  • the fumarate ester is a mono-or di-alkyl fumarate of Formula I:
  • R 1 and R 2 which may be the same or different, independently represent linear, branched, or cyclic, saturated or unsaturated Ci-20 alkyl radical, which may be optionally substituted with halogen (CI, F, I, Br), hydroxy, Ci-4 alkoxy, nitro, or cyano for preparing a pharmaceutical composition as described herein.
  • Ci-20 alkyl radicals, Ci-8 alkyl radicals, and C4-5 alkyl radicals are, for example, methyl, ethyl, ⁇ -propyl, isopropyl, «-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethyl hexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxy ethyl, 2 or 3 -hydroxy propyl, 2-methoxy ethyl, methoxy methyl or 2- or 3-methoxy propyl.
  • R 1 or R 2 is a Ci-5 alkyl, especially methyl or ethyl.
  • R 1 and R 2 are the same or different Ci-5 alkyl radicals such as methyl, ethyl, ⁇ -propyl, or t-butyl.
  • R 1 and R 2 are the same or different C1-5 alkyl radicals such as methyl and ethyl.
  • R 1 and R 2 are identical and are methyl or ethyl.
  • the fumarate ester is monomethyl fumarate, dimethyl fumarate, methyl ethyl fumarate, or diethyl fumarate.
  • the fumarate ester is monomethyl fumarate, dimethyl fumarate, or a combination thereof.
  • the fumarate ester is monomethyl fumarate.
  • the fumarate ester is dimethyl fumarate.
  • the fumarate ester is:
  • R comprises any Ci-20 alkyl, any Ci-20 acid, any Ci-20 ether, any Ci-20 ester, any Ci-20 amino, any Ci-20 amide, or any Ci-20 heterocycle.
  • the fumarate ester is a prodrug of monomethyl fumarate.
  • the monomethyl fumarate prodrug is dimethyl fumarate.
  • Exemplary monomethyl fumarate prodrugs are described in U.S. Patent Nos. 8,669,281 and 9,090,558 and U.S. Patent Application Publication Nos. US 2014/0275048; US 2014/0275205; US 2014/0275250; US 2015/0190360; US 2014/057918; US 2014/348914; US 2014/350018; US 2014/056973; US 2014/0348915; and US 2015/0252013, each of which is incorporated by reference herein for such teachings.
  • the prodrug comprises one or more of N,N-diethylcarbamoyl)m ethyl methyl(2£)but-2-ene-l,4-dioate; methyl [N- benzylcarbamoyl]methyl (2£)but-2-ene-l,4-dioate; methyl 2-morpholin-4-yl-2-oxoethyl (2£)but- 2-ene-l,4-dioate; (N-butylcarbamoyl)methyl methyl(2£)but-2-ene-l,4-dioate; [N-(2- methoxyethyl)carbamoyl]methyl methyl(2£)but-2-ene-l,4-dioate; methyl(N-(l,3,4-thiadiazol- 2yl)carbamoyl)methyl(2£)but-2ene- 1 ,4-dioate; (N,N-d
  • the prodrug is (N,N- diethylcarbamoyl)methyl methyl (2£)but-2-ene-l,4-dioate, or a salt thereof.
  • the prodrug is 2-(2,5-dioxopyrrolidin-l-yl)ethyl methyl fumarate, or a salt thereof.
  • the pharmaceutical compositions described herein comprise pharmaceutically acceptable salts of the fumarate ester active pharmaceutical ingredient.
  • pharmaceutically acceptable salts of an active ingredient includes alkali metal salts such as, sodium or potassium salts, alkaline earth metal salts such as, for example, calcium and magnesium salts, and salts with organic or inorganic acid such as, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, succinic acid, tartaric acid, methanesulphonic acid, toluenesulphonic acid, inter alia.
  • the active ingredient may also be in the form of pharmaceutically acceptable uncharged or charged molecules, molecular complexes, solvates, or anhydrates thereof, and, if relevant, single isomers, enantiomers, racemic mixtures, or mixtures thereof.
  • the active pharmaceutical ingredient may be in any of its crystalline, polymorphous, semi-crystalline, amorphous or polyamorphous forms, or mixtures thereof.
  • the fumarate esters described herein can be prepared by processes known in the art. See, e.g., EP 0 312 697 and U.S. Patent Application Publication Nos. US 2013/0295169; US 2014/0179779; US 2014/0200363; and US 2014/0364604, each of which is incorporated by reference herein for such teachings.
  • the pharmaceutical composition comprises an active ingredient or drug.
  • the active ingredient or drug is a pharmacologically active fumarate ester.
  • the active ingredient is a monoalkyl fumarate.
  • the active ingredient is a dialkyl fumarate.
  • the active ingredient is a fumarate ester or combination of fumarate esters.
  • the active ingredient is dimethyl fumarate.
  • the active ingredient is monomethyl fumarate (methyl hydrogen fumarate).
  • the active ingredient is a combination of dimethyl fumarate and monomethyl fumarate.
  • the active ingredient is a combination of dimethyl fumarate, monomethyl fumarate, and other pharmacologically active fumarate esters, acids, salts, or derivatives thereof.
  • the active ingredient or drug comprises dimethyl fumarate, monomethyl fumarate, other pharmacologically active fumarate esters, acids, or salts, derivatives thereof, or combinations thereof.
  • the active ingredient comprises dimethyl fumarate, monomethyl fumarate, or derivatives thereof, combined with aspirin, ibuprofen, naproxene, diclofenac, ketoprofen, celecoxib, other non-steroidal anti-inflamatory active drugs (NSAIDs), or combinations thereof.
  • the pharmaceutical composition comprises a fumarate ester combined with aspirin.
  • the pharmaceutical composition comprises a fumarate ester combined with one or more leukotriene receptor antagonists.
  • the pharmaceutical composition comprises a fumarate ester combined with montelukast (Singulair ® ) or zafirlukast (Accolate ® ).
  • the pharmaceutical composition comprises a fumarate ester combined with montelukast or zafirlukast and an NSAID.
  • the pharmaceutical composition comprises a fumarate ester combined with montelukast or zafirlukast and aspirin.
  • the fumarate ester-to-matrix fill ratio range (e.g., the ratio of the fumarate ester weight to the weight of the other components of the matrix fill or vehicle) comprises from about 1 : 50 to about 1 : 1 by weight, including all ratios within the specified range. In another embodiment, the fumarate ester-to-matrix ratio range comprises from about 1 : 10 to about 1 : 1 by weight, including all ratios within the specified range. In one aspect, the fumarate ester-to-matrix ratio comprises about 1 :9 to about 1 : 1 by weight, including all ratios within the specified range.
  • the fumarate ester-to-matrix ratio range comprises from about 1 :5 to about 1 : 1 by weight, including all ratios within the specified range. In another aspect, the fumarate ester-to- matrix ratio range comprises from about 1 :3 to about 1 : 1.4 by weight, including all ratios within the specified range. In another aspect, the fumarate ester-to-matrix ratio is about 1 :5; about 1 :4; about 1 :3; about 1 :2; about 1 : 1; or about 0.5: 1.
  • the fumarate ester-to-matrix ratio is 1 :3.5; 1 :3.1; 1 :2.9; 1 :2.3; 1 :2.5; 1 : 1.92; 1 : 1.77; 1 : 1.5; 1 : 1.4; 1 : 1.35; 1 : 1.2, or about 1 : 1.2.
  • the active ingredient comprises about 1% to about 70% of the matrix, including all integers and fractions within the specified range. In another embodiment, the active ingredient comprises about 70%; about 60%; about 50%; about 40%; about 30%; about 20%; about 15%; about 10%; about 5%; about 2%; or about 1% of the matrix fill. In one aspect, the active ingredient comprises about 64% of the matrix. In another embodiment, the active ingredient comprises about 57% of the matrix. In another embodiment, the active ingredient comprises about 50% of the matrix. In another embodiment, the active ingredient comprises about 34% of the matrix. In another embodiment, the active ingredient comprises about 32% of the matrix. In another embodiment, the active ingredient comprises about 30% of the matrix. In another embodiment, the active ingredient comprises about 28% of the matrix. In another embodiment, the active ingredient comprises about 25% of the matrix.
  • the lipid or lipophilic liquid vehicle comprises about 50% to about 88% of the matrix by weight, including all integers and fractions within the specified range. In one embodiment the lipid or lipophilic liquid vehicle comprise about 60% of the matrix by weight.
  • the solid fumarate ester particles are milled or micronized.
  • the fumarate ester comprises a particle size range of about 1 ⁇ to about 500 ⁇ , including all integers and fractions within the specified range.
  • the micronized solid fumarate ester particles have a particle size of about 1 ⁇ , 2 ⁇ , about 5 ⁇ , about 10 ⁇ , about 15 ⁇ , about 20 ⁇ , about 25 ⁇ , about 30 ⁇ , about 35 ⁇ , about 40 ⁇ , about 45 ⁇ , about 50 ⁇ , about 55 ⁇ , about 60 ⁇ , about 65 ⁇ , about 70 ⁇ , about 75 ⁇ , about 80 ⁇ , about 85 ⁇ , about 90 ⁇ , about 95 ⁇ , about 100 ⁇ , about 105 ⁇ , about 110 ⁇ , about 115 ⁇ , about 120 ⁇ , about 125 ⁇ , about 130 ⁇ , about 135 ⁇ , about 140 ⁇ , about 145 ⁇ , about 150 ⁇ , about 155 ⁇ , about 160 ⁇
  • the solid particles of fumarate ester comprise a distribution of particle sizes, comprising particles of any of the foregoing particle sizes.
  • the solid fumarate ester particles have mean particle size distributions (PSD) ranging from about 20 ⁇ to about 300 ⁇ , including all integers and fractions within the specified range.
  • the solid particles of fumarate ester comprise mean particle size distributions of about 20 ⁇ , about 30 ⁇ , about 40 ⁇ , about 50 ⁇ , about 60 ⁇ , about 70 ⁇ , about 80 ⁇ , about 90 ⁇ , about 100 ⁇ , about 120 ⁇ , about 140 ⁇ , about 160 ⁇ , about 180 ⁇ , about 190 ⁇ , about 200 ⁇ , about 220 ⁇ , about 240 ⁇ , about 260 ⁇ , about 280 ⁇ , or about 300 ⁇ .
  • the solid particles of fumarate ester have a mean particle size distribution of about 260 ⁇ .
  • the solid particles of fumarate ester have a mean particle size distribution of about 170 ⁇ .
  • the solid particles of fumarate ester have a mean particle size distribution of about 140 ⁇ . In one aspect, the solid particles of fumarate ester have a mean particle size distribution of about 100 ⁇ . In one aspect, the solid particles of fumarate ester have a mean particle size distribution of about 90 ⁇ . In one aspect, the solid particles of fumarate ester have a mean particle size distribution of about 80 ⁇ . In one aspect, the solid particles of fumarate ester have a mean particle size distribution of about 25 ⁇ .
  • the solid fumarate ester particles have a particle size distribution with a d90 of less than or equal to about 500 ⁇ .
  • the particle size distribution of solid particles of fumarate ester have a d90 of ⁇ to about 20 ⁇ , about 30 ⁇ , about 40 ⁇ , about 50 ⁇ , about 60 ⁇ , about 70 ⁇ , about 80 ⁇ , about 90 ⁇ , about 100 ⁇ , about 120 ⁇ , about 140 ⁇ , about 160 ⁇ , about 180 ⁇ , about 190 ⁇ , about 200 ⁇ , about 220 ⁇ , about 240 ⁇ , about 260 ⁇ , about 280 ⁇ , about 300 ⁇ , or about 400 ⁇ .
  • the solid particles of fumarate ester have a particle size distribution with a d90 of ⁇ about 260 ⁇ (d90 ⁇ 260 ⁇ ). In one aspect, the solid particles of fumarate ester have a particle size distribution with a d90 of ⁇ about 170 ⁇ (d90 ⁇ 170 ⁇ ). In one aspect, the solid particles of fumarate ester have a particle size distribution with a d90 of ⁇ about 140 ⁇ (d90 ⁇ 140 ⁇ ). In one aspect, the solid particles of fumarate ester have a particle size distribution with a d90 of ⁇ about 100 ⁇ (d90 ⁇ 100 ⁇ ).
  • the solid particles of fumarate ester have a particle size distribution with a d90 of ⁇ about 90 ⁇ (d90 ⁇ 90 ⁇ ). In one aspect, the solid particles of fumarate ester have a particle size distribution with a d90 of ⁇ about 80 ⁇ (d90 ⁇ 80 ⁇ ). In one aspect, the solid particles of fumarate ester have a particle size distribution with a d90 of ⁇ about 25 ⁇ (d90 ⁇ 25 ⁇ ).
  • the solid fumarate ester particles have a mean particle size distribution comprising a range of particle sizes with a dlO of ⁇ 10 ⁇ and a d90 of ⁇ 500 ⁇ .
  • the solid particles of fumarate ester have a particle size distribution with a dlO of ⁇ to about 10 ⁇ and a d90 of ⁇ to about 400 ⁇ , a dlO of ⁇ to about 10 ⁇ and a d90 of ⁇ to about 300 ⁇ , a dlO of ⁇ to about 10 ⁇ and a d90 of ⁇ to about 250 ⁇ , a dlO of ⁇ to about 10 ⁇ and a d90 of ⁇ to about 200 ⁇ , a dlO of ⁇ to about 10 ⁇ m and a d90 of ⁇ to about 150 ⁇ , a dlO of ⁇ to about 10 ⁇ and a d90 of ⁇ to about 100 ⁇ .
  • the solid particles of fumarate ester have a particle size distribution with a dlO of ⁇ to about 10 ⁇ and a d90 of ⁇ to about 100 ⁇ , a dlO of ⁇ to about 20 ⁇ and a d90 of ⁇ to about 100 ⁇ , a dlO of ⁇ to about 30 ⁇ and a d90 of
  • ⁇ to about 100 ⁇ a dlO of ⁇ to about 40 ⁇ m and a d90 of ⁇ to about 100 ⁇ , a dlO of ⁇ to about 50 ⁇ and a d90 of ⁇ to about 100 ⁇ , a dlO of ⁇ to about 60 ⁇ m and a d90 of ⁇ to about 100 ⁇ , a dlO of ⁇ to about 70 ⁇ and a d90 of ⁇ to about 100 ⁇ , a dlO of ⁇ to about 80 ⁇ m and a d90 of
  • the solid particles of fumarate ester comprise multiple distributions of particle sizes.
  • the solid particles of fumarate ester may comprise a plurality of independently combined mean particle size distributions, wherein each independent mean particle size distribution ranges from about 20 ⁇ to about 300 ⁇ , including all integers and fractions within the specified range.
  • the plurality of mean particle size distributions can comprise a mean particle size distribution of about 261 ⁇ , a mean particle size distribution of about 168 ⁇ , a mean particle size distribution of about 148 ⁇ , a mean particle size distribution of about 100 ⁇ , a mean particle size distribution of about 90 ⁇ , a mean particle size distribution of about 80 ⁇ , or a mean particle size distribution of about 26 ⁇ .
  • the plurality of mean particle size distributions can comprise combinations of independent mean particle size distributions, wherein each independently combined mean particle size distribution is about 261 ⁇ , about 168 ⁇ , about 148 ⁇ , about 100 ⁇ ; about 90 ⁇ , about 80 ⁇ , or about 26 ⁇ .
  • the solid particles of fumarate ester comprise a combination of independently combined mean particle size distributions of about 30 ⁇ to about 260 ⁇ in a single matrix fill. Any of the foregoing particle size distributions may be combined to provide the desired controlled release profile.
  • the forgoing sizes of fumarate ester particles may be determined using standard techniques known to one of ordinary skill in the art.
  • the exemplary techniques that can be used for measuring the size of fumarate ester particles may include laser diffraction analysis, light scattering (e.g., dynamic light scattering), microscopic particle image analysis, elutriation, or aerosol mass spectrometry.
  • the sample of fumarate ester particles may be measured as a dry sample or a wet sample. Any commercially available instrument for measuring particle sizes may be used, including instruments from Cilas; Brookhaven Instruments Corporation; Malvern Instruments; Horiba Scientific; or Wyatt following the recommended operating procedures according to the manufacturer's instructions.
  • the measured particle sizes using the techniques described herein may be expressed as a derived diameter with a normal distribution or non-normal distribution with a mean, median (e.g., mass median diameter), and mode of particle diameter sizes.
  • the particle size distribution may be expressed as a diameter number distribution, a surface area distribution, or a particle volume distribution.
  • the mean of the particle size distribution may be calculated and expressed in various ways, such as the volume mean diameter (D[4,3] or dni), mean surface area diameter (D[3,2] or d-ii) or the mean number particle diameter (D[1,0] or dio). Because the particle size distribution values vary depending on the measurement methodology and how the distribution is expressed, the comparison of different mean particle size distributions must be calculated by the same methodology in order to yield an accurate comparison.
  • a sample with a measured and calculated volume mean diameter must be compared with a second sample having a measured and calculated volume mean diameter, ideally measured using the same measuring instrument under the same conditions.
  • the specific particle size distributions described herein are not intended to be limited to any one type of method for measuring or calculating a particle size distribution (e.g., a diameter number distribution, a surface area distribution, or a particle volume distribution), but rather indicate particle size values and distributions thereof for each method of measuring particle sizes described herein.
  • Another embodiment described herein is a method for manufacturing a fill for a controlled release pharmaceutical composition
  • a fill for a controlled release pharmaceutical composition comprising particles of fumarate esters such as dimethyl fumarate, monomethyl fumarate, or combinations thereof of defined sizes.
  • the particles are of a similar size distribution.
  • the fumarate ester particles comprise varied size distributions.
  • the fumarate ester particles comprise several size distributions.
  • the fumarate ester particles comprise a mixture of smaller and larger size distributions.
  • smaller particles are generally solubilized and released more rapidly than larger particles. The release rate can be adjusted to achieve a specific therapeutic window over a defined period and produce controlled release, delayed release, or extended release compositions by combining multiple fumarate ester particle sizes or size distributions.
  • Another embodiment described herein is a method for manufacturing a pharmaceutical composition comprising fumarate ester(s) where the fumarate ester does not sublime during processing, manufacturing, after production, or during storage.
  • Soft capsules comprising fumarate ester in the matrix fills described herein are stable for months or years. Without being bound to any theory, it is believed that suspending solid fumarate ester in a lipid or lipophilic vehicle prevents or retards sublimation and stabilizes the fumarate ester.
  • the pharmaceutical compositions described herein are stable at 25 °C and 60% relative humidity (RH) for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 24 months, or even longer.
  • RH relative humidity
  • the pharmaceutical compositions described herein are stable for at least 1 year, or longer at 25 °C and 60% RH.
  • the pharmaceutical compositions described herein are stable for at least 2 years, or longer at 25 °C and 60% RH.
  • FIG. 1 Another embodiment described herein is a method for preparing a pharmaceutical matrix comprising a fumarate ester.
  • An exemplary scheme of a manufacturing process is shown in Figure 1.
  • the method comprises applying heat to the matrix components during mixing or prior to mixing at about the melting point of the matrix fill composition; and then mixing the fumarate ester with the lipid or lipophilic matrix ingredients using mechanical or ultrasonic forces to form the matrix fill.
  • the matrix fill is flowable such that it can be encapsulated using a rotary die encapsulation machine.
  • the matrix components are heated to a temperature in the range of from about 25 °C to about 70 °C.
  • the matrix components are heated to a temperature in the range of from about 25 °C to about 30 °C.
  • the matrix comprises a lipid or lipophilic vehicle, solid particles of one or more fumarate esters, an optional neutralizing agent, and optional pharmaceutically acceptable excipients.
  • the matrix comprises oils, polyvinylpyrrolidones, and surfactants.
  • the surfactant comprises polysorbate 80 or polyoxyl 40 hydrogenated castor oil.
  • the matrix comprises, a mixture of mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and solid particles of one or more fumarate esters.
  • the matrix comprises one or more oils, and solid particles of one or more fumarate esters.
  • the solid particles of one or more fumarate esters are soluble in the matrix fill.
  • the matrix comprises the composition shown in Table 1 including all possible iterations of the specified ranges that provide 100% total weight percentage.
  • the matrix comprises about 29% by weight of fumarate ester (PSD: d90 ⁇ 100 ⁇ ); about 50% by weight of a mixture of mono- and di-glycerides; at least about 1- 15%) by weight of polyvinylpyrrolidone; at least about 2-10% by weight of polyoxyl 40 hydrogenated castor oil, and at least about 0-5% by weight of lactic acid, including all iterations of the specified ranges.
  • the composition prevents sublimation of the FAE during processing and manufacturing.
  • the composition reduces the onset of symptoms of gastrointestinal side effects.
  • the composition is stable for at least 6 months at 25 °C and 60% relative humidity. In one aspect, the composition is stable for at least 24 months.
  • the composition comprises one of those shown in Table 2 including all possible iterations of the specified ranges that provide 100% total weight percentage.
  • the matrix fill comprises about 32% to 35% of fumarate ester (PSD: d90 ⁇ 100 ⁇ ); about 20% to about 50% of a mixture of mono- and di-glycerides; at least about 0.75-5%) polyvinylpyrrolidone; at least about 2-12% polyoxyl 40 hydrogenated castor oil; and at least about 0-5% lactic acid, including each integer within each of the specified ranges.
  • the lactic acid is optional.
  • the matrix fill comprises about 32%) to 35% of fumarate ester (PSD: d90 ⁇ 100 ⁇ ) and about 65% to about 70% of soybean oil, including each integer within each of the specified ranges.
  • the lactic acid is optionally added to the soybean oil matrix.
  • the composition prevents sublimation of the FAE during processing and manufacturing. In another aspect, the composition reduces the onset of symptoms of any gastrointestinal side effects. In another aspect, the composition is stable for at least 6 months at 25 °C and 60% relative humidity. In another aspect, the composition is stable for at least 24 months at 25 °C and 60% relative humidity. In another aspect, the composition is liquid at room temperature.
  • the fumarate ester pharmaceutical composition comprises a capsule dosage form. In one embodiment, the fumarate ester pharmaceutical composition comprises a soft capsule encapsulating a matrix fill comprising a liquid lipid or lipophilic fill comprising one or more fumarate esters.
  • the soft capsule shell has the composition of Table 3, including all possible iterations of the specified ranges that provide 100% for the total weight percentage, including or excluding optional colorings, opacifiers, flavorings, or other excipients.
  • Film-former polymers that are useful for creating soft capsules are gelatin, hydroxypropylmethylcellulose (UPMC) or carrageenan (e.g., iota carrageenan and kappa carrageenan).
  • the film-forming polymer is gelatin.
  • gelatin compositions that are useful for creating soft capsule shells as described herein comprise acid bone gelatin, pig skin gelatin, chicken skin gelatin, fish gelatin, acid hide gelatin, gelatin hydrolysate, lime bone gelatin, or combinations thereof.
  • Gelatins that are useful for creating soft capsules described herein can be classified as either Type A or Type B gelatin.
  • Type A gelatin is derived from the acid hydrolysis of collagen (e.g., acid bone gelatin or pig skin gelatin), while Type B gelatin (e.g., lime bone gelatin) is derived from the alkaline hydrolysis of collagen.
  • Type B gelatin e.g., lime bone gelatin
  • bovine bones and skins are used as raw materials for manufacturing Type A and Type B gelatin, while porcine skins are used extensively for manufacturing Type A gelatin.
  • Type A gelatins (acid processed gelatins) are typically net cationic (e.g., isoelectric point of about 7-9)
  • Type B gelatins alkali processed gelatins
  • Type A gelatin typically has higher plasticity and elasticity than type B gelatin; type B gelatin typically has higher gel strength than type A gelatin.
  • the strength of gelatin compositions is typically defined by their Bloom strength or grade.
  • the Bloom test determines the weight (in grams) needed by a 0.5-inch diameter probe to deflect the surface of a gel 4 mm without breaking it. The result is expressed as "Bloom” or "Bloom strength.”
  • the soft capsules described herein utilize gelatins with Bloom strengths in the range of about 20 Bloom to about 400 Bloom, including each integer within the specified range.
  • Bloom strengths for soft capsules described herein are about 50 Bloom to about 250 Bloom including each integer within the specified range.
  • the gelatin Bloom strenght is about 50 Bloom, about 80 Bloom, about 100 Bloom, about 120 Bloom, about 150 Bloom, about 180 Bloom, about 200 Bloom, or about 250 Bloom.
  • the gelatin Bloom strength is 100 Bloom.
  • the gelatin Bloom strength is 150 Bloom.
  • the gelatin Bloom strength is 195 Bloom.
  • the gelatin Bloom strength is 200 Bloom.
  • Plasticizers that are useful for creating soft capsules as described herein are glycerol, sorbitol, partially dehydrated sorbitol (a blend of D-sorbitol, 1,4-sorbitan, mannitol, and water; e.g., Sorbitol Special ® (SPI Pharma); Anidrisorb ® or Polysorb ® , (Roquette)), maltitol (hydrogenated corn syrup; e.g., Lycasin ® , Roquette), corn syrup, xylitol, mannitol, propylene glycol, low molecular weight polyethylene glycols, poly-alcohols with 3 to 6 carbon atoms, or a combination thereof.
  • Plasticizers typically comprise about 10-30% of the total wet mass of a shell, including each integer within the specified range. The weight ratio between the film-forming polymer, plasticizer, and solvent is adjusted so that the gel mass is flowable and not too viscous, and can be made into soft capsules using rotary die encapsulation methods.
  • the soft capsule shell has the exemplary composition shown in Table 4.
  • the weight percentage range of film-forming polymer of the soft capsule described herein is about 20% to about 50%, including all integers within the specified range. In one aspect, the film-forming polymer weight percentage is about 38%>. In another aspect, the film-forming 1 polymer weight percentage is about 42%. In another aspect, the film-forming polymer weight percentage is about 44%.
  • the weight percentage range of plasticizer is about 15%> to about 30%>, including all iterations of integers with the specified range. In one aspect, the plasticizer weight percentage is about 24%. In another aspect, the plasticizer weight percentage is about 22%. In another aspect, the plasticizer weight percentage is about 20%.
  • the solvent comprises about 20% to about 40% of the soft capsule composition, including all integers and fractions within the specified range.
  • the solvent is water.
  • the quantity of water in the composition varies depending on the quantities of the other ingredients. For example, the quantity of plasticizer, opacifier, colorant, flavoring, or other excipients can change the percentage of water present in the composition.
  • the weight percentage of water is as much as suffices to bring the total weight percentage to 100% (i.e., quantum sufficiat; q.s.).
  • the water comprises about 20%), about 25%, about 30%, about 35%, or about 40% of the enteric soft capsule composition.
  • water comprises about 30% to about 40% of the enteric soft capsule composition.
  • water comprises about 34% of the composition.
  • the final moisture (water) content of the soft capsule after manufacturing and drying is from about 8% to about 15%, including all integers and fractions within the specified range. In another embodiment, the moisture content is about 8% to about 12%), including all integers and fractions within the specified range. In one aspect, the final moisture content is about 12%. In one aspect, the final moisture content is about 11%. In one aspect, the final moisture content is about 10%. In one aspect, the final moisture content is about 9%. In another aspect, the final moisture content is about 8%.
  • the weight percentage ratio range of plasticizer to film-forming polymer is about 0.33 : 1 to about 0.56: 1, including all iterations of iterations of ratios with the specified range. In one embodiment, the weight percentage ratio range of plasticizer to film- forming polymer is about 0.38: 1. In one embodiment, the weight percentage ratio range of plasticizer to film-forming polymer is about 0.42: 1. In one embodiment, the weight percentage ratio range of plasticizer to film-forming polymer is about 0.46: 1. In one embodiment, the weight percentage ratio range of plasticizer to film-forming polymer is about 0.52: 1.
  • the soft capsule comprises about 42% of at least one film-forming polymer; about 24% of at least one plasticizer; and about 34% water.
  • the soft capsule shell has the exemplary composition shown in Table 5
  • the soft gel capsule shell has the exemplary composition shown in Table 6.
  • soft capsules are made using a rotary die apparatus as described in U.S. Patent Nos. 5,459,983; 5, 146,730; and 6,482,516, each of which are incorporated by reference herein for such teachings.
  • Another embodiment described herein includes a process of manufacturing soft capsules comprising any of the pharmaceutical composition as described herein.
  • the process includes preparing a gel mass composition comprising a film-forming, water-soluble polymer, an appropriate plasticizer, and solvent; casting the gel mass into films or ribbons using heat-controlled drums or surfaces; and manufacturing a soft capsule comprising a matrix fill using rotary die technology.
  • the thickness of the films or ribbons that form the soft capsule shell is from about 0.010 inches (-0.254 mm) to about 0.050 inches (-1.27 mm), including all integers within the specified range.
  • the shell thickness can be about 0.010 inch (-0.254 mm), about 0.015 inch (-0.381 mm), about 0.02 in (-0.508 mm), about 0.03 in (-0.762 mm), about 0.04 in (-1.02 mm), or about 0.05 in (-1.27 mm). In one embodiment, the thickness is about 0.02 inches (-0.508 mm) to about 0.040 inches (-1.02 mm). In one embodiment, the shell thickness is about 0.028 inches (-0.711 mm). In another embodiment, the shell thickness is about 0.033 inches (-0.838 mm). In another embodiment, the shell thickness is about 0.038 inches (-0.965 mm). In another embodiment, the shell thickness is about 0.035 inches (-0.889 mm). In another embodiment, the shell thickness is about 0.038 inches (-0.965 mm). In another embodiment, the shell thickness is about 0.040 inches (-1.02 mm).
  • the soft capsule shell described herein encapsulates a matrix fill as described herein.
  • the soft capsule shell and encapsulated matrix fill comprises an outer dimension from about 2 oval to about 30 oval including all iterations of capsule size within the specified range (e.g., 2 oval, 3 oval, 4 oval, 5 oval, 6 oval, 7 oval, 8 oval, 10 oval, 12 oval, 16 oval, 20, or 30 oval).
  • the soft capsule shell and encapsulated matrix fill comprises an outer dimension from about 2 round to about 28 round including all iterations of capsule size within the specified range (e.g., 2 round, 3 round, 4 round, 5 round, 6 round, 7 round, 8 round, 10 round, 12 round, 16 round, 20 round or 28 round).
  • the soft capsule shell and encapsulated matrix fill comprises an outer dimension from about 2 oblong to about 22 oblong including all iterations of capsule size within the specified range (e.g., 2 oblong, 3 oblong, 4 oblong, 5 oblong, 6 oblong, 7 oblong, 8 oblong, 10 oblong, 11, oblong, 12 oblong, 14 oblong, 16 oblong, 20 oblong, or 22 oblong).
  • Dimension specifications of soft capsules and tablets are known to those skilled in the art. See Remington 's Essentials of Pharmaceutics, Pharmaceutical Press Publishing Company, London, UK, 1 st Edition, 2013, which is incorporated by reference herein for such teachings.
  • the fumarate ester pharmaceutical composition can comprise an enteric soft capsule shell comprising a matrix comprising a fumarate ester.
  • Enteric soft capsules e.g., soft capsules having enteric polymers integrated into the capsule shell, are described in International Patent Application Publication No. WO 2004/030658; U.S. Patent Application Publication No. US 2006/0165778; and U.S. Patent No. 8,685,445, each of which is incorporated by reference herein for such teachings.
  • the enteric soft capsule shell may comprise one or more film forming polymers, one or more enteric acid-insoluble polymers, one or more plasticizers, one or more alkali-neutralizing agents, one or more solvents, optionally one or more colorants, and optionally one or more flavorings or other conventionally accepted pharmaceutical excipients or additives.
  • Film-forming polymers that are useful for creating enteric soft capsules are gelatin or hydroxypropylmethylcellulose (HPMC).
  • HPMC hydroxypropylmethylcellulose
  • the film-forming polymer is gelatin.
  • enteric, acid-insoluble polymers examples include acrylic and methacrylate acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate (HPMCP), algenic acid salts such as sodium or potassium alginate, or shellac.
  • Poly(methacylic acid-co-methyl methacrylate) anionic copolymers based on methacrylic acid and methyl methacrylate are particularly stable and are preferred in some embodiments.
  • Poly(meth)acrylates (methacrylic acid copolymer) available under the trade name EUDRAGIT ® (Evonik Industries AG, Essen, Germany), are provided as powder or aqueous dispersions.
  • the methacrylic acid copolymer comprises EUDRAGIT ® L 30 D- 55; EUDRAGIT ® L 100-55; EUDRAGIT ® L 100; EUDRAGIT ® L 12.5; EUDRAGIT ® S 100; EUDRAGIT ® S 12.5; EUDRAGIT ® FS 30 D; EUDRAGIT ® E 100; EUDRAGIT ® E 12.5; EUDRAGIT ® E PO; EUDRAGIT ® RL 100; EUDRAGIT ® RL PO; EUDRAGIT ® RL 30 D; EUDRAGIT ® RL 12.5; EUDRAGIT ® RS 100; EUDRAGIT ® RS PO; EUDRAGIT ® RS 30 D; EUDRAGIT ® RS 12.5; EUDRAGIT ® E 30 D; EUDRAGIT ® E 40 D; EUDRAGIT ® M 30 D; other poly(meth)acrylate polymers; or a mixture thereof.
  • the enteric polymer comprises EUDRAGIT
  • the enteric polymer in the enteric soft capsule shell comprises poly(methacylic acid-co-ethyl acrylate) 1 : 1 (e.g., EUDRAGIT ® L 100-55). In one embodiment described herein, the enteric polymer comprises poly(ethyl acrylate-co-methyl methacrylate) 2: 1 (e.g., EUDRAGIT ® NE 40 D). In another embodiment described herein, the enteric polymer comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3 : 1 (e.g., EUDRAGIT ® FS 30 D).
  • the enteric polymer comprises a combination of poly(methacylic acid-co-ethyl acrylate) 1 : 1 and poly(methyl acrylate- co-methyl methacrylate-co-methacrylic acid) 7:3 : 1.
  • the enteric polymer comprises a combination of poly(methacylic acid-co-ethyl acrylate) 1 : 1 and poly(ethyl acrylate- co-methyl methacrylate) 2: 1.
  • the enteric polymer comprises a combination of poly(methacylic acid-co-ethyl acrylate) 1 : 1, poly(ethyl acrylate-co-methyl methacrylate) 2: 1, and poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3 : 1.
  • plasticizers that are useful for creating enteric soft capsules as described herein are glycerol, sorbitol, Sorbitol Special ® , maltitol, corn syrup, propylene glycol, poly-alcohols with 3 to 6 carbon atoms, polyethylene glycol, citric acid, citric acid esters, such as tri-ethyl citrate, or combinations thereof.
  • the weight ratio between the film-forming polymer, the enteric acid-insoluble polymer, and plasticizer is adjusted so that the gel mass is flowable and not too viscous, and can be made into soft capsules using rotary die encapsulation methods.
  • enteric soft capsule shell compositions are made by dissolving the enteric acid-insoluble polymer in an aqueous solution of an alkali-neutralizing agent such as ammonia, sodium hydroxide, potassium hydroxide, or liquid amines such as tri-ethanol amine or ethylene diamine.
  • an alkali-neutralizing agent such as ammonia, sodium hydroxide, potassium hydroxide, or liquid amines such as tri-ethanol amine or ethylene diamine.
  • the amount of alkali is adjusted to give a final pH value of the gel mass less than or equal to about pH 9.0. In one embodiment, the final pH does not exceed 8.5.
  • the volatile alkali-neutralizing agent, ammonia is preferred.
  • the film-forming polymer can then be combined with the plasticizer and solvent and then blended with the acid-insoluble gel to make a final homogeneous mix in a heat-controlled vessel with degassing by vacuum.
  • the fugitive ammonia evaporates during degassing.
  • the enteric soft capsule shell is made using an aqueous dispersion of the acid-insoluble polymer by adding an alkali-neutralizing agent such as ammonium, sodium, or potassium hydroxides, other alkalis, or a combination thereof that will cause the enteric acid-insoluble polymer to dissolve.
  • an alkali-neutralizing agent such as ammonium, sodium, or potassium hydroxides, other alkalis, or a combination thereof that will cause the enteric acid-insoluble polymer to dissolve.
  • the plasticizer-wetted, film-forming polymer can then be mixed with the solution of the acid-insoluble polymer.
  • enteric acid-insoluble polymers in the form of salts of the bases or alkalis as described herein are dissolved directly in water and mixed with the plasticizer-wetted, film-forming polymer.
  • enteric acid-insoluble polymers in the form of salts of the bases or alkalis described herein are dissolved directly in water and mixed with the plasticizer-wetted, film-forming polymer.
  • an aqueous dispersion of the acid-insoluble polymer or polymers is used, which obviates the need for the addition of the alkali-neutralizing agent described herein.
  • the enteric soft capsule shell has the composition of Table 7, including all possible iterations of the specified ranges that provide 100% for the total weight percentage, including or excluding the optional, excipients, opacifiers, colorants, and flavorings.
  • the enteric soft capsule shell comprises a composition of about 30% film forming polymer; about 10% enteric, acid-insoluble polymer; about 20% plasticizer; about 1%) alkali-neutralizing agent; and about 37% solvent.
  • the weight percentage range of total polymer content (i.e., film forming polymer and enteric acid-insoluble polymer) of the enteric soft capsule described herein is about 30% to about 45%, including all integers and fractions within the specified range.
  • the total polymer weight percentage is about 40%.
  • the total polymer weight percentage is about 42%.
  • the total polymer weight percentage is about 45%).
  • the total polymer weight percentage is about 38%.
  • the weight percentage range of total plasticizer is about 15% to about
  • the total plasticizer weight percentage is about 19%. In another aspect, the total plasticizer weight percentage is about 17.7%. In another aspect, the total plasticizer weight percentage is about 18.9%). In another aspect, the total plasticizer weight percentage is about 19.3%.
  • the alkali-neutralizing agent is ammonia (ammonium hydroxide; 30% w/v) that is added to comprise a weight percentage of about 1% to about 5% of the total enteric soft capsule composition. In one aspect, 30% w/v ammonia is added to comprise a weight percentage of about 2%. In another aspect, 30% w/v ammonia is added to comprise a weight percentage of about 1.1%. In one aspect, ammonia is added to provide a final pH of about 9 in the enteric soft capsule composition. In another aspect, ammonia is added to provide a final pH of about 8.5 in the enteric soft capsule composition.
  • ammonia ammonia (ammonium hydroxide; 30% w/v) that is added to comprise a weight percentage of about 1% to about 5% of the total enteric soft capsule composition. In one aspect, 30% w/v ammonia is added to comprise a weight percentage of about 2%. In another aspect, 30% w/v ammonia is added to comprise a weight percentage of about 1.1%.
  • the ammonia concentration is substantially reduced, owing to the fugitive nature of the volatile alkali-neutralizing agent.
  • practically all of the ammonia is evaporated except for ammonium ions comprising salts with other moieties in the composition.
  • the weight ratio range of film forming polymer to enteric acid- insoluble polymer is about 25 :75 (-0.33) to about 40:60 (-0.67) (i.e., -0.33-0.67), including all ratios within the specified range.
  • the ratio of film forming polymer to enteric acid-insoluble polymer is about 30:70 (-0.43).
  • the ratio of film forming polymer to enteric acid-insoluble polymer is about 28:72 (-0.38).
  • the weight ratio of total plasticizer to film forming polymer is about
  • the weight ratio of total plasticizer to film forming polymer is about 20:40 (-0.5). In another aspect, the weight ratio of total plasticizer to film forming polymer is about 21 :30 (-0.7). In another aspect, the weight ratio of total plasticizer to film forming polymer is about 19:29 (-0.65). In another aspect, the weight ratio of total plasticizer to film forming polymer is about 19.3 :29.2 (-0.66).
  • the weight ratio of total plasticizer to enteric acid-insoluble polymer is about 1 : 1 to about 2: 1 (-1-2), including all ratios within the specified range. In one aspect, the weight ratio of total plasticizer to enteric acid-insoluble polymer is about 11 : 10 (-1.1). In another aspect, the weight ratio of total plasticizer to enteric acid-insoluble polymer is about 14: 10 (-1.4). In another aspect, the weight ratio of total plasticizer to enteric acid-insoluble polymer is about 17: 10 (-1.7). In another aspect, the weight ratio of total plasticizer to enteric acid-insoluble polymer is about 20: 10 (-2). In another aspect, the weight ratio of total plasticizer to enteric acid- insoluble polymer is about 19.3 : 11.2 (-1.73).
  • the weight ratio range of total plasticizer to total polymer is about 18:45 to about 20:40 (i.e., -0.40-0.5), including all ratios within the specified range.
  • the weight ratio range of total plasticizer to total polymer is about 18:45 (-0.40).
  • the weight ratio range of total plasticizer to total polymer is about 19:40 (-0.475).
  • the weight ratio range of total plasticizer to total polymer is about 20:40 (-0.5).
  • the weight ratio range of total plasticizer to total polymer is about 19.3 :40.4 (-0.477).
  • the solvent comprises about 20% to about 40% of the enteric soft capsule composition, including all integers and fractions within the specified range.
  • the solvent is water.
  • the quantity of water in the composition varies depending on the quantities of the other ingredients. For example, the quantity of opacifier, colorant, flavoring, or other excipients can change the percentage of water present in the composition.
  • the weight percentage of water is as much as suffices to bring the total weight percentage to 100% (i.e., quantum sufficiat; q.s.).
  • the water comprises about 20%), about 25%>, about 30%>, about 35%>, or about 40%> of the enteric soft capsule composition.
  • water comprises about 35%> to about 40%> of the enteric soft capsule composition.
  • water comprises about 37%> of the composition.
  • the final moisture (water) content of the enteric soft capsule is from about 8% to about 15%, including all integers and fractions within the specified range.
  • the moisture content is about 8% to about 12%, including all integers and fractions within the specified range.
  • the final moisture content is about 8%.
  • the final moisture content is about 9%.
  • the final moisture content is about 10%.
  • the final moisture content is about 1 1%.
  • the final moisture content is about 12%.
  • the enteric soft capsule shell has the exemplary composition shown in Table 8
  • the enteric soft capsule shell comprises about 30% gelatin; about 10% poly(methyl) acrylate copolymer; about 18% glycerol; about 1% triethyl citrate; about 1.5% ammonia; about 37% water; and about 1.5% titanium dioxide.
  • enteric soft capsule is described in U. S. Patent Application No.
  • One embodiment described herein provides an enteric acid-insoluble polymer dispersed within the film-forming polymer gel mass that provides the total soft gel composition with enteric acid-insoluble properties, at relatively low concentrations of the enteric acid-insoluble polymer (e.g., from about 8% to about 20% of the total wet gel mass composition) and without the need of excessive amounts of alkali, thus avoiding denaturation or degradation of the film-forming polymer that can weaken the integrity of the enteric soft capsule shell.
  • relatively low concentrations of the enteric acid-insoluble polymer e.g., from about 8% to about 20% of the total wet gel mass composition
  • Films of the enteric soft capsule shell do not dissolve or disintegrate in acids, such as 0.1
  • N hydrochloric acid or simulated gastric fluid (ca. pH 1.2), despite the fact that the majority of the shell ingredients (i.e., greater than 50%) normally dissolve in, or are miscible with, acids.
  • Enteric soft capsules made using the compositions described herein remain intact in hydrochloric acid or simulated gastric fluid for at least two hours. The capsules readily release the contents upon shifting the pH of the solution to ca. 6.8, such as that of simulated intestinal fluid.
  • the final enteric capsule composition provides films of increased strength without substantially compromising film elasticity.
  • films made from the enteric soft capsule compositions as described herein are sealed at normal temperature range typically used for making traditional soft gel capsules.
  • enteric soft capsules are made using a rotary die apparatus as described herein.
  • Another embodiment described herein includes a process of manufacturing enteric soft capsules comprising the pharmaceutical composition as described herein.
  • the process includes preparing a gel mass composition comprising a film-forming, water-soluble polymer and an enteric acid-insoluble polymer and mixing with appropriate plasticizers and solvent; casting the gel mass into films or ribbons using heat-controlled drums or surfaces; and manufacturing a soft capsule comprising a matrix fill using rotary die technology.
  • the thickness of the films that form the enteric capsule and the dimensions of the capsules are similar to those described herein.
  • enteric soft capsules are "traditional" soft capsules coated with an enteric coating.
  • enteric soft capsules are soft capsules having enteric polymers embedded within the capsule shell (e.g., an enteric soft capsule) and are coated with an enteric coating.
  • enteric coatings in addition to providing acid-resistance or pH-dependently release, also prevent the influx of water or other solvents into soft capsules or soft capsules having enteric polymers imbedded in the shell wall that solubilize the fumarate ester and facilitate diffusion of the fumarate ester out of the capsule.
  • soft capsules are coated with an enteric coating comprising the exemplary composition shown in Table 9.
  • Enteric polymers useful for enteric coatings include pH-dependent polymers that are less soluble in an aqueous media with acidic pH and more soluble in an aqueous media with basic pH.
  • the enteric of pH dependent material dissolves or rapidly disperses at a pH level above pH 5.0, above pH 5.5, or above pH 6.0.
  • Exemplary enteric polymers useful for coats include cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylcellulose, methacrylic acid copolymers such as, Eudragit L (polymethacrylic acid, methylmethacrylate, 1 : 1 ratio), or Eudragit S (polymethacrylic acid, methylmethacrylate, 1 :2 ratio), shellac, zein, or combinations thereof.
  • Eudragit L polymethacrylic acid, methylmethacrylate, 1 : 1 ratio
  • Eudragit S polymethacrylic acid, methylmethacrylate, 1 :2 ratio
  • shellac zein
  • Suitable plasticizers include acetyl triethyl citrate, dibutyl phthalate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, propylene glycol, triacetin, polyethylene glycol, diethyl phthalate, or combinations thereof.
  • Suitable solubilizers include sodium lauryl sulfate, sodium lauroyl sarcosinate sodium dodecyl sulfate, polysorbate 20, polysorbate 80, other detergents or surfactants, or combinations thereof.
  • Anti-adherent agents serve to prevent potential agglomeration in acid media.
  • Suitable anti- adherents include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, polyethylene glycols, fumed silica, silicon dioxide, or combinations thereof.
  • Pore-forming agents serve to create pores or channels in the enteric coating after administration to a human.
  • Suitable pore-forming agents include sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycols (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohols, methacrylic acid copolymers, poloxamers, or combinations thereof.
  • the enteric coating comprises methacrylic acid and ethyl acrylate copolymer (e.g., EUDRAGIT ® L100-55, Evonik), talc, triethyl citrate, sodium bicarbonate, colloidal silica, sodium lauryl sulfate, and water.
  • methacrylic acid and ethyl acrylate copolymer e.g., EUDRAGIT ® L100-55, Evonik
  • talc e.g., EUDRAGIT ® L100-55, Evonik
  • triethyl citrate e.g., sodium bicarbonate
  • colloidal silica sodium lauryl sulfate
  • water water
  • adjusting the amount of enteric coating and the ratio of polymer to other components allows for tuning the release profile of the dosage form.
  • Subcoats can be applied to the soft capsules prior to coating to prevent shell-coat interactions and improve coating adhesion to the capsule.
  • Exemplary subcoatings can comprise polyvinylpyrrolidone, polyvinyl alcohols, hydroxpropyl methylcellulose, polyethylene glycol, oils, or combinations thereof.
  • Coatings, top coatings, or subcoatings are applied to the soft capsules using various methods know in the art.
  • the coatings are typically prepared as suspensions and sprayed on capsules in perforated coating pans through one or more spray nozzles at a specific temperature.
  • Coating solutions or dispersion may be applied at spray rates between 100 and 400 g/min. The spray rate may be proportionately higher for coatings with higher solid content and lower for more dilute dispersions.
  • capsules are coated using a pan coater. After the enteric coating suspension is applied, the coated capsules are dried in the pan coater for a period of time at a specific temperature.
  • Another embodiment described herein comprises a subcoating that is applied prior to applying an enteric coating.
  • the subcoating comprises hydroxpropyl methylcellulose, methylcellulose, ethylcellulose, or a combination thereof.
  • the moisture barrier comprises one or more polyvinyl alcohols and appropriate pharmaceutically acceptable excipients.
  • the moisture barrier comprises polyvinyl alcohol, sodium lauryl sulfate, glyceryl mono-caprylate- caprate, and talc.
  • the moisture barrier aids in preserving the cosmetic appearance of the dosage forms by preventing dimpling, sticking, or other processing or storage induced blemishes.
  • the fumarate ester pharmaceutical composition can comprise an enteric hard capsule shell comprising a matrix comprising a fumarate ester.
  • the fumarate ester pharmaceutical composition can comprise a hard capsule shell comprising a matrix comprising a fumarate ester.
  • the pharmaceutical compositions described herein can contain a matrix fill that is liquid, semi-solid, or solid.
  • Capsules prepared as described herein can contain hydrophobic solutions or suspensions, such as vegetable oils, shortening, waxes, or combinations thereof.
  • the matrix fill can be formulated to prevent interaction with the capsule shell components and release the pharmaceutical composition at a specified rate.
  • One embodiment described herein is a pharmaceutical composition comprising a matrix fill formulation comprising any of the formulations shown in the Tables or Examples described herein. Any of the components in the formulations described herein, shown in the Tables, or illustrated in the Examples can be increased, decreased, combined, substituted, or omitted to provide for a formulation comprising about 100% by weight. Such compositions are hereby disclosed as if they were expressly disclosed herein.
  • the pharmaceutical compositions described herein provide a dosage form of one or more fumarate esters, or prodrugs thereof, for administration to a subject.
  • the dosage form can be administered, for example, to a subject, or a subject in need thereof.
  • the subject is a mammal, or a mammal in need thereof.
  • the subject is a human, or human in need thereof.
  • the human or human in need thereof is a medical patient.
  • the human subject is a child (-0-9 years old) or an adolescent (-10-17 years old).
  • the subject is from about 0 to about 9 years of age.
  • the human subject is from about 10 years to about 17 years of age.
  • the human subject is over 17 years of age.
  • the human subject is an adult (>18 years of age).
  • the dosage form can be administered, for example, lx, 2*, 3 ⁇ , 4 ⁇ , 5 ⁇ , 6 ⁇ , or even more times per day.
  • One or more dosage forms can be administered, for example, for 1, 2, 3, 4, 5, 6, 7 days, or even longer.
  • One or more dosage forms can be administered, for example, for 1, 2, 3, 4 weeks, or even longer.
  • One or more dosage forms can be administered, for example, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, 1 year, 2, years, 3 years, 4 years, 5 years, over 5 years, a decade, multiple decades, or even longer.
  • One or more dosage forms can be administered at a regular interval until the subject or subject in need thereof, does not require treatment, prophylaxis, or amelioration of any disease or condition including but not limited to, general autoimmune or neurodegenerative disorders.
  • the pharmaceutical composition described herein is administered in multiple doses simultaneously. For example, two or more identical doses are administered at one time. In another embodiment, two or more different doses are administered at one time. Such dual or different simultaneous doses can be used to provide an effective amount of the pharmaceutical composition to a subject in need thereof.
  • the pharmaceutical compositions described herein may be used to treat, prevent, retard the progression of, delay the onset, ameliorate, reduce the symptoms of, or prophylaxis of general autoimmune or neurodegenerative disorders.
  • Neurodegenerative disorders include multiple sclerosis (MS), which includes relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), primary progressive multiple sclerosis (PPMS), progressive relapsing multiple sclerosis (PPvMS), amyotrophic lateral sclerosis (ALS), psoriasis, psoriatic arthritis, Alzheimer's disease, Parkinson's disease, or any combination thereof.
  • MS multiple sclerosis
  • RRMS relapsing remitting multiple sclerosis
  • SPMS secondary progressive multiple sclerosis
  • PPMS primary progressive multiple sclerosis
  • PPvMS progressive relapsing multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • psoriasis psoriatic arthritis
  • other conditions, disorders, or diseases are controlled by administration of fumarate esters.
  • the administration of pharmaceutical compositions comprising fumarate esters, as described herein, may be used for treating, preventing, retarding the progression of, delaying the onset, ameliorating, reducing the symptoms of, or prophylaxis of general autoimmune or neurodegenerative disorders, including but not limited to, acute dermatitis, adrenal leukodystrophy, AGE-induced genome damage, Alexander's disease, alopecia areata (totalis and universalis), Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, angina pectoris, arthritis, asthma, autoimmune diseases, balo concentric sclerosis, Behcet's syndrome, bullous pemphigoid, Canavan disease, cardiac insufficiency including left ventricular insufficiency, central nervous system vasculitis, Charcot-Marie-Tooth disease, childhood ataxia with central nervous system hypomyelination, chronic active (lup)
  • One embodiment described herein comprises a method for orally administering a dosage form that provides a total amount of fumarate ester of about 20 mg to about 1000 mg (e.g., -20- 1000 mg), including all integers and fractions within the specified range.
  • the fumarate ester (FAE) dosage form can comprise, but is not limited to about 50 mg FAE, about 55 mg FAE, about 60 mg FAE, about 65 mg FAE, about 70 mg FAE, about 75 mg FAE, about 80 mg FAE, about 85 mg FAE, about 90 mg FAE, about 95 mg FAE, about 100 mg FAE, about 105 mg FAE, about 110 mg FAE, about 115 mg FAE, about 120 mg FAE, about 125 mg FAE, about 130 mg FAE, about 135 mg FAE, about 140 mg FAE, about 145 mg FAE, about 150 mg FAE, about 155 mg FAE, about 160 mg FAE, about 165 mg FAE, about 170 mg FAE, about 175 mg FAE, about 180 mg FAE, about 185 mg FAE, about 190 mg FAE, about 195 mg FAE, about 200 mg FAE, about 205 mg FAE, about 210 mg FAE, about 215 mg FAE, about 220 mg FAE, about 185 mg FAE, about
  • the foregoing doses comprise a partial dosage, e.g., including but not limited to one dose of a twice, thrice or quadrice daily regimen. In another embodiment, any of the foregoing doses comprise a total daily dosage. In another embodiment, any of the foregoing doses may be administered simultaneously, such as two 95 mg FAE or two 100 mg FAE, to provide 190 mg or 200 mg FAE for a particular dosing period.
  • the fumarate ester (FAE) dosage form can comprise, but is not limited to about 50 mg FAE, about 52 mg FAE, about 54 mg FAE, about 56 mg FAE, about 58 mg FAE, about 60 mg FAE, about 62 mg FAE, about 64 mg FAE, about 66 mg FAE, about 68 mg FAE, about 70 mg FAE, about 72 mg FAE, about 74 mg FAE, about 76 mg FAE, about 78 mg FAE, about 80 mg FAE, about 82 mg FAE, about 84 mg FAE, about 86 mg FAE, about 88 mg FAE, about 90 mg FAE, about 92 mg FAE, about 94 mg FAE, about 96 mg FAE, about 98 mg FAE, about 100 mg FAE, about 102 mg FAE, about 104 mg FAE, about 106 mg FAE, about 108 mg FAE, about 110 mg FAE, about 112 mg FAE, about 114 mg FAE, about 116 mg FAE, about
  • the foregoing doses comprise a partial dosage, e.g., including but not limited to one dose of a twice thrice, or quadrice daily regimen. In another embodiment, any of the foregoing doses comprise a total daily dosage. In another embodiment, any of the foregoing doses may be administered simultaneously, such as two 95 mg FAE or two 100 mg FAE, to provide 190 mg or 200 mg FAE for a particular dosing period.
  • the daily dosage is about 80 mg FAE to about 460 mg FAE including all integers and fractions within the specified range. In another embodiment, the daily dosage is about 90 mg FAE to about 110 mg FAE, including all integers and fractions within the specified range. In another embodiment, the daily dosage is about 95 mg FAE to about 100 mg FAE, including all integers and fractions within the specified range. In another embodiment, the daily dosage is about 90 mg FAE to about 220 mg FAE, including all integers and fractions within the specified range. In another embodiment, the daily dosage is about 100 mg FAE to about 200 mg FAE, including all integers and fractions within the specified range.
  • the daily dosage is about 100 mg FAE to about 220 mg FAE, including all integers and fractions within the specified range. In another embodiment, the daily dosage is about 170 mg FAE to about 200 mg FAE, including all integers and fractions within the specified range. In another embodiment, the daily dosage is about 180 mg FAE to about 200 mg FAE, including all integers and fractions within the specified range. In another embodiment, the daily dosage is about 190 mg FAE to about 200 mg FAE, including all integers and fractions within the specified range. In one embodiment, the daily dosage is about 200 mg FAE to about 220 mg FAE, including all integers and fractions within the specified range.
  • the daily dosage is about 380 mg FAE to about 400 mg FAE, including all integers and fractions within the specified range. In another embodiment, the daily dosage is about 320 mg FAE to about 460 mg FAE, including all integers and fractions within the specified range. In another embodiment, the daily dosage is about 400 mg FAE to about 460 mg FAE, including all integers and fractions within the specified range. In another embodiment, the daily dosage is about 460 mg FAE.
  • the total daily dose may be administered in any number of individual dosage forms that cumulatively total the daily dose. For example, four 95 mg FAE dosage forms may be administered in a regimen of two dosage forms in the morning and two in the evening for a total daily dose of 380 mg FAE. Alternatively, four 95 mg FAE dosage forms may be administered QID (e.g., every six hours) for a total daily dose of 380 mg FAE.
  • the daily dosage can comprise, but is not limited to, a total amount of FAE of about 80 mg FAE, about 82 mg FAE, about 84 mg FAE, about 86 mg FAE, about 88 mg FAE, about 90 mg FAE, about 92 mg FAE, about 94 mg FAE, about 96 mg FAE, about 98 mg FAE, about 100 mg FAE, about 102 mg FAE, about 104 mg FAE, about 106 mg FAE, about 108 mg FAE, about 110 mg FAE, about 112 mg FAE, about 114 mg FAE, about 116 mg FAE, about 118 mg FAE, about 120 mg FAE, about 122 mg FAE, about 124 mg FAE, about 126 mg FAE, about 128 mg FAE, about 130 mg FAE, about 132 mg FAE, about 134 mg FAE, about 136 mg FAE, about 138 mg FAE, about 140 mg FAE, about 142 mg FAE, about 144 mg FAE, about 146 mg FAE,
  • the daily dosage can contain a total amount of fumarate ester effective for treatment of retarding the progression of, prophylaxis of delaying the onset of, amelioration of, or reducing symptoms of multiple sclerosis or psoriasis or other neurodegenerative disorders.
  • the daily dosage is about 380 mg FAE to about 420 mg FAE.
  • the daily dosage is about 380 mg FAE to about 400 mg FAE.
  • the daily dosage is about 380 mg FAE.
  • the daily dosage is about 400 mg FAE.
  • the amount of fumarate ester can comprise about 80 mg to about 500 mg (e.g., 80-500 mg) of fumarate ester, including all integers and fractions within the specified range. In one embodiment, the amount can comprise, but is not limited to, about 80 mg to about 480 mg FAE, including all integers and fractions within the specified range.
  • the amount of fumarate ester can comprise about 80 mg FAE to about 85 mg FAE, about 85 mg FAE to about 90 mg FAE, about 85 mg FAE to about 100 mg FAE, about 90 mg FAE to about 95 mg FAE, about 90 mg FAE to about 100 mg FAE, about 90 mg FAE to about 105 mg FAE, about 90 mg FAE to about 110 mg FAE, about 90 mg FAE to about 115 mg FAE, about 90 mg FAE to about 120 mg FAE, about 95 mg FAE to about 100 mg FAE, about 95 mg FAE to about 110 mg FAE, about 95 mg FAE to about 120 mg FAE, about 95 mg FAE to about 190 mg FAE, about 95 mg FAE to about 200 mg FAE, about 100 mg FAE to about 105 mg FAE, about 100 mg FAE to about 110 mg FAE, about 100 mg FAE to about 115 mg FAE, about 100 mg FAE to about 120 mg FAE, about 100 mg FAE to about 180 mg FAE, about 100 mg FAE to about 105 g
  • the pharmaceutical composition comprises from about 80 mg FAE to about 119 FAE including each integer within the specified range. In one embodiment described herein, the pharmaceutical composition comprises about 80 mg FAE, about 81 mg FAE, about 82 mg FAE, about 893 mg FAE, about 84 mg FAE, about 85 mg FAE, about 86 mg FAE, about 87 mg FAE, about 88 mg FAE, about 89 mg FAE, about 90 mg FAE, about 91 mg FAE, about 92 mg FAE, about 93 mg FAE, about 94 mg FAE, about 95 mg FAE, about 96 mg FAE, about 97 mg FAE, about 98 mg FAE, about 99 mg FAE, about 100 mg FAE, about 101 mg FAE, about 102 mg FAE, about 103 mg FAE, about 104 mg FAE, about 105 mg FAE, about 106 mg FAE, about 107 mg FAE, about 108 mg FAE, about 109 mg FAE, about 110 mg FAE, about 111 mg
  • the pharmaceutical composition comprises from about 180 mg FAE to about 238 FAE including each integer within the specified range. In one embodiment described herein, the pharmaceutical composition comprises about 180 mg FAE, about 182 mg FAE, about 184 mg FAE, about 186 mg FAE, about 188 mg FAE, about 190 mg FAE, about 192 mg FAE, about 194 mg FAE, about 196 mg FAE, about 198 mg FAE, about 200 mg FAE, about 202 mg FAE, about 204 mg FAE, about 206 mg FAE, about 208 mg FAE, about 210 mg FAE, about 212 mg FAE, about 214 mg FAE, about 216 mg FAE, about 218 mg FAE, about 220 mg FAE, about 222 mg FAE, about 224 mg FAE, about 226 mg FAE, about 228 mg FAE, about 230 mg FAE, about 232 mg FAE, about 234 mg FAE, about 236 mg FAE, or about 238 mg FAE.
  • the pharmaceutical composition comprises from about 360 mg FAE to about 476 FAE including each integer within the specified range. In one embodiment described herein, the pharmaceutical composition comprises about 360 mg FAE, about 362 mg FAE, about 364 mg FAE, about 368 mg FAE, about 372 mg FAE, about 376 mg FAE, about 380 mg FAE, about 384 mg FAE, about 388 mg FAE, about 392 mg FAE, about 396 mg FAE, about 400 mg FAE, about 404 mg FAE, about 408 mg FAE, about 412 mg FAE, about 416 mg FAE, about 420 mg FAE, about 424 mg FAE, about 428 mg FAE, about 432 mg FAE, about 436 mg FAE, about 440 mg FAE, about 444 mg FAE, about 448 mg FAE, about 452 mg FAE, about 456 mg FAE, about 460 mg FAE, about 464 mg FAE, about 468 mg FAE, about 472 mg FAE, or about 476 mg
  • the pharmaceutical composition comprises from about 90 mg FAE to about 476 FAE including each integer within the specified range. In one embodiment described herein, the pharmaceutical composition comprises about 90 mg FAE, about 91 mg FAE, about 92 mg FAE, about 93 mg FAE, about 94 mg FAE, about 95 mg FAE, about 96 mg FAE, about 97 mg FAE, about 98 mg FAE, about 99 mg FAE, about 100 mg FAE, about 101 mg FAE, about 102 mg FAE, about 103 mg FAE, about 104 mg FAE, about 105 mg FAE, about 106 mg FAE, about 107 mg FAE, about 108 mg FAE, about 109 mg FAE, about 1 10 mg FAE, about 111 mg FAE, about 112 mg FAE, about 113 mg FAE, about 114 mg FAE, about 115 mg FAE, about 116 mg FAE, about 117 mg FAE, about 118 mg FAE, about 119 mg FAE, about 180 mg FAE, about 18
  • the amount of fumarate ester can comprise about 85 mg to about 100 mg FAE, about 85 mg to about 110 mg FAE, about 85 mg to about 115 mg FAE, about 90 mg to about 100 mg FAE, about 90 mg to about 110 mg FAE, about 90 mg to about 115 mg FAE, about 90 mg to about 120 mg FAE, about 90 mg to about 200 mg FAE, about 90 mg to about 220 mg FAE, about 90 mg to about 230 mg FAE, about 95 mg to about 100 mg FAE, about 95 mg to about 110 mg FAE, about 95 mg to about 120 mg FAE, about 95 mg to about 200 mg FAE, about 95 mg to about 380 mg FAE, about 95 mg to about 400 mg FAE, about 100 mg to about 105 mg FAE, about 100 mg to about 110 mg FAE, about 100 mg to about 115 mg FAE, about 100 mg to about 120 mg FAE, about 100 mg to about 205 mg FAE, about 100 mg to about 210 mg FAE, about 100 mg to about 215 mg FAE, about
  • the effective amount of fumarate ester can comprise, but is not limited to, about 70 mg FAE to about 480 mg FAE (e.g., 70-480 mg FAE), including all integers and fractions within the specified range.
  • the daily effective amount of fumarate ester can comprise, but is not limited to, an effective amount of about 70 mg to about 90 mg FAE, about 75 mg to about 95 mg FAE, about 80 mg to about 100 mg FAE, about 85 mg to about 105 mg FAE, about 90 mg to about 100 mg FAE, about 90 mg to about 105 mg FAE, about 90 mg to about 100 mg FAE, about 95 mg to about 100 mg FAE, about 95 mg to about 108 mg FAE, about 100 mg to about 110 mg FAE, about 100 mg to about 115 mg FAE, about 100 mg to about 120 mg FAE, about 105 mg to about 110 mg FAE, about 105 mg to about 115 mg FAE, about 105 mg to about 120 mg FAE, about 105 mg to about 125 mg FAE
  • the daily effective amount of fumarate ester can comprise about 85 mg to about 118 mg FAE, about 90 mg to about 105 mg FAE, about 90 mg to about 110 mg FAE, about 90 mg to about 115 mg FAE, about 90 mg to about 120 mg FAE, about 90 mg to about 230 mg FAE, about 100 mg to about 105 mg FAE, about 100 mg to about 107 mg FAE, about 100 mg to about 108 mg FAE, about 100 mg to about 110 mg FAE, about 100 mg to about 115 mg FAE, about 100 mg to about 120 mg FAE, about 100 mg to about 205 mg FAE, about 100 mg to about 210 mg FAE, about 100 mg to about 215 mg FAE, about 100 mg to about 220 mg FAE, about 100 mg to about 230 mg FAE, about 170 mg to about 230 mg FAE, about 200 mg to about 210 mg FAE, about 200 mg to about 212 mg FAE, about 200 mg to about 214 mg FAE, about 200 mg to about 215 mg FAE,
  • the pharmaceutical compositions described herein are indicated for the treatment of patients with relapsing forms of multiple sclerosis.
  • Another embodiment described herein is a method for treating a patient with a relapsing form of multiple sclerosis comprising the administration of a dose of a fumarate ester as described herein.
  • the fumarate ester is DMF, MMF, or a combination thereof.
  • the dose is between about 85 mg FAE and about 120 mg FAE, including each integer within the specified range.
  • the total daily dose is between about 100 mg FAE and about 230 mg FAE, including each integer within the specified range.
  • the total daily dose is between about 170 mg FAE and about 230 mg FAE, including each integer within the specified range. In another aspect, the total daily dose is between about 340 mg FAE and about 460 mg FAE, including each integer within the specified range. In one embodiment the total daily dose is about 210 mg FAE, about 211 mg FAE, about 212 mg FAE, about 213 mg FAE, about 214 mg FAE, about 215 mg FAE, about 216 mg FAE, about 217 mg FAE, about 218 mg FAE, about 219 mg FAE, or about 220 mg FAE.
  • the total daily dose is about 420 mg FAE, about 422 mg FAE, about 424 mg FAE, about 426 mg FAE, about 428 mg FAE, about 430 mg FAE, about 432 mg FAE, about 434 mg FAE, about 436 mg FAE, about 438 mg FAE, or about 440 mg FAE.
  • the FAE may comprise a solution or suspension having an active pharmaceutical ingredient load (e.g., drug load) of about 1% to about 65% by weight, including all integers and fractions within the specified range.
  • the drug load can comprise about 10% to about 45% by weight, including all integers and fractions within the specified range.
  • the drug load can comprise about 12% to about 16%) by weight, including all integers and fractions within the specified range.
  • the drug load can comprise about 24% to about 32% by weight, including all integers and fractions within the specified range.
  • the drug load can comprise about 20% to about 22%) by weight, including all integers and fractions within the specified range.
  • the drug load can comprise about 20% to about 50% by weight, including all integers and fractions within the specified range. In one embodiment, the drug load can comprise about 40% to about 43%) by weight, including all integers and fractions within the specified range. In one embodiment, the drug load can comprise about 25% to about 45% by weight, including all integers and fractions within the specified range. In one embodiment, the drug load can comprise about 29% to about 43%) by weight, including all integers and fractions within the specified range. In one embodiment, the drug load can comprise about 48%> to about 64%> by weight, including all integers and fractions within the specified range.
  • the drug load can comprise about 1%, about 2%, about 2.5%, about 5%, about 10%, about 15%, about 20%, about 25%, about 29% about 30%, about 35%, about 40%, about 42%, about 45%, about 40%, about 50%, about 60%, about 65%, or even higher, by weight. In one embodiment, the drug load can comprise about 1 1.3%, 1 1.7%,
  • the drug load can comprise about 34% FAE, by weight.
  • pharmaceutical composition can comprise about 0.4 mmol FAE to about 4.0 mmol FAE, including all integers and fractions within the specified range.
  • the pharmaceutical composition comprises 0.4 mmol FAE, 0.5 mmol FAE, 0.6 mmol FAE, 0.7 mmol FAE, 0.8 mmol FAE, 0.9 mmol FAE, 1.0 mmol FAE, 1.1 mmol FAE, 1.2 mmol FAE, 1.3 mmol FAE, 1.4 mmol FAE, 1.5 mmol FAE, 1.6 mmol FAE, 1.7 mmol FAE, 1.8 mmol FAE, 1.9 mmol FAE, 2.0 mmol FAE, 2.1 mmol FAE, 2.2 mmol FAE, 2.3 mmol FAE, 2.4 mmol FAE, 2.5 mmol FAE, 2.6 mmol FAE, 2.7 mmol FAE, 2.8 mmol FAE, 2.9 mmol FAE, 3.
  • the pharmaceutical composition comprises about 0.7 mmol FAE to about 1.6 mmol FAE. In one aspect, the pharmaceutical composition comprises about 0.7 mmol FAE. In another aspect, the pharmaceutical composition comprises about 0.8 mmol FAE. In another aspect, the pharmaceutical composition comprises about 1.5 mmol FAE.
  • the effective dose of fumarate ester for treating multiple sclerosis or psoriasis is about 2.8 mmole FAE to about 3.1 mmol FAE. In one aspect the effective dose of fumarate ester is about 2.8. In another aspect the effective dose of fumarate ester is about 3.1.
  • a pharmaceutical dosage form comprising any one of the pharmaceutical compositions described herein for administration to a subject having a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis, comprising a therapeutically effective amount of one or more fumarate esters, wherein the administration is sufficient to achieve a reduction of about 0.224 annualized relapse rate relative to baseline in the subject without substantially inducing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject; and wherein the administration does not require titration of the pharmaceutical composition.
  • a general autoimmune or neurodegenerative disorder including but not limited to multiple sclerosis
  • the administration is sufficient to achieve a reduction of about 0.224 annualized relapse rate relative to baseline in the subject without substantially inducing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject
  • the administration does not require titration of the pharmaceutical composition.
  • Another embodiment described herein is a method for treating, retarding the progression of, prophylaxis of, delaying the onset of, ameliorating, or reducing the symptoms of multiple sclerosis or psoriasis comprising the administration of a therapeutically effective amount of one or more fumarate esters comprising any one of the pharmaceutical compositions described herein to a subject with multiple sclerosis, wherein the administration is sufficient to achieve a reduction of about 0.224 annualized relapse rate relative to baseline in the subject without substantially inducing one or more of flushing, abdominal pain, diarrhea, and nausea in the subject.
  • the subject experiences one or more of flushing, abdominal pain, diarrhea, and nausea at a rate of less than about 10%.
  • the endpoint may be less than about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 45%, about 50%, or greater than about 50%.
  • Another embodiment described herein is a pharmaceutical composition and a method for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of a general autoimmune or neurodegenerative disorder, including but not limited to multiple sclerosis or psoriasis, the method comprising the administration of a therapeutically effective amount of one or more fumarate esters comprising any one of the pharmaceutical compositions described herein to a subject in need thereof, wherein the subject achieves a reduction of annualized relapse rate relative to baseline without substantially experiencing one or more of flushing, abdominal pain, diarrhea, and nausea.
  • the endpoint may be less than about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%), about 35%, about 45%, about 50%, or greater than about 50%, relative to baseline.
  • Another embodiment described herein is a pharmaceutical composition for administration to a subject with multiple sclerosis or psoriasis comprising a therapeutically effective amount of one or more fumarate esters, wherein the subject achieves a reduction of annualized relapse rate relative to baseline without substantially experiencing one or more of flushing, abdominal pain, diarrhea, and nausea.
  • the reduction of annualized relapse rate may be about 1%, about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 45%), about 50%), or greater than about 50%.
  • the dosage form administered to the subject or subject in need thereof comprises a pharmaceutical composition comprising micronized solid particles of a fumarate ester as the only active ingredient or in combination with one or more NSAIDS (e.g., aspirin) or leukotriene receptor antagonists (e.g., montelukast or zafirlukast).
  • NSAIDS e.g., aspirin
  • leukotriene receptor antagonists e.g., montelukast or zafirlukast.
  • the effective amount of fumarate ester is about 320 mg to about 460 mg FAE per day and the subjects can receive the effective amount, e.g., about 80 mg to about 115 mg FAE quater in die (QID), in the form of four capsules a day, to be taken orally, including all integers and fractions within the specified ranges.
  • the effective amount is about 85 mg to about 110 mg FAE quater in die (QID).
  • the effective amount is about 90 mg to about 100 mg FAE quater in die (QID).
  • the effective amount is about 90 mg to about 107 mg FAE quater in die (QID).
  • the effective amount is about 100 mg to about 108 mg FAE quater in die (QID). In another aspect, the effective amount is about 105 mg to about 110 mg FAE quater in die (QID). In one aspect, the effective amount of fumarate ester is about 340 mg to about 460 mg FAE per day and the subjects can receive the effective amount, e.g., about 170 mg to about 230 mg FAE bis in die (BID), in the form of two capsules a day, to be taken orally, including all integers and fractions within the specified ranges. In another aspect, the effective amount is about 205 mg to about 230 mg FAE BID. In a further aspect, the effective amount is about 210 mg to about 220 mg FAE BID.
  • the effective amount is about 210 mg to 216 mg FAE BID. In a further aspect, the effective amount is about 212 mg to 216 mg FAE BID. In another aspect, the effective amount of FAE is about 340 mg to about 460 mg FAE per day and the subjects can receive the effective amount, e.g., about 340 to about 460 mg FAE quaque die (QD), in the form of one capsule a day, to be taken orally, including all integers and fractions within the specified ranges.
  • QD FAE quaque die
  • the daily effective amount of FAE is from 80 mg FAE to 85 mg FAE, 80 mg FAE to 90 mg FAE, 80 mg FAE to 95 mg FAE, 85 mg FAE to 100 mg FAE, 85 mg FAE to 90 mg FAE, 85 mg FAE to 95 mg FAE, 90 mg FAE to 100 mg FAE, 90 mg FAE to 105 mg FAE, 90 mg FAE to 95 mg FAE, 95 mg FAE to 100 mg FAE, 95 mg FAE to 105 mg FAE, 95 mg FAE to 110 mg FAE, 100 mg FAE to 105 mg FAE, 100 mg FAE to 110 mg FAE, 100 mg FAE to 115 mg FAE, 105 mg FAE to 110 mg FAE, 105 mg FAE to 115 mg FAE, 105 mg FAE to 120 mg FAE, l lO mg FAE to 115 mg FAE, 105 mg FAE to 120 mg FAE, l lO mg FAE to 115 mg FAE, 105 mg FAE to 120 mg FAE, l lO
  • the dosage form administered to the subject or subject in need thereof comprises a pharmaceutical composition comprising micronized solid particles of a fumarate ester as the only active ingredient.
  • the effective amount of fumarate ester is about 340 mg to about 440 mg FAE per day and the subjects can receive the effective amount, e.g., about 340 mg to about 440 mg FAE per day, in the form of two dosage forms comprising 85 mg to about 110 mg FAE, simultaneously administered bis in die (BID), for a total of four capsules per day to be taken orally (e.g., two capsules administered ante meridiem and two capsules administered post meridiem).
  • BID bis in die
  • the effective amount of fumarate ester is about 380 mg to about 400 mg FAE per day and the subjects can receive the effective amount, e.g., about 380 mg to about 400 mg FAE per day, in the form of two dosage forms comprising about 95 mg to about 100 mg FAE, simultaneously administered bis in die (BID), for a total of four capsules a day to be taken orally (e.g., two capsules administered ante meridiem and two capsules administered post meridiem).
  • the dosage form comprises about 95 mg FAE.
  • the dosage form comprises 100 mg FAE.
  • dosing regimen comprises two 95 mg dosage forms administered BID for a total of 380 mg FAE per day.
  • dosing regimen comprises two 100 mg dosage forms administered BID for a total of 400 mg FAE per day.
  • two small dosage forms such as two 95 mg FAE or 100 mg FAE soft capsule dosage forms (e.g., total fill weight of about 250 to about 300 mg in a 5 oval capsule) provides more rapid gastric emptying and transit to the duodenum as compared to a single larger dosage form, such as a single 200 mg of FAE soft capsule dosage form (e.g., total fill weight of about 500 mg to about 600 mg in a 12 oval capsule).
  • a single larger dosage form such as a single 200 mg of FAE soft capsule dosage form (e.g., total fill weight of about 500 mg to about 600 mg in a 12 oval capsule).
  • This may provide a more rapid Jmax and also reduce Cmax because of the lower FAE dose. This may also reduce gastrointestinal side effects.
  • the effective amount of fumarate ester is about 400 mg to about
  • the subjects can receive the effective amount, e.g., about 400 mg to about 420 mg FAE per day, in the form of two dosage forms comprising about 180 mg to about 210 mg in the form of two capsules per day, to be taken orally (e.g., one capsule administered ante meridiem and one capsules administered post meridiem).
  • the dosage form comprises 180 mg FAE.
  • the dosage form comprises 190 mg FAE.
  • the dosage form comprises about 200 mg FAE.
  • the dosage form comprises 205 mg FAE.
  • the dosage form comprises 210 mg FAE.
  • the effective amount of fumarate ester is about 400 mg to about 440 mg FAE per day and the subjects can receive the effective amount, e.g., about 400 mg to about 440 mg FAE per day, in the form of two dosage forms comprising about 200 mg to about 220 mg in the form of two capsules a day, to be taken orally (e.g., one capsule administered ante meridiem and one capsules administered post meridiem).
  • the dosage form comprises about 200 mg FAE.
  • the dosage form comprises 210 mg FAE.
  • the dosage form comprises 215 mg FAE.
  • the dosage form comprises 220 mg FAE.
  • the dosage form administered to the subject or subject in need thereof comprises a pharmaceutical composition comprising micronized solid particles of a fumarate ester as the only active ingredient or in combination with one or more NSAIDS (e.g., aspirin) or leukotriene receptor antagonists (e.g., montelukast or zafirlukast).
  • NSAIDS e.g., aspirin
  • leukotriene receptor antagonists e.g., montelukast or zafirlukast.
  • the effective amount of fumarate ester is about 340 mg to about 440 mg FAE per day and the subjects can receive the effective amount, e.g., about 85 mg to about 110 mg FAE quater in die (QID), in the form of four capsules a day, to be taken orally, including all integers and fractions within the specified ranges.
  • the effective amount of fumarate ester is about 340 mg to about 440 mg FAE per day and the subjects can receive the effective amount, e.g., about 170 mg to about 220 mg FAE bis in die (BID), in the form of two capsules a day, to be taken orally, including all integers and fractions within the specified ranges.
  • the effective amount of fumarate ester is about 340 mg to about 440 mg FAE per day and the subjects can receive the effective amount, e.g., about 340 mg to about 440 mg FAE quaque die (QD), in the form of one capsule a day, to be taken orally, including all integers and fractions within the specified ranges.
  • QD FAE quaque die
  • Fumarate esters can cause flushing and gastrointestinal (GI) side effects in some subjects. While the side effects generally subside soon after subjects start on the treatment, in one aspect the starting dose is about 85 mg to about 110 mg FAE BID orally for the first 7 days, including all integers and fractions within the specified range.
  • the dose is increased to the effective dose of about 170 mg to about 220 mg FAE BID (e.g., about 340 mg to about 440 mg FAE per day), including all integers and fractions within the specified ranges.
  • the starting dose is about 170 mg to about 220 mg FAE BID orally for the first 7 days, including all integers and fractions within the specified ranges.
  • the dose is increased to the effective dose of about 340 mg to about 440 mg FAE QD (e.g., about 340 mg to about 440 mg FAE per day), including all integers and fractions within the specified ranges.
  • FAE is administered after a meal.
  • FAE is administered after a high- fat meal to reduce or ameliorate the one or more symptoms of flushing, abdominal pain, diarrhea, and nausea in the subject.
  • the pharmaceutical compositions described herein can be administered without titration of the pharmaceutical composition.
  • the pharmaceutical compositions can be administered without titration and without substantially inducing one or more side effects including, but not limited to flushing, abdominal pain, diarrhea, or nausea.
  • the pharmaceutical composition described herein does not elicit the flushing and gastrointestinal side effects when the dose is about 85 mg to about 110 mg FAE quater in die (QID) or two doses simultaneously bis in die (BID) (e.g., 340 mg to about 440 mg FAE per day), including all integers and fractions within the specified ranges.
  • the pharmaceutical composition described herein does not elicit the flushing and gastrointestinal side effects when the dose is about 170 mg to about 220 mg FAE bis in die (BID) (e.g., 340 mg to about 440 mg FAE per day), including all integers and fractions within the specified ranges.
  • the pharmaceutical composition described herein does not elicit the flushing and gastrointestinal side effects when the dose is about 340 mg to about 440 mg FAE quaque die (QD) (e.g., 340 mg to about 440 mg FAE per day), including all integers and fractions within the specified ranges.
  • QD FAE quaque die
  • the pharmaceutical composition described herein does not elicit flushing and gastrointestinal side effects when the effective amount is about 180 mg FAE quaque die (QD) (e.g., 180 mg FAE per day). In another embodiment, the pharmaceutical composition described herein does not elicit the flushing and gastrointestinal side effects when the effective amount is about 170 mg to about 220 mg FAE quaque die (QD) (e.g., 170 mg to about 220 mg FAE per day), including all integers and fractions within the specified ranges.
  • QD 180 mg FAE quaque die
  • the pharmaceutical composition described herein does not elicit the flushing and gastrointestinal side effects when the effective amount is about 170 mg to about 220 mg FAE quaque die (QD) (e.g., 170 mg to about 220 mg FAE per day), including all integers and fractions within the specified ranges.
  • the pharmaceutical composition described herein does not elicit the flushing and gastrointestinal side effects when the effective amount is about 340 mg to about 440 mg FAE quaque die (QD) (e.g., 340 mg to about 440 mg FAE per day), including all integers and fractions within the specified ranges.
  • QD FAE quaque die
  • compositions described herein comprising liquid dosage forms of FAE provide effective treatment of multiple sclerosis at total daily dosages of about 380 mg FAE to about 400 mg FAE when compared to a total daily dosage of 480 mg dimethyl fumarate administered as TECFIDERA
  • the FAE is DMF.
  • the FAE is monomethyl fumarate.
  • the FAE is DMF, MMF, other MMF prodrug, or a combination thereof.
  • the administration of about 325 mg of non-enteric coated aspirin 30- minutes prior to FAE dosing can reduce the occurrence and severity of flushing.
  • subjects who experience flushing with gastrointestinal side effects may reduce the dose to about 100 mg to about 120 mg FAE BID temporarily, including all integers and fractions within the specified range.
  • the effective dose of about 170 mg to about 220 mg FAE BID should be resumed, including all integers and fractions within the specified range.
  • subjects who experience flushing with gastrointestinal side effects may reduce the dose to about 170 mg to about 220 mg FAE BID temporarily, including all integers and fractions within the specified range.
  • the effective dose of about 340 mg to about 440 mg FAE QD should be resumed, including all integers and fractions within the specified range.
  • a subject administered a FAE pharmaceutical composition described herein may take one or more non-steroidal anti -inflammatory drugs (NS AID) before (for example, about 10 minutes to an hour, e.g., about 30 minutes before) taking a FAE pharmaceutical composition described herein.
  • the subject administered a dosage form takes the one or more non-steroidal anti-inflammatory drugs to reduce flushing.
  • the one or more non-steroidal anti-inflammatory drugs comprise aspirin, ibuprofen, naproxen, ketoprofen, celecoxib, or combinations thereof.
  • the one or more non-steroidal anti-inflammatory drugs can be administered in an amount of about 50 mg to about 500 mg before taking the dosage form described herein.
  • a subject takes 325 mg aspirin about 30-minutes before taking the dosage forms described herein.
  • a subject administered a FAE pharmaceutical composition described herein may take one or more leukotriene receptor antagonists.
  • a subject administered a FAE pharmaceutical composition described herein may take 10 to 20 mg of montelukast (Singulair ® ) or zafirlukast (Accolate ® ).
  • subjects are orally administered one or more nonsteroidal anti-inflammatory drugs before taking the dosage form described herein exhibit the same pharmacokinetic properties (e.g., Cmax and AUC) as subjects orally administered the dosage form described herein without administering one or more non-steroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen, naproxen, ketoprofen, celecoxib, or combinations thereof).
  • the NSAID can be administered about 30-minutes before taking the dosage form described herein.
  • a subject is administered one or more dosage forms containing about 80 mg to about 460 mg FAE, one or more times daily for a total daily dose of about 320 mg to about 460 mg, including all integers and fractions within the specified range.
  • the pharmaceutical composition comprises an immediate release, delayed release, controlled release, or extended release formulation of a fumarate ester.
  • the matrix is a controlled release matrix.
  • the matrix is a delayed release matrix.
  • the matrix is an extended release matrix.
  • the pharmaceutical composition comprises a soft capsule.
  • the pharmaceutical composition comprises a soft capsule comprising one or more subcoatings, top coatings, enteric coatings, or combinations thereof.
  • subjects having a general autoimmune or neurodegenerative disorder including but not limited to multiple sclerosis or psoriasis, are administered one or more dosage forms comprising about 80 mg to about 110 mg FAE, twice-daily for a total daily dose of about 320 mg to about 440 mg, wherein the dosage form comprises solid microparticles of FAE in a liquid matrix.
  • the matrix is a controlled release matrix.
  • subjects having a general autoimmune or neurodegenerative disorder including but not limited to multiple sclerosis or psoriasis, are administered one or more dosage forms comprising about 95 mg to about 100 mg FAE, twice-daily for a total daily dose of about 190 mg to about 200 mg, wherein the dosage forms comprise solid microparticles of FAE suspended in a liquid matrix.
  • the matrix is a controlled release matrix.
  • subjects having a general autoimmune or neurodegenerative disorder including but not limited to multiple sclerosis or psoriasis, are simultaneously administered two dosage forms comprising about 95 mg to about 100 mg FAE, twice-daily for a total daily dose of about 380 mg to about 400 mg, wherein the soft capsule comprises solid microparticles of FAE suspended in a liquid matrix.
  • the matrix is a controlled release matrix.
  • subjects having a general autoimmune or neurodegenerative disorder including but not limited to multiple sclerosis or psoriasis, are administered a dosage form containing about 200 mg FAE, twice daily for a total daily dose of about 400 mg, wherein the dosage form comprises solid microparticles of FAE suspended in a matrix.
  • the matrix is a controlled release matrix.
  • the pharmaceutical composition described herein is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose exhibit a mean plasma monomethyl fumarate Cmax ranging from about 0.2 mg/L to about 2.41 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose exhibit a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 2.41 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1.5 mg/L to about 3.4 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1.03 mg/L to about 2.41 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose exhibit a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 0.75 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose exhibit a mean plasma monomethyl fumarate Cmax ranging from about 0.76 mg/L to about 1.03 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1.04 mg/L to about 1.75 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1.75 mg/L to about 2.41 mg/L, including all integers and fractions within the specified ranges.
  • the composition in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose exhibit a mean plasma monomethyl fumarate Cmax of at least 0.4 mg/L, at least 0.5 mg/L, at least 0.6 mg/L, at least 0.7 mg/L, at least 0.8 mg/L, at least 0.9 mg/L, at least 1 mg/L, at least
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form four times daily exhibit a mean plasma monomethyl fumarate AUCoveraii ranging from about 1.0 h mg/L to about 15.2 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form four times daily exhibit a mean plasma monomethyl fumarate AUCoveraii ranging from about 2.01 h mg/L to about 5.2 h mg/L, including all integers and fractions within the specified ranges.
  • composition in another aspect, is provided in a dosage form containing a total amount of about 85 mg to about 1 10 mg of a fumarate ester, wherein subjects administered the dose form four times daily exhibit a mean plasma monomethyl fumarate AUCoveraii ranging from about 1.0 h mg/L to about
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form four times daily exhibit a mean plasma monomethyl fumarate AUCoveraii ranging from about 1 1.3 h mg/L to about 15.2 h mg/L, including all integers and fractions within the specified ranges.
  • the composition in another aspect, is provided in a dosage form containing a total amount of about 85 mg to about 1 10 mg of a fumarate ester, wherein subjects administered the dose form four times daily exhibit a mean plasma monomethyl fumarate AUCoveraii ranging from about 3.2 h mg/L to about 1 1.2 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 1 10 mg of a fumarate ester, wherein subjects administered the dose form four times daily exhibit a mean plasma monomethyl fumarate AUCoveraii ranging from about 5.2 h mg/L to about 1 1.2 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 1 10 mg of a fumarate ester, wherein subjects administered the dose form four times daily exhibit a mean plasma monomethyl fumarate AUCoveraii at least about 1.0 h mg/L, at least 1.2 h mg/L, at least 1.4 h mg/L, at least 1.6 h mg/L, at least 1.8 h mg/L, at least 2.0 h mg/L, at least 2.3 h mg/L, at least about 2.6 h mg/L, at least about 2.9 h mg/L, at least 3.2 h mg/L, at least 3.5 h mg/L, at least 3.8 h mg/L, at least 4.1 h mg/L, at least 4.4 h mg/L, at least 4.7 h mg/L, at least 5.0 h mg/L, at least 5.3 h mg/L, at least 5.6 h mg/L, at least 5.9 h mg/L,
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 1 10 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 0.5 h mg/L to about 5.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 1 10 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 0.5 h mg/L to about 2.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 2.6 h mg/L to about 5.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h of at least about 0.5 h mg/L, at least 1.0 h mg/L, at least 1.2 h mg/L, at least 1.4 h mg/L, at least 1.6 h mg/L, at least 1.8 h mg/L, at least 2.0 h mg/L, at least 2.1 h mg/L, at least 2.2 h mg/L, at least 2.3 h mg/L, at least 2.4 h mg/L, at least 2.5 h mg/L, at least 2.6 h mg/L, at least 2.7 h mg/L, at least 2.8 h mg/L, at least 2.9 h mg/L, at least 3 h mg/L, at least 3.1 h mg/L, at least 3.2 h mg/L, at least 3.3 h
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 0.5 h mg/L to about 5.6 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 0.5 h mg/L to about 2.6 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 2.6 h mg/L to about 5.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ of at least about 0.5 h mg/L, at least 1.0 h mg/L, at least 1.2 h mg/L, at least 1.4 h mg/L, at least 1.6 h mg/L, at least 1.8 h mg/L, at least 2 h mg/L, at least 2.1 h mg/L, at least 2.2 h mg/L, at least 2.3 h mg/L, at least 2.4 h mg/L, at least 2.5 h mg/L, at least 2.6 h mg/L, at least 2.7 h mg/L, at least 2.8 h mg/L, at least 2.9 h mg/L, at least 3 h mg/L, at least 3.1 h mg/L, at least 3.2 h mg/L, at least 3.3 h mg/L
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Jmax ranging from about 1.5 hours to about 8.5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Jmax ranging from about 1.6 hours to about 2.5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Jmax ranging from about 2.6 hours to about 5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Jmax ranging from about 5.1 hours to about 7.5 hours, including all integers and fractions within the specified ranges.
  • the composition in another aspect, is provided in a dosage form containing a total amount of about 85 mg to about 110 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Jmax ranging from about 7.6 hours to about 8.5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 240 mg to about 240 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Jmax of at least 1.6 hours, at least 1.8 hours, at least 2 hours, at least 2.2 hours, at least 2.4 hours, at least 2.6 hours, at least 2.8 hours, at least 3 hours, at least 3.2 hours, at least 3.4 hours, at least 3.6 hours, at least 3.8 hours, at least 4 hours, at least 4.2 hours, at least 4.4 hours, at least 4.6 hours, at least 4.8 hours, at least 5 hours, at least 5.2 hours, at least 5.4 hours, at least 5.6 hours, at least 5.8 hours, at least 6 hours, at least 6.2 hours, at least 6.4 hours, at least 6.6 hours, at least 6.8 hours, at least 7 hours, at least 7.2 hours, at least 7.4 hours, at least 7.6 hours, at least 7.8 hours, at least 8 hours, at least 8.2 hours,
  • a subject is administered a capsule containing about 170 mg to about 220 mg FAE, twice daily for a total daily dose of about 340 mg to about 440 mg, including all integers and fractions within the specified range.
  • the pharmaceutical composition comprises an immediate release, delayed release, controlled release, or extended release formulation of a fumarate ester.
  • the pharmaceutical composition comprises a soft capsule.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 2.41 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1.0 mg/L to about 3.4 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1.03 mg/L to about 2.41 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 0.75 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Cmax ranging from about 0.76 mg/L to about 1.03 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1.04 mg/L to about 1.75 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1.75 mg/L to about 2.41 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Cmax of at least 0.4 mg/L, at least 0.5 mg/L, at least 0.6 mg/L, at least 0.7 mg/L, at least 0.8 mg/L, at least 0.9 mg/L, at least 1 mg/L, at least 1.1 mg/L, at least 1.2 mg/L, at least 1.3 mg/L, at least 1.4 mg/L, at least 1.5 mg/L, at least 1.6 mg/L, at least 1.7 mg/L, at least 1.8 mg/L, at least 1.9 mg/L, at least 2 mg/L, at least 2.1 mg/L, at least 2.2 mg/L, at least 2.3 mg/L, at least 2.4 mg/L, at least 2.5 mg/L, at least 2.6 mg/L, at least 2.7 mg/L, at least 2.8 mg/L, at
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form twice-daily exhibit a mean plasma monomethyl fumarate AUCoveraii ranging from about 1.0 h mg/L to about 15.2 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form twice- daily exhibit a mean plasma monomethyl fumarate AUCoveraii ranging from about 2.01 h mg/L to about 5.2 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form twice-daily exhibit a mean plasma monomethyl fumarate AUCoveraii ranging from about 1.0 h mg/L to about 5.2 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form twice-daily exhibit a mean plasma monomethyl fumarate AUCoveraii ranging from about 11.3 h mg/L to about 15.2 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form twice-daily exhibit a mean plasma monomethyl fumarate AUCoveraii ranging from about 4.8 h mg/L to about 1 1.2 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subj ects administered the dose form twice-daily exhibit a mean plasma monomethyl fumarate AUCoveraii at least about 1.0 h mg/L, at least 1.2 h mg/L, at least 1.4 h mg/L, at least 1.6 h mg/L, at least 1.8 h mg/L, at least 2.0 h mg/L, at least 2.3 h mg/L, at least about 2.6 h mg/L, at least about 2.9 h mg/L, at least 3.2 h mg/L, at least 3.5 h mg/L, at least 3.8 h mg/L, at least 4.1 h mg/L, at least 4.4 h mg/L, at least 4.7 h mg/L, at least 5.0 h mg/L, at least 5.3 h mg/L, at least 5.6 h mg/L, at
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 1.0 h mg/L to about 5.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 1.0 h mg/L to about 2.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 2.6 h mg/L to about 5.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h of at least about 1.0 h mg/L, at least 1.2 h mg/L, at least 1.4 h mg/L, at least 1.6 h mg/L, at least 1.8 h mg/L, at least 2.0 h mg/L, at least 2.1 h mg/L, at least 2.2 h mg/L, at least 2.3 h mg/L, at least 2.4 h mg/L, at least 2.5 h mg/L, at least 2.6 h mg/L, at least 2.7 h mg/L, at least 2.8 h mg/L, at least 2.9 h mg/L, at least 3 h mg/L, at least 3.1 h mg/L, at least 3.2 h mg/L, at least 3.3 h mg/L, at least 3.4
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 1.0 h mg/L to about 5.6 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 1.0 h mg/L to about 2.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 2.6 h mg/L to about 5.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCo ⁇ of at least about 1.0 h mg/L, at least 1.2 h mg/L, at least 1.4 h mg/L, at least 1.6 h mg/L, at least 1.8 h mg/L, at least 2 h mg/L, at least 2.1 h mg/L, at least 2.2 h mg/L, at least 2.3 h mg/L, at least 2.4 h mg/L, at least 2.5 h mg/L, at least 2.6 h mg/L, at least 2.7 h mg/L, at least 2.8 h mg/L, at least 2.9 h mg/L, at least 3 h mg/L, at least 3.1 h mg/L, at least 3.2 h mg/L, at least 3.3 h mg/L, at least 3.4 h mg
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monom ethyl fumarate Jmax ranging from about 1 .5 hours to about 8.5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Jmax ranging from about 1 .6 hours to about 2.5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Jmax ranging from about 2.6 hours to about 5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Jmax ranging from about 5. 1 hours to about 7.5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Jmax ranging from about 7.6 hours to about 8.5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate Jmax of at least 1 .6 hours, at least 1 .8 hours, at least 2 hours, at least 2.2 hours, at least 2.4 hours, at least 2.6 hours, at least 2.8 hours, at least 3 hours, at least 3.2 hours, at least 3.4 hours, at least 3.6 hours, at least 3.8 hours, at least 4 hours, at least 4.2 hours, at least 4.4 hours, at least 4.6 hours, at least 4.8 hours, at least 5 hours, at least 5.2 hours, at least 5.4 hours, at least 5.6 hours, at least 5.8 hours, at least 6 hours, at least 6.2 hours, at least 6.4 hours, at least 6.6 hours, at least 6.8 hours, at least 7 hours, at least 7.2 hours, at least 7.4 hours, at least 7.6 hours, at least 7.8 hours, at least 8 hours, at
  • a subject is administered a capsule containing about 340 mg to about 440 mg FAE, once daily for a total daily dose of about 340 mg to about 440 mg, including all integers and fractions within the specified ranges.
  • the pharmaceutical composition comprises an immediate release, delayed release, controlled release, or extended release formulation of a fumarate ester.
  • the pharmaceutical composition comprises a soft capsule.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate C max ranging from about 0.4 mg/L to about 5.2 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1.5 mg/L to about 5.2 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Cmax ranging from about 0.4 mg/L to about 0.75 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Cmax ranging from about 0.76 mg/L to about 1.03 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1.04 mg/L to about 1.75 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1.75 mg/L to about 2.41 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Cmax ranging from about 2.42 mg/L to about 3.5 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Cmax ranging from about 3.6 mg/L to about 5.2 mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Cmax of at least about 1.0 mg/L, at least 1.1 mg/L, at least 1.2 mg/L, at least 1.3 mg/L, at least 1.4 mg/L, at least 1.5 mg/L, at least 1.6 mg/L, at least 1.7 mg/L, at least 1.8 mg/L, at least 1.9 mg/L, at least 2.0 mg/L, at least 2.1 mg/L, at least 2.2 mg/L, at least 2.3 mg/L, at least 2.4 mg/L, at least 2.5 mg/L, at least 2.6 mg/L, at least 2.7 mg/L, at least 2.8 mg/L, at least 2.9 mg/L, at least 3.0 mg/L, at least 3.1 mg/L, at least 3.2 mg/L, at least 3.3 mg/L, at least 3.4 mg
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 1.0 h mg/L to about 15.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 1.0 h mg/L to about 2.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 2.6 h mg/L to about 5.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 5.6 h mg/L to about 7.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCo ⁇ i2h ranging from about 7.6 h mg/L to about 10.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monom ethyl fumarate AUCo ⁇ i2h ranging from about 10.5 h mg/L to about 15.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monom ethyl fumarate AUCo ⁇ i2h of at least about 1.0 h mg/L, at least 1.2 h mg/L, at least 1.4 h mg/L, at least 1.6 h mg/L, at least 1.8 h mg/L, at least 2.0 h mg/L, at least 2.3 h mg/L, at least 2.6 h mg/L, at least 2.9 h mg/L, at least 3.2 h mg/L, at least 3.5 h mg/L, at least 3.8 h mg/L, at least 4.1 h mg/L, at least 4.4 h mg/L, at least 4.7 h mg/L, at least 5 h mg/L, at least 5.3 h mg/L, at least 5.6 h mg/L, at least 5.9 h
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 1.0 h mg/L to about 15.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 1.5 h mg/L to about 2.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 2.6 h mg/L to about 5.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 5.6 h mg/L to about 7.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 7.6 h mg/L to about 11.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCo ⁇ ranging from about 10.5 h mg/L to about 15.5 h mg/L, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCo ⁇ of at least about 1.0 h mg/L, at least 1.2 h mg/L, at least 1.4 h mg/L, at least 1.6 h mg/L, at least 1.8 h mg/L, at least 2.0 h mg/L, at least 2.3 h mg/L, at least 2.6 h mg/L, at least 2.9 h mg/L, at least 3.2 h mg/L, at least 3.5 h mg/L, at least 3.8 h mg/L, at least 4.1 h mg/L, at least 4.4 h mg/L, at least 4.7 h mg/L, at least 5 h mg/L, at least 5.3 h mg/L, at least 5.6 h mg/L, at least 5.9 h mg/L, at least 6.2
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Jmax ranging from about 1.5 hours to about 10.5 hours including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Jmax ranging from about 1.6 hours to about 2.5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Jmax ranging from about 2.6 hours to about 5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Jmax ranging from about 5.1 hours to about 7.5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Jmax ranging from about 7.6 hours to about 8.5 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Jmax ranging from about 8.6 hours to about 10.6 hours, including all integers and fractions within the specified ranges.
  • the composition is provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate Jmax of at least 1.6 hours, at least 1.8 hours, at least 2 hours, at least 2.2 hours, at least 2.4 hours, at least 2.6 hours, at least 2.8 hours, at least 3 hours, at least 3.2 hours, at least 3.4 hours, at least 3.6 hours, at least 3.8 hours, at least 4 hours, at least 4.2 hours, at least 4.4 hours, at least 4.6 hours, at least 4.8 hours, at least 5 hours, at least 5.2 hours, at least 5.4 hours, at least 5.6 hours, at least 5.8 hours, at least 6 hours, at least 6.2 hours, at least 6.4 hours, at least 6.6 hours, at least 6.8 hours, at least 7 hours, at least 7.2 hours, at least 7.4 hours, at least 7.6 hours, at least 7.8 hours, at least 8 hours, at least 8.2
  • compositions for treating, prophylaxis, or amelioration of general autoimmune or neurodegenerative disorders comprising a fumarate ester, wherein the composition exhibits an in vitro dissolution rate (% dissolution per minute) at pH 6.8, as described herein in any one of Drawings 2-14, 16, or 20-23.
  • compositions for treating, prophylaxis, or amelioration of general autoimmune or neurodegenerative disorders comprising a fumarate ester, wherein the composition exhibits an in vitro dissolution rate comprising about 10% to about 80% dissolution after about 5 minutes to about 480 minutes at pH 6.8, including all integers and fractions within the specified ranges of dissolution and time.
  • the in vitro dissolution rate at pH 6.8 is about 50% after about 20 minutes to about 1080 minutes, including all integers and fractions within the specified ranges of dissolution and time.
  • the in vitro dissolution rate at pH 6.8 is about 50%) after about 5 min, is about 50% after about 10 min, about 50% after about 20 min, about 50%) after about 30 min, about 50% after about 40 min, about 50% after about 50 min, about 50%) after about 60 min, about 50% after about 70 min, about 50% after about 80 min, about 50% after about 90 min, about 50% after about 120 min, about 50% after about 150 min, about 50% after about 180 min, about 50% after about 210 min, about 50% after about 240 min, about 50% after about 300 min, is about 50% after about 330 min, about 50% after about 360 min, is about 50%) after about 390 min, about 50% after about 420 min, about 50% after about 480 min, about 50%) after about 540 min, about 50% after about 600 min, about 50% after about 660 min, about 50%) after about 720 min, about 50% after about 780 min, about 50% after about 840 min, about 50% after about 900 min, about 50% after about 960 min, or about 50% after 1080 min.
  • the in vitro dissolution rate at pH 6.8 is about 50% after about 0.5 hour, about 50% after about 1 hour, about 50% after about 2 hours, about 50% after about 3 hours, about 50% after about 4 hours, about 50% after about 5 hours, about 50% after about 6 hours, about 50% after about 7 hours, about 50% after about 8 hours, about 50% after about 9 hours, about 50% after about 10 hours, about 50% after about 1 1 hours, about 50% after about 12 hours, about 50% after about 13 hours, about 50% after about 14 hours, about 50% after about 15 hours, about 50% after about 16 hours, about 50% after about 17 hours, or about 50% after about 18 hours. In one aspect, the in vitro dissolution rate at pH 6.8 is about 50% after about 10 minutes.
  • the in vitro dissolution rate at pH 6.8 is about 50% after about 20 minutes. In another aspect, the in vitro dissolution rate at pH 6.8 is about 50% after about 45 minutes. In another aspect, the in vitro dissolution rate at pH 6.8 is about 50% after about 60 minutes. In one aspect, the in vitro dissolution rate at pH 6.8 is about 50% after about 120 minutes. In another aspect, the in vitro dissolution rate at pH 6.8 is about 50% after about 180 minutes. In another aspect, the in vitro dissolution rate at pH 6.8 is about 50% after about 240 minutes. In one aspect, the in vitro dissolution rate at pH 6.8 is about 50% after about 480 minutes.
  • An analagous process can be used to produce pharmaceutical compositions comprising soybean oil where steps (a)-(c) above are replaced with (r) and (s):
  • step (d) If lactic acid is omitted from the formulation, then step (d).
  • step (s) is omitted and the process has step (r) followed by step (d).
  • Another embodiment described herein is a method for treating a neurological disease, neurodegenerative disease, autoimmune disease, or an iatrogenic disease or disorder comprising orally administering one or more doses of one or more fumarate esters described herein to a patient in need thereof, wherein the administration activates or modulates one or more cellular signaling pathways.
  • the cellular signaling pathway comprises the nuclear erythroid-derived 2-like 2 (NrfZ) dependent antioxidant response element (ARE) pathway.
  • Nrf2 pathway is involved in the cellular response to oxidative stress, which has been linked to neuronal degeneration in multiple sclerosis and in other neurodegenerative or autoimmune diseases (e.g., HIV), see, e.g., Gao et al., Clin. Pharmacol. 6: 19- 34 (2014), which is incorporated by reference herein for its teachings thereof.
  • Nrf2 is sequestered in the cytoplasm to the actin-bound Kelch-like ECH-associated protein 1 (Keapl). Keapl associates with the Cullin3 ubiquitin ligase adaptor protein, which positions Keapl and its substrate in proximity (e.g., NRF2) to the E3 ubiquitin ligase Rbxl .
  • the substrate e.g., NRF2
  • Nrf2 is polyubiquitinated and targeted for degradation.
  • Nrf2 is released from the Keapl/Nrf2 complex, preventing its degradation resulting in the concommitant translocation of NRF2 to the nucleus and activation of ARE-mediated gene transcription.
  • any of the non-limiting methods for determining the activation of Nrf2 may be used that are further described herein. See U. S. Patent No. 8,399,514, which is incorporated by reference herein for its teachings thereof.
  • Nrf2 activation may be determined by assessing the in vitro activation levels of Nrf2 and/or Nrf2 mRNA or protein expression levels.
  • the sequence of the promoter region of the Nrf2 gene (-1065 to -35) is known.
  • In vitro Nrf2 activation may be measured using a cell model system transfected or transduced with an expression construct containing the Nrf2 promoter element described above and an artificial reporter gene (e.g., luciferase or a fluorescent reporter gene (GFP, RFP, YFP etc.,). See, e.g., Chan et al., Proc. Natl. Aacd. Sci. USA 93 : 13943-13948 (1996) and Kwak et al., Mol. Cell.
  • an artificial reporter gene e.g., luciferase or a fluorescent reporter gene (GFP, RFP, YFP etc.
  • Nrf2 activation may be assessed by measuring reporter gene expression in treated vs. non-treated cells using standard imaging or fluorescence quantification techniques.
  • PCR e.g., qRT-PCR
  • Northern blotting may be used to determine expression levels of Nrf2 mRNA, or Western blotting to determine Nrf2 protein levels. See, e.g., Kwak et al., Mol. Cell. Biol. 22(9):2883-2892 (2002) and Kwak et al., Mol. Med. 7: 135-145 (2001), each of which is incorporated by reference herein for their teachings thereof.
  • Antibodies against Nrf2 are can be produced by methods known in the art and are commercially available from, for example, Stressgen ® , Enzo Life Sciences.
  • Nrf2 activation may be assessed by determining the subcellular localization and/or nuclear translocation of Nrf2 in treated vs. non-treated cells.
  • Such assays include cell staining, or analysis of cytoplasmic versus nuclear cell extracts.
  • an Nrf2-green fluorescence protein (GFP) fusion protein construct can be introduced into cells and visualized as described in, e.g., Kraft et al., J. Neurosci. 24: 1101-1112 (2004) and in Satoh et al., Proc. Natl. Aacd. Sci. USA 103(3):768-773 (2006).
  • Nrf2 activation may be determined through indirect measurement of the expression levels and/or activity of one or more genes under the control of Nrf2 in treated vs. non-treated cells.
  • the expression levels of NADPH dehydrogenase quinone 1 (NQOl) may be determined using, for example, qRT-PCR, Northern blotting, or Western blotting, see, e.g., Wierinckx et al., J. Neuroimmunology 166: 132-143 (2005).
  • Methods for measuring enzymatic activity of NQOl, using menadione as a substrate, are described in Dinkova-Kostova et al., Proc. Natl. Aacd. Sci. USA 98:3404-09 (2001).
  • the cell type being contacted with the one or more fumarate esters described herein may comprise a neuron or a neuronal cell line, a colon carcinoma cell line (e.g., DLD1), a neuroblastoma cell line (e.g., SkNSH or EVIR32), or a primary immune cell (e.g., a monocyte or T-lymphocyte or B -lymphocyte).
  • the cell may be a cell in culture (in vitro) or be inside of a mammal (in vivo).
  • endogenous Nrf2 activation may be determined by measuring the levels of Nrf2 or a Nrf2 regulated gene (e.g., NQOl) in a primary cell or cell population (e.g., a monocyte, T-lymphocyte, or neuronal cell) taken from a human patient having neurological disease, neurodegenerative disease, or autoimmune disease (e.g., multiple sclerosis or psoriasis).
  • a primary cell or cell population e.g., a monocyte, T-lymphocyte, or neuronal cell
  • autoimmune disease e.g., multiple sclerosis or psoriasis
  • compositions and methods provided are exemplary and are not intended to limit the scope of any of the specified embodiments. All of the various embodiments, aspects, and options disclosed herein can be combined in any and all variations or iterations.
  • the scope of the compositions, formulations, methods, and processes described herein include all actual or potential combinations of embodiments, aspects, options, examples, and preferences herein described.
  • the exemplary compositions and formulations described herein may omit any component, substitute any component disclosed herein, or include any component disclosed elsewhere herein.
  • enteric soft gelatin capsules Based on results of dimethyl fumarate (DMF) solubility testing in various lipid or lipophilic vehicles (data not shown), two formulations were selected for further studies and encapsulated in enteric soft gelatin capsules: one having polyethylene glycol and one with medium chain mono- and diglycerides. Organic acids such as caprylic acid, lactic acid, or oleic acid, were incorporated into the matrix fill to prevent the hydrolysis of dimethyl fumarate and to retain enteric properties of the shell. Application batches of enteric soft capsules were prepared by rotary die encapsulation using the fill compositions shown in Table 10.
  • the enteric soft capsules comprising the matrix formulations shown in Table 9 were subject to two-stage dissolution experiments in a USP Apparatus II (e.g., paddle method at 100 rpm). For these experiments, the capsules were introduced in to simulated gastric fluid, 0.1 NHC1, pH 1.2, for 2 hours. After 2 hours, the capsules were transferred to simulated intestinal fluid, phosphate buffer, pH 6.8. The results are shown in Figure 2. The results show that the capsules retain their enteric properties for at least 2 hours in simulated gastric fluid at pH 1.2. Both types of capsules released DMF shortly (-10 minutes) after being transferred to simulated intestinal fluid, pH 6.8.
  • the temporal stability of the dimethyl fumarate enteric soft capsule fill formulation shown in Table 11 was assessed.
  • a sample of DMF enteric soft capsules was subjected to accelerated aging by a 1 month of exposure to 40 °C and 75% relative humidity conditions and then evaluated in two-stage dissolution experiment.
  • a second sample of DMF enteric soft capsules was subject to two-stage dissolution shortly after manufacturing. Both sets of enteric capsules remained intact in the acidic conditions for at least 2 hours.
  • Figure 3 The freshly manufactured capsules released DMF slightly faster than the age-accelerated capsules when the pH was shifted to 6.8 (phosphate buffer).
  • enteric soft capsules comprising a Capmul® MCM matrix containing particles of dimethyl fumarate (Table 11) was subject to two-stage dissolution at pH 1.2 in simulated gastric fluid for 2 hours, then the buffer was changed to phosphate buffer, pH 6.8, containing 2% Cremophor® RH 40.
  • Figure 4 The enteric capsules remained intact in the acidic condition, and then began releasing DMF within 20 minutes of the pH-shift to simulated intestinal fluid.
  • Enteric soft capsules were prepared with matrices comprising 10% Tween® 80 (Uniqema,
  • Cremophor® RH 40 (BASF SE; polyoxyl 40 hydrogenated castor oil) (Table 12) and then tested in dissolution experiments at pH 6.8.
  • Figure 5 The enteric soft capsules with fills containing
  • Cremophor® released DMF much more rapidly than those containing Tween® 80.
  • Enteric soft capsules prepared containing fills with of 3% or 5% concentrations of Povidone K30 (e.g., PVP; 30,000 average MW) (Table 13) were tested in dissolution experiments at pH 6.8.
  • Figure 6 The enteric soft capsules with matrices containing 5% Povidone K30 released DMF more rapidly at pH 6.8 than those with fills containing 3% Povidone K30.
  • Capmul® MCM-based formulation was selected for further analysis.
  • a batch was manufactured using the formulation below (Table 14).
  • the release profile of DMF is modified by varying the enteric soft capsule shell composition or by altering the fill composition or particle size of the active ingredient.
  • Three different release profiles were observed under two-stage dissolution experiments. All enteric soft capsules were resistant to acid for at least 2 hours, and begin releasing DMF upon transition to pH 6.8.
  • Figure 7. A release profile was observed in an enteric soft capsule comprising a matrix of Capmul® MCM and Cremophor® RH 40 (Table 15; Release Profile 1).
  • a different release profile was observed with an enteric soft capsule shell comprising a Capmul® MCM and Tween® 80 matrix (Table 11; Release Profile 2).
  • Another release profile was observed with an enteric soft capsule shell comprising a matrix of soybean oil, Tween® 80, and solid particles of DMF having a mean particle distribution size of 148 ⁇ (Table 16; Release Profile 3).
  • Enteric soft capsules comprising matrices with DMF particles of differing mean particle size distributions as shown in Table 17 were subject to dissolution at pH 6.8.
  • Enteric soft capsules comprising various matrices comprising DMF particles having particle size distribution of d90 ⁇ 90 ⁇ were prepared and analyzed in two stage (pH 1.2 and pH 6.8) or single stage (pH 6.8) dissolution experiments (data not shown). (Tables 18-20).
  • enteric soft capsules with shell thicknesses of 0.028 inches or 0.033 inches were prepared comprising DMF particles having particle size distributions of d90 ⁇ 90 ⁇ in various matrices (Table 2 " ) and analyzed in two stage (pH 1.2 and pH 6.8) dissolution experiments (Figure 9).
  • a GMP batch of enteric soft capsules (0.038-inch shell thickness) comprising DMF particles having a particle size distribution of PSD: d90 ⁇ 90 ⁇ was prepared with the matrix composition shown in Table 22 and analyzed in two stage (pH 1.2 and pH 6.8) dissolution experiments ( Figure 14) and compared to application batches (Table 19).
  • DMF matrices were prepared with and without Povidone K30 or PEG 600 (Table 23) and analyzed in single stage (pH 6.8) dissolution experiments (Figure 11).
  • a batch of enteric soft capsules comprising DMF particles having particle size distribution of PSD: d90 ⁇ 90 ⁇ was prepared with the matrix composition shown in Table 24 and analyzed in two stage (pH 1.2 and pH 6.8) dissolution experiments (Figure 12).
  • This example provides a lower dose of DMF (120 mg) compared with that shown in Table 11 (240 mg).
  • a batch of enteric soft capsules (0.038-inch shell thickness) comprising monomethyl fumarate (MMF) particles having particle size distribution of PSD: d90 ⁇ 90 ⁇ was prepared with the matrix composition shown in Table 25. This example provides MMF (240 mg).
  • a batch of enteric soft capsules (0.038-inch shell thickness) comprising monomethyl fumarate (MMF) particles having particle size distribution of PSD: d90 ⁇ 90 ⁇ was prepared with the matrix composition shown in Table 26. This example provides MMF (480 mg).
  • Enteric soft capsules comprising particles of dimethyl fumarate, monomethyl fumarate, or a combination thereof having particle size distribution of PSD: d90 ⁇ 90 ⁇ can be prepared with an 850 mg matrix in the compositions shown in Table 27.
  • This example provides DMF or MMF in a QD formulation (-480 mg).
  • Enteric soft capsules comprising particles of dimethyl fumarate, monomethyl fumarate, or a combination thereof having particle size distribution of PSD: d90 ⁇ 90 ⁇ can be prepared with a 1000 mg matrix in the compositions shown in Table 28. This example provides DMF or MMF in a QD formulation (-480 mg).
  • the temporal stability of the dimethyl fumarate enteric soft capsule pharmaceutical composition shown in Table 29 was assessed under three ICH conditions.
  • a sample of DMF enteric soft capsules was subject to chemical analysis and two-stage dissolution shortly after manufacturing (To). Samples of DMF enteric soft capsules were subjected to Room Temperature Conditions (25 °C and 60% relative humidity) for 1 month, 2, months, 3 months, and 6 months. Other samples of DMF enteric soft capsules were subjected to Intermediate Conditions (30 °C and 65% relative humidity) for 1 month, 2 months, and 3 months. Additional samples of DMF enteric soft capsules were subjected to Accelerated Conditions (40 °C and 75% relative humidity) for 1 month and 2 months.
  • Fill compositions with increasing amounts of one or more fumarate esters e.g., dimethyl fumarate, monomethyl fumarate, or a combination thereof ranging from about 0.5 mmol to about 4.0 mmol
  • Millimole values for DMF or MMF (shaded rows) specify the millimoles of the respective species at the specified mass (mg).
  • These fill compositions may be encapsulated by a soft capsule shell composition as described herein.
  • the one or more fumarate esters comprise about 0.5 mmol to about 3.7 mmol FAE.
  • the fumarate ester (FAE) comprises DMF.
  • the fumarate ester comprises MMF.
  • the fumarate ester comprises MMF, DMF, or a combination thereof.
  • Fill compositions having one or more fumarate esters e.g., dimethyl fumarate, monomethyl fumarate, or a combination thereof ranging from about 0.5 mmol to about 3.5 mmol
  • a constant weight ratio of fumarate ester to fill e.g., about 0.40
  • Millimole values for DMF or MMF (shaded rows) specify the millimoles of the respective species at the specified mass (mg).
  • These fill compositions may be encapsulated by a soft capsule shell composition as described herein.
  • the fumarate ester comprises DMF.
  • the fumarate ester comprises MMF.
  • the fumarate ester comprises MMF, DMF, or a combination thereof.
  • a batch of enteric soft capsules (0.038-inch shell thickness) comprising monomethyl fumarate particles having particle size distribution of PSD: d90 ⁇ 90 ⁇ were prepared with the matrix composition shown in Table 33.
  • Samples from a batch of enteric soft capsules comprising the composition shown in Table 33 were subject to two-stage dissolution experiments in a USP Apparatus II with the parameters shown in Table 34.
  • the capsule was introduced in to simulated gastric fluid, 0.1 N HC1, pH 1.2, for 2 hours. After 2 hours, the capsule was transferred to simulated intestinal fluid, phosphate buffer, pH 6.8. Samples were removed from the apparatus at the indicated time points and the analyte was detected using high performance liquid chromatography (HPLC) with a UV detector. The results are shown in Figure 14. The results show that the capsules retain their enteric properties for at least 2 hours in simulated gastric fluid at pH 1.2. The capsules began releasing monomethyl fumarate within -10 minutes after being transferred to simulated intestinal fluid, pH 6.8, and achieved 100% dissolution after 120 minutes at pH 6.8.
  • HPLC high performance liquid chromatography
  • Fumarate ester particles (dimethyl fumarate or mono methyl fumarate) in the form of a dry powder were measured using a Malvern Mastersizer 2000 instrument equipped with vacuum unit and air pressure following manufacturer instructions; see, e.g. The Mastersizer 2000 Operators Guide; MAN0247-2-0, Malvern Instruments Ltd. (1999), which is incorporated by reference herein for such teachings.
  • Approximately 1.0 gram of the test sample was introduced into the dry powder feeder and measured under the parameters shown in Table 35, and the volume size distribution and the volume mean diameter were determined.
  • the particle size distribution is expressed as a particle volume distribution and the mean particle size of the distribution is expressed as a volume mean diameter.
  • BMI Body Mass Index
  • the patient demographics and number of patients dosed is provided in Table 36. They did not have any significant diseases or clinically significant abnormal findings during screening, medical history, physical and clinical examinations, laboratory evaluation, 12-lead ECG recording and vital sign measurement.
  • the performed study was a randomized, pilot, two-way crossover, open-label, single-dose, fasting study, with a screening period of 28-days prior to the first dose administration.
  • 19 blood samples, including one pre-dose blood sample, were collected from each subject except for the subject who did not complete the study to analyze the pharmacokinetic profile of the Test pharmaceutical composition as well as the Reference pharmaceutical product.
  • a single oral dose (240 mg) of a Test controlled release pharmaceutical composition comprising a fumarate ester or a Reference dimethyl fumarate composition was administered to the subjects in sitting posture with 240 mL of drinking water at ambient temperature. The administration was as per the randomization schedule and under open- label conditions.
  • Dosing water was measured and poured into individual containers before dosing. The containers were then covered and allowed to remain at ambient temperature until used. The drug was provided to the subjects in unit-dose containers. A visual inspection of each subject's mouth and hands was performed immediately after dosing to ensure drug ingestion.
  • Standardized meals with beverages were provided to the subjects at the following times: between 4.5- and 5.5-hours post-dose; between 9.5- and 10.5-hours post-dose; and at 13.5-hours post-dose.
  • a total of 19 pharmacokinetic blood samples (6 mL each) were drawn in each period according to the following schedule: 0 (pre-dose), and at intervals of 0.33, 0.67, 1, 1.25, 1.5, 1.75,
  • the plasma samples of subjects were analyzed using a validated LC-MS/MS method for monomethyl fumarate.
  • Calibration curve using an 8-point calibration curve standards, with concentrations ranging from 21.35 ng/mL to 4967.75 ng/mL were used to determine the concentrations of monomethyl fumarate in the samples of various subjects.
  • the pharmacokinetic parameters were calculated from the drug concentration versus time point by non-compartmental model using WinNonlin Professional Software Version 5.3 (Pharsight Corporation) for monomethyl fumarate. Statistical comparison of the pharmacokinetic parameters of the two products (Test, Reference) was performed using PROC MIXED of SAS ® Version 9.3 (SAS Institute Inc.).
  • the maximum measured plasma concentration (Cmax) and the time of observing the peak concentration (Jmax) was taken directly from the plasma concentration versus time profile of the individual subjects.
  • the AUCo ⁇ was the sum of measurable and extrapolated parts.
  • First order rate constants associated with the terminal (log-linear) portion of the curve were estimated via linear regression of time versus log concentration. This parameter was calculated by linear least squares regression analysis using last three or more non-zero plasma concentration values. The units of ⁇ ⁇ were hours -1 (1/h).
  • the terminal half-life was calculated using the formula: 0.693/ ⁇ ⁇ .
  • the unit of t1 ⁇ 2 was hour
  • the residual area in percentage was determined by the formula:
  • Descriptive statistics were calculated and reported for all pharmacokinetic parameters of monomethyl fumarate. ANOVA, power, and ratio analysis for ln-transformed pharmacokinetic parameters Cmax, AUCo ⁇ x, and AUCo ⁇ were calculated and reported for monomethyl fumarate. The 90% confidence interval for the ratio of the geometric least-squares means were calculated for the ln-transformed pharmacokinetic parameters, Cmax, AUCo ⁇ x, and AUCo ⁇ for monomethyl fumarate. All statistical analyses for monomethyl fumarate were performed using PROC MIXED of SAS® Version 9.3 (SAS Institute Inc., USA).
  • oils such as soybean oil, mineral oil, and vegetable oil were incorporated into the fill and tested. Based on the results, batches of soft capsules were prepared by rotary die encapsulation using the fill compositions shown in Table 40.
  • Soft capsules comprising particles of dimethyl fumarate, monomethyl fumarate, or a combination thereof having particle size distribution of PSD: d90 ⁇ 100 ⁇ can be prepared with 750 mg or 500 mg matrix fills as shown in Tables 42 and 43.
  • Soft capsules comprising particles of dimethyl fumarate, monomethyl fumarate, or a combination thereof having particle size distributions of PSD: d90 ⁇ 100 ⁇ were prepared with 750 mg or 500 mg matrix fills as shown in Tables 44-46.
  • Soft capsules comprising particles of a fumarate ester having particle size distributions of PSD: d90 ⁇ 100 ⁇ were prepared with 750 mg or 500 mg matrix fills as shown in Tables 47-49. Note that lactic acid is optional; when lactic acid is omitted, the amount of mono and di-glycerides (Tables 47 ⁇ 8) or soybean oil (Table 49) is increased accordingly.
  • Figures 17-19 show the release of a fumarate ester from different matrix fills in enteric soft capsules over 180 minutes in pH 1.2 media.
  • Figure 17 shows a fill comprising soybean oil
  • Figure 18 shows a fill comprising mixture of soybean and vegetable oil
  • Figure 19 shows a fill comprising a mixture of mono- and di- glycerides (e.g., Capmul ® MCM).
  • Soft capsules and enteric soft capsules were manufactured containing monomethyl fumarate fill matrices (e.g., Tables 44-46). These capsules were then coated with an enteric coating (e.g., aqueous methacrylic acid copolymer (Eudragit ® LI 00-55) and tri ethyl citrate) and evaluated in two-stage dissolution experiments.
  • Typical soft gel capsules e.g., Table 5
  • high- Bloom soft capsules e.g., Table 6
  • enteric soft capsules e.g., Table 8
  • Figure 20 illustrates the average of three two-stage dissolutions of monomethyl fumarate capsules in a coated soft gel capsules or a high-Bloom soft capsules.
  • the enterically coated soft capsules released about 50% of the monomethyl fumarate afer about 30-40 minutes after transition to pH 6.8.
  • Figure 21 illustrates the average of three two-stage dissolutions of monomethyl fumarate capsules in a coated soft gel capsules, high-Bloom soft capsules, or enteric soft capsules.
  • the enterically coated enteric soft capsules released about 50% of the monomethyl fumarate afer about 40-50 minutes after transition to pH 6.8.
  • Figure 22 compares the data shown in Figure 21 with the release of DMF from an enteric soft capsule (as shown in Figure 16).
  • Figure 23 compares the effect of a pre-coating (aqueous hydroxypropyl methylcellulose) applied prior to the application of the enteric coating of typical soft capsules or enteric soft capsules comprising a matrix fill of monomethyl fumarate.
  • the enterically coated soft capsules released about 50% of the monomethyl fumarate afer about 30-40 minutes after transition to pH 6.8.
  • the enterically coated enteric soft capsule released about 50% of the monomethyl fumarate after about 40-50 minutes after transition to pH 6.8.
  • Soft capsules comprising particles of fumarate esters (e.g., monomethyl fumarate, dimethyl fumarate, or a combination thereof) having particle size distributions of PSD: d90 ⁇ 100 ⁇ were prepared with 600 mg, 700 mg, or 800 mg matrix fills as shown in Tables 50-55.
  • lactic acid is optional; when lactic acid is omitted, the amount of mono and di-glycerides (Tables 50, 52, 54) or soybean oil (Tables 51, 53, 55) is increased accordingly.
  • Soft capsules comprising particles of fumarate esters (e.g., monomethyl fumarate, dimethyl fumarate, or a combination thereof) having particle size distributions of PSD: d90 ⁇ 100 ⁇ were prepared with 625 mg, matrix fills as shown in Tables 56-57.
  • fumarate esters e.g., monomethyl fumarate, dimethyl fumarate, or a combination thereof
  • Soft capsules comprising particles of monomethyl fumarate having particle size distributions of PSD: d90 ⁇ 100 ⁇ were manufactured for clinical investigations. Six different formulations were prepared. See Table 58. The dosage forms comprised two different doses of monomethyl fumarate, two different fill formulations, and two different shell components. The doses were either 200 mg or 214 mg of monomethyl fumarate and the fill formulations either comprised a mixture of mono- and di-glycerides (e.g., Capmul® MCM) or soybean oil. Tables 59-64. The soft capsules were either an enteric soft capsule (EnteriCare®, Banner Life Sciences) or soft gelatin capsules. See Tables 65-66. Both types of capsules were manufactured using rotary die encapsulation.
  • enteric soft capsule EnteriCare®, Banner Life Sciences
  • the capsules were coated with a hydroxypropylmethylcellulose undercoat and dried.
  • the capsules were then coated with an enteric coating containing methacrylic acid, ethyl acrylate copolymer (e.g., EUDRAGIT® L100-55, Evonik; Acryl-EZE®, Colorcon).
  • an enteric coating containing methacrylic acid, ethyl acrylate copolymer e.g., EUDRAGIT® L100-55, Evonik; Acryl-EZE®, Colorcon.
  • a polyvinyl alcohol moisture barrier top- coating was applied to the enterically coated capsules (e.g., Opadry® amb II, Clear, Colorcon). Table 68
  • a single-dose, randomized, open-label, 4-way crossover, pilot comparative bioavailability study of delay ed-release monomethyl fumarate (MMF) at a dose of 200 mg and 214 mg in capsules and TECFIDERA ® 240 mg dimethyl fumarate (DMF) delayed-release capsules in healthy male and female volunteers under fasting conditions was performed.
  • This pilot study assessed the tolerability, pharmacokinetics and comparative bioavailability of monomethyl fumarate in three test formulations and at two dose strengths (200 mg and 214 mg delayed-release capsules) and one reference drug, TECFIDERA ® (dimethyl fumarate; Biogen) 240 mg delayed-release capsules, in healthy male and female volunteers under fasting conditions.
  • a sample size of 24 subjects was selected for this study.
  • the study population included healthy, non-smoking, male and nonpregnant female volunteers, 18 years of age or older, with a body mass index (BMI) within 18.5— 29.9 kg/m 2 , inclusive.
  • BMI body mass index
  • TECFIDERA ® (dimethyl fumarate) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. See TECFIDERA ® product label, incorporated by reference herein for such teachings.
  • DMF dimethyl fumarate
  • MMF monomethyl fumarate
  • Nrf2 Nuclear factor-derived 2
  • MMF has been identified as a nicotinic acid receptor agonist in vitro.
  • TECFIDERA ® After oral administration of TECFIDERA ® , dimethyl fumarate undergoes rapid pre- systemic hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF). Dimethyl fumarate is not quantifiable in plasma following oral administration of TECFIDERA ® .
  • Pharmacokinetic analyses related to TECFIDERA ® were performed by evaluating plasma MMF concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers.
  • the median Jmax of MMF is 2-2.5 hours.
  • the peak plasma concentration (Cmax) and overall exposure (AUCoveraii) increased approximately dose proportionally in the dose range studied (120 mg to 360 mg).
  • the mean Cmax of MMF was 1.87 mg/L and AUCoveraii was 8.21 mg hr/L in MS patients.
  • a high-fat, high-calorie meal did not affect the AUC of MMF but decreased its Cmax by 40%; the Jmax was delayed from 2.0 hours to 5.5 hours. The incidence of flushing was reduced by approximately 25% in the fed state.
  • the apparent volume of distribution of MMF varies between 53 and 73 L in healthy subjects. Human plasma protein binding of MMF is 27-45%) and independent of concentration.
  • MMF tricarboxylic acid
  • CYP cytochrome P450
  • Exhalation of CO2 is the primary route of elimination, accounting for approximately 60%> of the TECFIDERA ® DMF dose. Renal and fecal are minor elimination routes, accounting for 16%) and 1%> of the dose, respectively. Trace amounts of MMF were present in urine.
  • the terminal half-life of MMF is approximately 1 hour and no circulating MMF is present at 24 hours in the majority of individuals. Accumulation of MMF does not occur with multiple doses of TECFIDERA ® .
  • This study will be conducted in normal healthy male and non-pregnant female volunteers. This will be a single-dose, randomized, open-label, 4-way crossover, four-period, four-sequence, four-treatment, single-center, comparative bioavailability study of three formulations of monomethyl fumarate 214 mg and 200 mg delay ed-release capsules and TECFIDERA ® (dimethyl fumarate) 240 mg delayed-release capsules (Biogen, Inc.).
  • the formulations will be studied using a crossover design with 24 healthy, non-smoking male and non-pregnant female volunteers being administered an oral dose of 1 ⁇ 214 mg, 1 ⁇ 200 mg, or 1 ⁇ 240 mg delayed-release capsule under fasting conditions. There will be at least a 2-day washout period between the study periods. The washout period of at least 2 days is estimated to be adequate in avoiding carry-over effects of the preceding treatments.
  • Blood samples were obtained by direct venipuncture in the arm and collected in pre-chilled sodium fluoride/potasium oxalate 6 mL Vacutainers ® . Blood sample collection times were recorded on the appropriate source documents and reported for each subject. Blood samples were collected at pre-dose (0 hour), and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 and 24-hours post-dose in each study period.
  • Subjects were confined to the clinic from at least 10-hours prior to dosing until at least 24- hours post-dose in Period 4, for a total of at least 178 hours (approximately 8 days) in the study.
  • Soybean oil Soybean oil, Soybean oil, Soybean oil,
  • Pharmacokinetic parameters were calculated using non-compartmental analysis (NCA) method using SAS® Version 9.4. The following pharmacokinetic parameters were estimated (where possible) for monomethyl fumarate and included in the pharmacokinetic and statistical analysis for the subjects in the final data set:
  • Jmax Time when the maximal plasma concentration is observed.
  • AUCo ⁇ x Area under the concentration-time curve from time zero until the last measurable concentration or last sampling time ⁇ , whichever occurs first. AUCo ⁇ x is estimated using the trapezoidal method.
  • AUCo ⁇ Area under the concentration-time curve from time zero to infinity, calculated as AUCo ⁇ x + Ciast/ ⁇ , where Ciast is the last measurable concentration.
  • ⁇ Terminal elimination rate constant, estimated by linear regression analysis of the terminal portion of the natrual log of concentration (ln-concentration) vs. time plot.
  • t1 ⁇ 2 Terminal elimination half-life, estimated as 1 ⁇ (2)/ ⁇ .
  • Missed samples and non-reportable concentrations (e.g. quantity not sufficient) from the analytical laboratory were treated in the pharmacokinetic analysis as if they had not been scheduled for collection.
  • Descriptive statistics (min., max., median, mean, standard deviation, and coefficient of variability) of all pharmacokinetic parameters were calculated for monomethyl fumarate for the Test and Reference products.
  • the dosage forms comprised six doses of monomethyl fumarate, all with the same fill composition and the same soft gelatin shell.
  • the doses were either 90 mg, 95 mg, 100 mg, 1 15 mg, 200 mg, or 220 mg monomethyl fumarate and comprised 34% monomethyl fumarate, 48% of a mixture of mono- and di-glycerides (e.g., Capmul® MCM), 3% polyvinylpyrrolidone, 10% polyoxyl 40 hydrogenated castor oil, and 5% lactic acid.
  • Tables 71- 72 Tables 71- 72.
  • the matrix fill was encapsulated in soft gelatin capsules comprising 195 Bloom gelatin using rotary die encapsulation. See Table 66.
  • the 90 mg, 95 mg, 100 mg, and 1 15 mg dosage forms were 5 oval capsules and the 200 mg and 220 mg dosage forms were 12 oval capsules.
  • the capsules were coated with a hydroxypropylmethylcellulose undercoat and dried.
  • the capsules were then coated with an enteric coating containing methacrylic acid, ethyl acrylate copolymer (e.g., EUDRAGIT® L100-55, Evonik; Acryl-EZE®, Colorcon).
  • Table 67 A polyvinyl alcohol moisture barrier top-coating was applied to the enterically coated capsules (e.g., Opadry® amb II, Clear, Colorcon).
  • Table 68 The enterically coated capsules comprising 195 Bloom gelatin using rotary die encapsulation. See Table 66.
  • the 90 mg, 95 mg, 100 mg, and 1 15 mg dosage forms
  • TOTAL 336 100.0% 584 100.0% 643.2 100.0%
  • Ratio API Lipid 1.78 1.78 1.77 1.77 1.78 1.78
  • Ratio API Vehicle 1.92 1.92 1.92 1.92 1.92 1.92 mmol MMF 0.88 1.54 1.69

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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant des esters de fumarate, des procédés pour les préparer et des procédés de traitement de sujets nécessitant un tel traitement. En particulier, elle concerne des compositions pharmaceutiques orales à libération contrôlée comprenant des esters de fumarate en suspension dans des matrices liquides. Un mode de réalisation de la présente invention concerne une composition pharmaceutique comprenant des esters de fumarate en suspension dans un lipide ou un liquide lipophile présentant une biodisponibilité améliorée.
PCT/US2016/048976 2016-02-29 2016-08-26 Formes posologiques d'ester de fumarate WO2017151184A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10391160B2 (en) 2014-03-14 2019-08-27 Biogen Ma Inc. Dimethyl fumarate and vaccination regimens
US10959972B2 (en) 2014-11-17 2021-03-30 Biogen Ma Inc. Methods of treating multiple sclerosis
US11052062B2 (en) 2004-10-08 2021-07-06 Biogen Swiss Manufacturing Gmbh Controlled release pharmaceutical compositions comprising a fumaric acid ester

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US20150246016A1 (en) * 2014-02-28 2015-09-03 Banner Life Sciences Llc Controlled release enteric soft capsules of fumarate esters

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* Cited by examiner, † Cited by third party
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US20150246016A1 (en) * 2014-02-28 2015-09-03 Banner Life Sciences Llc Controlled release enteric soft capsules of fumarate esters

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11052062B2 (en) 2004-10-08 2021-07-06 Biogen Swiss Manufacturing Gmbh Controlled release pharmaceutical compositions comprising a fumaric acid ester
US11229619B2 (en) 2004-10-08 2022-01-25 Biogen Swiss Manufacturing Gmbh Controlled release pharmaceutical compositions comprising a fumaric acid ester
US10391160B2 (en) 2014-03-14 2019-08-27 Biogen Ma Inc. Dimethyl fumarate and vaccination regimens
US10555993B2 (en) 2014-03-14 2020-02-11 Biogen Ma Inc. Dimethyl fumarate and vaccination regimens
US10994003B2 (en) 2014-03-14 2021-05-04 Biogen Ma Inc. Dimethyl fumarate and vaccination regimens
US10959972B2 (en) 2014-11-17 2021-03-30 Biogen Ma Inc. Methods of treating multiple sclerosis
US11007167B2 (en) 2014-11-17 2021-05-18 Biogen Ma Inc. Methods of treating multiple sclerosis
US11007166B2 (en) 2014-11-17 2021-05-18 Biogen Ma Inc. Methods of treating multiple sclerosis
US11129806B2 (en) 2014-11-17 2021-09-28 Biogen Ma Inc. Methods of treating multiple sclerosis
US11246850B2 (en) 2014-11-17 2022-02-15 Biogen Ma Inc. Methods of treating multiple sclerosis

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