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|ANA MARIA THAI MATURANTIUS009814692B2 MATATAN (12 ) United States Patent (10 ) Patent No. : US 9 ,814 ,692 B2 Vaughn et al. (45 ) Date of Patent : * Nov . 14 , 2017

(54 ) FUMARATE ESTER DOSAGE FORMS 6 , 355 ,676 B1 3 / 2002 Joshi 6, 436 ,992 B1 8 / 2002 Joshi 6 , 482 , 516 B1 11/ 2002 Dietel (71 ) Applicant : BANNER LIFE SCIENCES LLC , 6 , 509 , 376 B1 1 / 2003 Joshi High Point, NC (US ) 7 , 157, 423 B2 1 / 2007 Joshi 7 ,320 ,999 B2 1 /2008 Joshi (72 ) Inventors : Jason M . Vaughn , Browns Summit , 7 , 432 , 240 B2 10 / 2008 Joshi NC (US ) ; Justin R . Hughey, Asheboro , 7 , 612 , 110 B2 11/ 2009 Joshi 7 , 619 , 001 B2 11 / 2009 Joshi NC (US ) ; Tanesha Roberts , 7 ,803 , 840 B2 9 /2010 Joshi Greensboro , NC (US ) ; Tatyana 7 , 915 , 310 B2 3 / 2011 Joshi Dyakonov , Greensboro , NC (US ) ; Sunil 8, 293 ,270 B2 10 / 2012 Sukuru Agnihotri, Scarborough , ME (US ) ; 8 , 333 , 989 B2 12 /2012 Sukuru Aqeel A . Fatmi, High Point, NC (US ) 8 ,399 , 514 B2 3 / 2013 O Neill 8 ,524 , 773 B2 9 / 2013 Joshi 8, 669, 281 B1 3 / 2014 Sanrame ( 73 ) Assignee : Banner Life Sciences LLC , High 8, 669 ,282 B2 3 / 2014 Zicker Point, NC (US ) 8 , 685 ,445 B2 4 /2014 Hassan 8 , 759 , 393 B2 6 / 2014 Joshi ( * ) Notice : Subject to any disclaimer , the term of this 9 , 090 , 558 B2 7 / 2015 Sanrame patent is extended or adjusted under 35 9 , 326 , 947 B1 * 5 / 2016 Dyakonov ...... A61K 9 /4875 9 , 511 ,043 B2 * 12 / 2016 Dyakonov ...... A61K 31 / 225 U . S . C . 154 (b ) by 0 days. 9 ,517 , 209 B2 * 12 / 2016 Dyakonov ...... A61K 9 /4875 9 , 526 , 965 B2 * 12 /2016 Gatherer A63B 71/ 0054 This patent is subject to a terminal dis 9 ,566 ,259 B1 * 2/ 2017 Vaughn A61K 31/ 225 claimer . 9 ,636 ,318 B2 * 5 /2017 Vaughn .. A61K 31 /225 9 ,636 ,319 B1 * 5 / 2017 Vaughn ...... A61K 31 / 225 (21 ) Appl. No. : 15 /386 ,175 2003/ 0018072 A11 /2003 Joshi 2004 /0054001 A1 3 / 2004 Petzelbauer ( 22 ) Filed : Dec . 21 , 2016 2006 / 0051345 Al 3 / 2006 Frohna (Continued ) (65 ) Prior Publication Data US 2017 /0100362 A1 Apr. 13, 2017 FOREIGN PATENT DOCUMENTS EP 0312697 A2 4 / 1989 Related U . S . Application Data wo 0030622 A2 6 /2000 (63 ) Continuation of application No . 15 /248 ,506 , filed on (Continued ) Aug. 26 , 2016 , now Pat. No . 9, 636 ,318 , which is a continuation - in -part of application No . 14 /840 ,072 , OTHER PUBLICATIONS filed on Aug . 31 , 2015 , now Pat. No . 9 ,326 ,947 , and a continuation - in - part of application No . Verma, R . K . , et al . , “ Formulation Aspects in the Development of Osmotically Controlled Oral Drug Delivery Systems” , Journal of PCT /US2015 /047636 , filed on Aug . 31, 2015 . Controlled Release , vol. 79 (2002 ), pp . 7 - 27 . (60 ) Provisional application No. 62/ 300 ,941 , filed on Feb . International Search Report for corresponding Application No. 29, 2016 , provisional application No . 62 /356 ,872 , PCT/ US2016 /048967 , dated Dec . 30 , 2016 . filed on Jun . 30 , 2016 . Tecfidera® Prescribing Information Mar. 2013 (Biogen IDEC ) . Sheikh et al. , “ Tolerability and pharmacokinetics of delayed -release (51 ) Int . Cl. dimethyl fumarate administered with and without aspirin in healthy volunteers ," Clinical Therapeutics 35 ( 10 ): 1582 - 1594 ( 2013 ). A61K 8 /04 ( 2006 .01 ) Schimrigk et al. , “ Oral fumaric acid esters for the treatment of active A61K 9 /48 ( 2006 . 01) multiple sclerosis : an open - label, baseline -controlled pilot study, " A61K 47 /44 ( 2017 .01 ) European J . Neurology 13 ( 6 ) : 604 -610 (2006 ) . A61K 8 /37 ( 2006 .01 ) A61K 31/ 225 ( 2006 .01 ) (Continued ) A61K 9 / 00 ( 2006 .01 ) ( 52 ) U .S . CI. Primary Examiner — Abigail Vanhorn CPC ...... A61K 31/ 225 ( 2013 .01 ); A61K 9 / 0053 (74 ) Attorney, Agent, or Firm — Brinks Gilson & Lione ( 2013 .01 ) ; A61K 9 /4858 ( 2013 .01 ) ; A61K 9 / 4866 ( 2013 .01 ) ; A61K 9 / 4875 ( 2013 . 01 ) ; (57 ) ABSTRACT A61K 9 /4891 (2013 .01 ) (58 ) Field of Classification Search Described herein are pharmaceutical compositions compris None ing fumarate esters , methods for making the same, and methods for treating subjects in need thereof . In particular, See application file for complete search history. oral controlled release pharmaceutical compositions com References Cited prising fumarate esters suspended in liquid matrices are (56 ) described . One embodiment described herein is a pharma U . S . PATENT DOCUMENTS ceutical composition comprising fumarate esters suspended in a lipid or lipophilic liquid with enhanced bioavailability . 5 , 146 , 730 A 9 / 1992 Dietel 5 ,424 , 332 A 6 / 1995 Speiser 5 ,459 , 983 A 10 / 1995 Dietel 20 Claims, 25 Drawing Sheets US 9, 814 ,692 B2 Page 2

References Cited 2015/ 0366803 Al 12 /2015 O Neill ( 56 ) 2017 / 0071891 A1 * 3 / 2017 Dyakonov ...... A61K 31/ 225 U . S . PATENT DOCUMENTS 2017 /0100360 A1 * 4 /2017 Dyakonov ...... A61K 31 / 225 2006 /0115527 A1 6 /2006 Chidambaram FOREIGN PATENT DOCUMENTS 2006 / 0165778 A1 7 / 2006 Hassan 2007 / 0104778 AL 5 / 2007 Ketsela WO 02055063 A2 7 /2002 2008 / 0004344 AL 1 / 2008 Nilsson WO 02055066 Al 7 / 2002 2008 /0233185 Al 9 / 2008 Joshi WO 02055067 A2 7 /2002 2008 /0299196 Al 12 / 2008 Nilsson wo 2004030658 A1 4 /2004 2008 /0300217 Al 12 / 2008 Nilsson WO 2005009409 A2 2 / 2005 2009 /0304790 Al 12 / 2009 Nilsson WO 2005023241 A1 3 / 2005 2010 /0034274 AL 2 /2010 Li WO 2006023629 A2 3 / 2006 2010 /0130607 AL 5 / 2010 Gold WO 2006023649 A2 3 / 2006 2010 / 0259906 A 10 /2010 Chang Wo 2006023651 A2 3 / 2006 2010 /0324327 Al 12 / 2010 Lee WO 2006036371 A2 4 / 2006 2011/ 0112196 A1 5 /2011 Lukashev WO 2006037342 A2 4 / 2006 2012 / 0034274 A12 / 2012 Rupp WO 2007042034 Al 4 / 2007 2012 /0165404 Al 6 / 2012 Lukashev wo 2007042035 A2 4 / 2007 2012 /0259012 A 10 / 2012 Lukashev WO 2008096271 A2 8 / 2008 2013 /0216615 AL 8 / 2013 Goldman WO 2010022177 A2 2 / 2010 2013 /0259906 A1 10 / 2013 Rupp WO 2010079222 AL 7 /2010 2013 / 0295169 Al 11/ 2013 Goldman WO 2010126605 Al 11 / 2010 2013 / 0302410 AL 11/ 2013 Gold WO 2012162669 A1 11 / 2012 2013 / 0303613 A1 11/ 2013 Lukashev WO 2012170923 A112 /2012 2013 / 0315993 AL 11/ 2013 Nilsson WO 2013076216 Al 5 / 2013 2013 / 0316003 AL 11/ 2013 Nilsson WO 2013090799 A1 6 / 2013 2013 /0317103 Al 11 / 2013 Lukashev WO 2013092269 Al 6 / 2013 2013 / 0324539 Al 12 / 2013 Annamalai Wo 2013112859 Al 8 / 2013 2014 / 0037720 Al 2 / 2014 Nilsson WO 2013119677 Al 8 / 2013 2014 / 0037740 A1 2 / 2014 Nilsson WO 2013148690 A1 10 / 2013 2014 / 0056973 Al 2 / 2014 Virsik WO 2013158969 A1 10 / 2013 2014 /0056978 A1 2 / 2014 Karaborni WO 2014028299 Al 2 / 2014 2014 / 0057917 A1 2 / 2014 Virsik WO 2014031844 Al 2 / 2014 2014 / 0057918 A1 2 / 2014 Shreeniwas WO 2014031892 Al 2 / 2014 2014 /0065211 Al 3 / 2014 Karaborni WO 2014031894 Al 2 / 2014 2014 / 0066505 Al 3 / 2014 Joshi WO 2014031897 Al 2 / 2014 2014 /0099364 A2 4 / 2014 Nilsson WO 2014031901 A1 2 / 2014 2014 /0163100 A1 6 / 2014 Dawson WO 2014143146 AL 9 / 2014 2014 /0179779 A1 6 / 2014 Chao WO 2014190056 A2 11 / 2014 2014 /0193495 A1 7 /2014 Nilsson WO 2014197860 A1 12 /2014 2014 / 0199386 Al 7 / 2014 Nilsson WO 2015017762 Al 2 / 2015 2014 /0199387 Al 7 /2014 Nilsson WO 2015028472 AL 3 / 2015 2014 /0199388 A1 7 / 2014 Nilsson WO 2015028473 A1 3 /2015 2014 / 0199390 A1 7 / 2014 Nilsson WO 2015042294 A 3 / 2015 2014 /0199392 Al 7 / 2014 Nilsson WO 2015044853 A2 4 /2015 2014 /0199393 Al 7 / 2014 Nilsson WO 2015086467 A1 6 / 2015 2014 /0200272 Al 7 / 2014 Nilsson wo 2015089420 A1 6 / 2015 2014 /0200273 A1 7 / 2014 Nilsson WO 2015105757 Al 7 / 2015 2014 /0200363 A1 7 / 2014 Irdam wo 2015128492 A1 9 / 2015 2014 / 0205659 Al 7 / 2014 Nilsson wo 2015130998 A1 9 /2015 2014 /0275048 AL 9 / 2014 Sanrame 2014 /0275205 Al 9 /2014 Sanrame OTHER PUBLICATIONS 2014 / 0275250 AL 9 / 2014 Cundy 2014 / 0323570 A1 10 / 2014 Gold Schilling et al. , “ Fumaric acid esters are effective in chronic 2014 /0348914 A9 11 /2014 Karaborni experimental autoimmune encephalomyelitis and suppress macro 2014 / 0348915 A9 11/ 2014 Karaborni phage infiltration , " Clinical and Experimental Immunology 2014 / 0350018 A9 11 / 2014 Virsik 145 ( 1 ) : 101- 107 ( 2006 ) . 2014 /0378542 Al 12 / 2014 Karaborni Gold et al ., " Safety of a novel oral single -agent fumarate, BG00012 , 2015 /0024049 AL 1 / 2015 Nilsson in patients with relapsing - remitting multiple sclerosis: results of a 2015 / 0079180 A1 3 / 2015 Karaborni et al. phase 2 study, ” Journal of Neurology 253 (Suppl . 2 ) : II144 - II145 2015 / 0132747 A1 5 / 2015 Lukashev ( 2006 ) . 2015 / 0190360 A17 / 2015 Cundy Kappos et al . , “ BG00012 , a novel oral fumarate , is effective in 2015 /0209318 A1 7 / 2015 Goldman patients with relapsing -remitting multiple sclerosis ” , Multiple Scle 2015 /0246016 A1 9 / 2015 Fatmi rosis 2 (Suppl . 1) :585 ( 2006 ). 2015 /0252013 AL 9 /2015 Annamalai 2015 /0307914 A9 10 / 2015 Virsik * cited by examiner atent Nov . 14 , 2017 Sheet 1 of 25 US 9 ,814 ,692 B2

FIGURE 1

whithin API

* * Encapsulation www*www Homogenization

Delayed release SGC U . S . Patent Nov . 14, 2017 Sheet 2 of 25 US 9 ,814 ,692 B2

FIGURE 2

pH 1 . 2 pH 6 . 8

%CumulativeRelease mwimmen

sulfamesCapmul PEG

lammut mmmm wwwwwwwwwwwwwwwwwwmmmmmmmmmmmm 0 30 60 90 120 150 180 210 240 270 300 330 Time (min ) U . S . Patent Nov . 14, 2017 Sheet 3 of 25 US 9 ,814 ,692 B2

FIGURE 3

pH 1 . 2 pH 6 . 8 e

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Initial modernes 1M 40 /75

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FIGURE 4

8aposee pH 1 . 2 pH 6 . 8 %CumulativeRelease

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FIGURE 5

8enes

%CumulativeRelease nesontpas pH 6 . 8 mengham Cremophor RH 40 mwenyewe Tween - 80

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FIGURE 6

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FIGURE 7

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FIGURE 8

min nkanmunandamanununua QQ %CumulativeRelease s mimi A contineMean PSD 1684 BoethiusMean PSD 1484 seguinte Come Mean PSD 904

a De Mean PSD 764 (PVP ) Elmoto Mean PSD 264 pH 6 . 8 F - Mean PSD 264 ( PVP ) 20 40 60 80 100 120 Time (min ) U . S . Patent Nov . 14, 2017 Sheet 9 of 25 US 9 ,814 ,692 B2

FIGURE 9

pH 1 . 2 pH 6 . 8

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FIGURE 10

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FIGURE 11

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FIGUREAY 12

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FIGURE 13

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FIGURE 14

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FIGURE 15

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FIGURE 16

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FIGURE 17

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FIGURE 18

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FIGURE 19

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FIGURE 20

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FIGURE 21

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FIGURE 22

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FIGURE 23

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80 %

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FIGURE 24

4500 4000 com T1 3500 T2 3000 energens T3 MeanMMFConc.(ng/mL) w man R 2500 2000 1500 1000 500

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FIGURE 25

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...... 0 ! 2 4 6 8 10 12 Time ( hours ) US 9 , 814 ,692 B2 FUMARATE ESTER DOSAGE FORMS No . WO 2013 / 119677 and U . S . Pat . No. 6 , 509 , 376 . TEC FIDERA® was intended to reduce the undesirable side CROSS REFERENCE TO RELATED effects by preventing release of DMF in the stomach . APPLICATIONS The enterically coated DMF granules in TECFIDERA? , 5 however , lack uniformity in shape and size , and the enteric This application is a continuation of U .S . patent applica - coating may not be evenly distributed over the minitablets . tion Ser. No. 15 /248 , 506 , filed Aug . 26 , 2016 , which claims This lack of homogeneity can diminish the enteric properties priority to U . S . Provisional Patent Application No . 62 /300 , and affect the acid - resistance , dissolution , and release rates . 941 , filed on Feb . 29 , 2016 and U . S . Provisional Patent In addition , the integrity of the acid - resistant coating fails Application No . 62 /356 ,872 , filed on Jun . 30 , 2016 ; and is 10 when the coating cracks or flakes off . This leads to DMF a continuation in part of U . S . patent application Ser. No. release in the stomach and can cause flushing and the 14 /840 ,072 , now issued as U . S . Pat . No. 9 , 326 , 947 , and negative gastrointestinal side effects . claims priority to International Patent Application No . PCT/ A subject ' s stomach content also affects delivery of DMF US2015 / 47636 , both filed on Aug . 31 , 2015 ; each of which from TECFIDERA® . A meal was shown to decrease C max is incorporated herein in its entirety by express reference 15 by 40 % and delay Tmor from 2 . 0 hours to 5 . 5 hours ; the AUC thereto . This application is related to U . S . patent application was unaffected . See WO 2006 / 037342 . A reduction in the Ser . Nos . 15 /073 , 714 and 15 / 073 , 720 , both filed on Mar. 18 , incidence of flushing by approximately 25 % in the post 2016 ; and U .S . patent application Ser . No . 14 /633 , 164, now prandial state was also observed . See TECFIDERA? Pre issued as U . S . Pat . No . 9 , 326 , 965 and International Patent scribing Information March 2013 ( Biogen Idec Inc . ) . Application No . PCT/ US2015 /017893 , both filed on Feb . 20 DMF sublimes at relatively low temperatures . About 27 , 2015 ; each of which is incorporated herein in its entirety 15 - 20 % of the DMF active ingredient is lost owing to by express reference thereto . This application is also related sublimation during the wet - granulation processing used to to International Patent Application No. PCT/ US2016 /48967 , manufacture TECFIDERA® . See WO 2013 /076216 . Subli having the same title and filed on Aug . 26 , 2016 , which is mation also causes loss of DMF during storage and unused incorporated herein in its entirety by express reference 25 TECFIDERA® capsules must be discarded 90 days after a thereto . bottle of the capsules is opened . Accordingly, it is desirable to develop oral controlled TECHNICAL FIELD release formulations of fumarate esters that: ( 1 ) provide enhanced bioavailability of the fumarate esters as compared Described herein are pharmaceutical compositions com - 30 to TECFIDERA? or other solid dosage forms comprising prising fumarate esters , methods for making the same, and granulated forms or minitablets; ( 2 ) prevent flushing and the methods for treating subjects in need thereof. In particular, undesirable GI side effects associated with oral administra oral controlled release pharmaceutical compositions com - tion of fumarate esters ; ( 3 ) reduce or eliminate fumarate prising fumarate esters suspended in liquid matrices are ester sublimation during manufacturing and storage; ( 4 ) described . One embodiment described herein is a pharma - 35 increase the long -term stability of the pharmaceutical com ceutical composition comprising fumarate esters suspended position ; and ( 5 ) provide a variety of different release in a lipid or lipophilic liquid with enhanced bioavailability . profiles , dose strengths, dosage forms, and dosing regimens. BACKGROUND SUMMARY 40 Fumaric acid esters (FAE ; fumarate esters , e . g . , alkyl or One embodiment described herein is an oral pharmaceu dialkyl fumarate esters such as dimethyl fumarate or tical composition comprising a liquid suspension of solid monomethyl fumarate ) are pharmacologically active sub - particles of one or more fumarate esters comprising dim stances used for treating hyperproliferative, inflammatory, ethyl fumarate , monomethyl fumarate , a pro -drug of or autoimmune disorders . They were first used to treat 45 monomethyl fumarate , or a combination thereof. In another psoriasis and were licensed for this indication in Germany in embodiment, the oral pharmaceutical compositions have 1995 as Fumaderm® (Biogen Idec , Inc . , Cambridge , Mass ., enhanced bioavailability and can be administered at lower USA ) . Fumaderm® produces various undesirable side doses of fumarate ester with equivalent clinical efficacy . effects, including flushing , headaches , dizziness , eructation , Another embodiment described herein is an oral pharma nausea , vomiting , abdominal and intestinal cramps , and 50 ceutical composition comprising a liquid suspension of one diarrhea . High concentrations of the drug released in the or more fumarate esters comprising dimethyl fumarate , stomach are believed to be responsible for such side effects . monomethyl fumarate , a pro - drug thereof, or a combination After oral intake , the main component of Fumaderm® , thereof. In one aspect, the liquid comprises a flowable , dimethyl fumarate (DMF ), is hydrolysed by esterases to single -phase liquid . In another aspect, the liquid comprises monomethyl fumarate (MMF ) , the bioactive metabolite . 55 a non - aqueous liquid . In another aspect , the liquid comprises After absorption in the small intestine , MMF is believed to a lipid or lipophilic liquid vehicle . In another aspect, the interact with immunocytes in the bloodstream . The primary composition comprises about 80 mg to about 230 mg of the plasma metabolites of DMF are monomethyl fumarate , fumarate ester. In another aspect, the composition comprises fumaric acid , citric acid , and glucose . Monomethyl fumarate about 90 mg to about 115 mg of the fumarate ester . In is further metabolized in the tricarboxylic acid cycle to 60 another aspect, the composition comprises about 180 mg to carbon dioxide and water . about 220 mg of the fumarate ester. In another aspect, the An oral formulation of DMF was developed and approved composition comprises about 180 mg to about 200 mg of the for the treatment of multiple sclerosis . This formulation , fumarate ester. In another aspect, the liquid comprises a lipid TECFIDERA? (Biogen Idec, Inc. ), is available as hard vehicle , one or more solubility enhancing agents , and a gelatin delayed -release capsules containing 120 mg or 240 65 neutralizing agent. In another aspect, the one or more mg of granulated dimethyl fumarate enterically coated solubility enhancing agents comprise polyvinylpyrrolidone , minitablets . See International Patent Application Publication polyoxyl 40 hydrogenated castor oil, or a combination US 9 ,814 ,692 B2 thereof. In another aspect, the liquid comprises mono - and a capsule comprising one or more subcoatings, one or more diglycerides, polyvinylpyrrolidone , polyoxyl 40 hydroge enteric coatings , and one or more top coatings . In another nated castor oil , and lactic acid . In another aspect , the weight aspect, the fumarate ester is a pro - drug of monomethyl ratio of the fumarate ester to non - aqueous liquid is about 1 : 1 fumarate . In another aspect , the fumarate ester is dimethyl to about 1 : 8 . In another aspect , the weight ratio of the 5 fumarate . In another aspect , the fumarate ester is monom fumarate ester to non - aqueous liquid is about 1 : 2 . In another ethyl fumarate . aspect , the fumarate ester comprises about 10 % to about Another embodiment described herein is an oral pharma 50 % of the composition by weight. In another aspect, the ceutical composition comprising a liquid suspension of one fumarate ester comprises about 20 % to about 40 % of the or more fumarate esters that is bioequivalent to a 240 mg composition by weight . In another aspect , the fumarate ester 10 dose of TECFIDERA® (dimethyl fumarate ) . In one aspect , comprises about 30 % to about 40 % of the composition by the composition comprises about 190 mg to about 220 mg of weight. In another aspect , the fumarate ester comprises the fumarate ester. In another aspect, bioequivalence is about 35 % of the composition by weight. In another aspect, achieved by simultaneously administering two dosage the liquid comprises about 50 % to about 85 % of the com forms, each comprising about 90 mg to about 100 mg of the position by weight. In another aspect, the liquid comprises 15 fumarate ester. In another aspect, the composition comprises about 60 % to about 70 % of the composition by weight. In about 190 mg to about 200 mg of dimethyl fumarate , another aspect , the liquid comprises about 60 % of the monomethyl fumarate , a pro - drug thereof, or a combination composition by weight. In another aspect, lactic acid com - thereof . In another aspect, the composition comprises about prises about 5 % of the composition by weight. In another 190 mg to about 200 mg of dimethyl fumarate or monom aspect , the composition comprises : about 30 % to about 40 % 20 ethyl fumarate . by weight of the one or more fumarate esters ; about 55 % to Another embodiment described herein is a method of about 65 % by weight of the liquid ; and about 5 % by weight treating or reducing the symptoms of multiple sclerosis in a of lactic acid . In another aspect, the composition comprises subject, the method comprising contacting peripheral blood about 90 mg to about 220 mg of one or more fumarate esters . mononuclear cells or monocytes of the subject with monom In another aspect, the composition comprises about 95 mg of 25 ethyl fumarate by administering in an oral pharmaceutical one or more fumarate esters . In another aspect, the compo - composition comprising one or more fumarate esters in a sition comprises about 100 mg of one or more fumarate liquid vehicle . In another aspect , the composition comprises esters . In another aspect, the composition comprises about a liquid suspension of solid particles of dimethyl fumarate , 200 mg to about 220 mg of one or more fumarate esters . In monomethyl fumarate , pro - drugs thereof, or combinations another aspect, the composition comprises about 200 mg of 30 thereof. In another aspect , the liquid comprises a flowable , one or more fumarate esters . In another aspect, the compo - single - phase liquid . In another aspect, the liquid comprises sition is encapsulated in a capsule . In another aspect, the a non -aqueous liquid . In another aspect, the liquid comprises composition is encapsulated in a soft capsule . In another a lipid or lipophilic liquid vehicle . In another aspect, the aspect , the composition is encapsulated in an enterically composition comprises about 80 mg to about 115 mg or coated soft capsule . In another aspect, the enteric coating 35 about 160 mg to about 230 mg of the fumarate ester . In comprises an acrylic polymer or copolymer . In another another aspect , the composition comprises about 95 mg to aspect , the composition is encapsulated in an enterically about 100 mg of the fumarate ester. In another aspect , the coated soft capsule shell comprising a subcoating . In another composition comprises about 180 mg to about 220 mg of the aspect , the subcoating comprises hydroxypropylmethylcel fumarate ester. In another aspect, the composition comprises lulose . In another aspect, the composition is encapsulated in 40 about 190 mg to about 200 mg of the fumarate ester . In an enterically coated soft capsule shell comprising a top - another aspect , the liquid comprises a lipid vehicle , one or coating . In another aspect , the topcoating comprises poly - more solubility enhancing agents , and a neutralizing agent. vinyl alcohol. In another aspect, the fumarate ester is a In another aspect, the one or more solubility enhancing prodrug to monomethyl fumarate . In another aspect, the agents comprise polyvinylpyrrolidone , polyoxyl 40 hydro fumarate ester is dimethyl fumarate . In another aspect, the 45 genated castor oil, or a combination thereof. In another fumarate ester is monomethyl fumarate . aspect, the liquid comprises mono - and di - glycerides, poly Another embodiment described herein is an oral pharma vinylpyrrolidone , polyoxyl 40 hydrogenated castor oil, and ceutical composition comprising : about 12 % to about 40 % lactic acid . In another aspect, the weight ratio of the fumar by weight of one or more fumarate esters ; about 50 % to a te ester to non - aqueous liquid is about 1 : 1 to about 1 : 8 . In about 80 % by weight of mono - and diglycerides , about 5 % 50 another aspect, the composition comprises : about 30 % to to about 15 % by weight of polyoxyl 40 hydrogenated castor about 40 % by weight of the one or more fumarate esters ; oil ; about 1 % to about 5 % by weight of polyvinylpyrroli - about 55 % to about 65 % by weight of the liquid ; and about done ; and about 1 % to about 5 % by weight lactic acid . In 5 % by weight of lactic acid . In another aspect, the compo another aspect, the composition comprises : about 34 % by sition comprises: about 12 % to about 40 % by weight of the weight one or more fumarate esters ; about 48 % by weight 55 one or more fumarate esters ; about 50 % to about 80 % by mono - and diglycerides ; about 10 % by weight polyoxyl 40 weight of mono - and diglycerides ; about 5 % to about 15 % hydrogenated castor oil ; about 3 % by weight polyvinylpyr - by weight of polyoxyl 40 hydrogenated castor oil ; about 1 % rolidone ; and about 5 % by weight lactic acid . In another to about 5 % by weight of polyvinylpyrrolidone ; and about aspect, the composition comprises about 80 mg to about 110 1 % to about 5 % by weight lactic acid . In another aspect, the mg or about 160 mg to about 230 mg of the fumarate ester . 60 administration comprises: ( a ) administering two dosage In another aspect, the composition comprises about 90 mg to forms simultaneously comprising about 80 mg to about 115 about 100 mg of the fumarate ester. In another aspect , the mg of fumarate ester twice per day ( BID ) ; ( b ) administering composition comprises about 180 mg to about 220 mg of the one dosage from comprising about 80 mg to about 115 mg fumarate ester . In another aspect , the composition comprises of fumarate ester four times per day ; or ( c ) administering one about 190 mg to about 200 mg of the fumarate ester . In 65 dosage from comprising about 160 to about 230 mg of another aspect, the composition is encapsulated in a capsule fumarate ester twice per day (BID ) . In another aspect , the shell . In another aspect, the composition is encapsulated in administration comprises a total daily dosage of about 160 US 9 ,814 ,692 B2 mg to about 440 mg of the fumarate ester. In another aspect, Another embodiment described herein is a method for the administration comprises a total daily dosage of about providing multiple sclerosis treatment to a subject in need 160 mg, about 180 mg, about 190 mg, about 200 mg, about thereof with increased subject compliance and optimal treat 220 mg, about 230 mg, about 360 mg, about 380 mg, about ment outcome comprising administering a liquid suspension 400 mg, or about 440 mg of the fumarate ester . In another 5 of solid particles of one or more fumarate esters comprising aspect, the subject achieves a reduction of annualized dimethyl fumarate , monomethyl fumarate , a pro - drug relapse rate relative to baseline without substantially expe - thereof, or a combination thereof to a subject in need thereof. riencing one or more of flushing, abdominal pain , diarrhea , Another embodiment described herein is a method for or nausea . In another aspect, the subject exhibits one or more providing multiple sclerosis treatment to a subject in need pharmacokinetic parameters comprising : ( a ) a mean plasma 10 thereof with improved treatment outcome compared to 240 monomethyl fumarate Cmorranging from about 1 .87 mg/ L to mg TECFIDERA? (dimethyl fumarate ) comprising admin about 2 .41 mg/ L ; ( b ) mean plasma monomethyl fumarate istering a liquid suspension of solid particles of one or more AUCO - s ranging from about 1 . 99 h ·mg / L to about 2 . 43 fumarate esters comprising dimethyl fumarate , monomethyl h mg/ L ; or ( c ) a mean plasma monomethyl fumarate fumarate , a pro - drug thereof, or a combination thereof to a AUCoverall ranging from about 3 . 2 h ·mg / L to about 11 . 2 15 subject in need thereof. | hmg/ L . Another embodiment described herein is a method for Another embodiment described herein is a method of providing long - term multiple sclerosis treatment with opti treating multiple sclerosis or psoriasis comprising adminis - mal treatment outcome to a subject in need thereof com tering to a subject one or more dosage forms that cumula - prising administering an oral pharmaceutical composition tively provide a daily dosage of a fumarate ester from about 20 comprising a liquid suspension of solid particles of one or 360 mg to about 440 mg fumarate ester. more fumarate esters comprising dimethyl fumarate , Another embodiment described herein is a method of monomethyl fumarate , a pro -drug thereof, or a combination treating multiple sclerosis or psoriasis comprising adminis - thereof to a subject in need thereof. tering to a subject one or more dosage forms that cumula Another embodiment described herein is an oral pharma tively provide a daily dosage of a fumarate ester from about 25 ceutical dosage from comprising liquid composition com 160 mg to about 230 mg fumarate ester . In one aspect, the prising : about 12 % to about 40 % by weight of one or more administration is twice per day. In another aspect , two fumarate esters ; about 50 % to about 80 % by weight of dosage forms comprising between about 80 mg to about 115 mono - and diglycerides ; about 5 % to about 15 % by weight mg of fumarate ester are simultaneously administered twice of polyoxyl 40 hydrogenated castor oil ; about 1 % to about per day. 30 5 % by weight of polyvinylpyrrolidone ; and about 1 % to Another embodiment described herein is an oral pharma - about 5 % by weight lactic acid ; wherein the liquid compo ceutical composition for activating a nuclear factor ( eryth - sition is encapsulated in a capsule comprising one or more roid -derived 2 ) - like 2 (Nrf2 ) pathway comprising a liquid subcoatings , one or more enteric coatings , one or more top suspension of one or more fumarate esters comprising coatings , or a combination thereof. In one aspect, the fumar dimethyl fumarate , monomethyl fumarate , a pro - drug 35 ate ester comprises from about 80 mg to about 440 mg of thereof, or a combination thereof. dimethyl fumarate , monomethyl fumarate , a prodrug of Another embodiment described herein is a method for monomethyl fumarate , or a combination thereof. In another activating a nuclear factor ( erythroid - derived 2 ) - like 2 aspect, one or more dosage forms, administered in a regi (Nrf2 ) pathway comprising administering a liquid suspen - men , is bioequivalent to 240 mg TECFIDERA® (dimethyl sion of solid particles of one or more fumarate esters 40 fumarate ) and has enhanced bioavailability . comprising dimethyl fumarate , monomethyl fumarate , a Another embodiment described herein is a controlled pro -drug thereof, or a combination thereof. release pharmaceutical composition comprising one or more Another embodiment described herein is a method of fumarate esters suspended in a lipid or lipophilic matrix . The manufacturing an oral pharmaceutical composition compris - pharmaceutical composition is encapsulated in a soft cap ing a liquid suspension of solid particles of one or more 45 sule . The oral soft capsules comprising controlled release fumarate esters comprising dimethyl fumarate , monomethyl matrix compositions prevent release of the fumarate ester fumarate , a pro - drug thereof, or a combination thereof. active ingredient in the gastric environment, but release the Another embodiment described herein is a pharmaceuti - active ingredient in the intestine in a controlled manner. The cal composition comprising a liquid suspension of solid compositions can be tailored to provide one or more release particles of one or more fumarate esters comprising dim - 50 profiles , including immediate release , controlled release , ethyl fumarate ,monomethyl fumarate , a pro -drug thereof , or delayed release, or extended release pharmacokinetics by a combination thereof, wherein the composition exhibits an the composition of the matrix fill . The formulations in vitro dissolution rate comprising about 50 % dissolution described herein comprise solid micronized particles of after about 30 minutes to about 50 minutes at pH 6 . 8 . fumarate esters suspended in a matrix . The controlled Another embodiment described herein is an oral pharma - 55 release pharmaceutical composition comprising a matrix of ceutical composition providing a consistent fumarate ester f umarate esters reduce , ameliorate , or eliminate the unde release profile that reduces side effects comprising a liquid sirable gastrointestinal side effects observed with prior suspension of solid particles of one or more fumarate esters fumarate ester pharmaceuticals . Further, the formulations comprising dimethyl fumarate , monomethyl fumarate , a preclude or reduce sublimation of the fumarate ester during pro -drug thereof, or a combination thereof. 60 manufacturing and storage . Another embodiment described herein is a method for Another embodiment described herein is an oral pharma providing a consistent fumarate ester release profile that ceutical composition comprising a controlled release com reduces side effects comprising administering a liquid sus position of one or more fumarate esters , including , but not pension of solid particles of one or more fumarate esters limited to , dialkyl fumarates , alkyl fumarates, dimethyl comprising dimethyl fumarate , monomethyl fumarate , a 65 fumarate (DMF ), monomethyl fumarate (MMF ), or combi pro -drug thereof, or a combination thereof to a subject in nations thereof. In one embodiment, the fumarate ester is need thereof. DMF. In one embodiment, the fumarate ester is MMF. In one US 9 ,814 ,692 B2 embodiment, the pharmaceutical composition comprises a 180 mg FAE , about 185 mg FAE , about 190 mg FAE , about controlled release pharmaceutical composition . In another 195 mg FAE , about 200 mg FAE , about 205 mg FAE , about embodiment, the pharmaceutical composition comprises a 210 mg FAE , about 215 mg FAE , about 220 mg FAE , about soft capsule shell encapsulating a matrix comprising one or 225 mg FAE , about 230 mg FAE, about 235 mg FAE , about more fumarate esters . In one aspect, the matrix comprises a 5 240 mg FAE , about 245 mg FAE , about 250 mg FAE , about lipid or lipophilic vehicle , a neutralizing agent, and solid 255 mg FAE , about 260 mg FAE , about 265 mg FAE , about particles of fumarate esters . In another aspect, the matrix 270 mg FAE , about 275 mg FAE , about 280 mg FAE , about comprises a lipid or lipophilic vehicle , a neutralizing agent, 285 mg FAE , about 290 mg FAE , about 295 mg FAE , about excipients , and solid particles of a fumarate ester. In another aspect , the matrix comprises a lipid or lipophilic vehicle , a 102300 mg FAE , about 305 mg FAE , about 310 mg FAE , about neutralizing agent, surfactants , and solid particles of a 315 mg FAE , about 320 mg FAE , about 325 mg FAE , about fumarate ester . In one aspect , the lipid or lipophilic vehicle 330 mg FAE , about 335 mg FAE , about 340 mg FAE , about comprises polyvinylpyrrolidones, mono - and di - glycerides, 345 mg FAE , about 350 mg FAE , about 355 mg FAE , about and oils . In another aspect, the surfactant can comprise 360 mg FAE , about 365 mg FAE , about 370 mg FAE , about polysorbate 80 or polyoxyl 40 hydrogenated castor oil. In 153375 mg FAE , about 380 mg FAE , about 385 mg FAE , about another aspect , the solid particles of fumarate ester comprise 390 mg FAE , about 395 mg FAE , about 400 mg FAE , about milled or micronized particles. In another aspect, the milled 405 mg FAE , about 410 mg FAE , about 415 mg FAE , about or micronized particles of one or more fumarate esters 420 mg FAE , about 425 mg FAE , about 430 mg FAE , about comprise mean particle distribution sizes of about 20 um toS 435 mg FAE , about 440 mg FAE , about 445 mg FAE , about about 300 um , including all integers within the specified 20 450 mg FAE , about 455 mg FAE, about 460 mg FAE , about range . In another aspect, the solid particles of fumarate 465 mg FAE , about 470 mg FAE , about 475 mg FAE , or esters comprise mean particle distribution sizes of about 65 about 480 mg FAE . In one aspect , the composition com um to about 260 um , including all integers within the prises one or more FAEs in an amount of about 0 . 5 mmol to specified range . In another aspect, the solid microparticles of about 4 . 0 mmol FAE . In one aspect, the composition com fumarate esters have mean particle distribution sizes of less 25 prises one or more FAEs in an amount of about 0 . 7 mmol to than 260 um . In another aspect, the solid particles of about 3 . 7 mmol FAE . In another aspect , the composition fumarate esters have mean particle distribution sizes of comprises DMF, MMF, or a combination thereof. In another about 100 um . In another aspect, the neutralizing agent aspect, the matrix comprises DMF. In another aspect, the comprises an organic acid , ester, or salt . In another aspect, composition comprises MMF . In another aspect, the com the neutralizing agent comprises at least one of lactate , 30 position further comprises one or more non - steroidal anti fumarate , caprylate , caprate , oleate, maleate , succinate , tar - inflammatory drugs (NSAIDS ) . In one aspect, the compo trate , citrate , glutamate , gluconate , or esters or salts thereof, sition prevents sublimation of the fumarate ester during or combinations thereof . In another aspect, the matrix com - manufacturing . In another aspect, the composition prophy prises a fumarate ester , a mixture of mono - and di- glycer - lactically reduces the onset or ameliorates the symptoms of ides, polyvinylpyrrolidone , polyoxyl 40 hydrogenated castor 35 any flushing side effects . In another aspect, the composition oil , and lactic acid . reduces the onset or ameliorates the severity of any gastro In another embodiment, the pharmaceutical composition intestinal side effects . In another aspect , the composition is comprises a matrix fill comprising about 10 % to about 64 % stable for at least 1 year at conditions comprising 25° C . and by weight of one or more fumarate esters ( PSD : d90s100 60 % relative humidity . In another aspect, the composition is um ) ; about 18 % to about 70 % by weight of a mixture of 40 stable for at least 2 years at conditions comprising 25° C . mono - and diglycerides ; at least about 1 % to about 10 % by and 60 % relative humidity . weight polyvinylpyrrolidone; at least about 1 % to about In one embodiment , the soft capsule comprises and 10 % by weight polyoxyl 40 hydrogenated castor oil, and at enteric soft capsule . In one embodiment , the soft capsule least about 1 % to about 5 % by weight lactic acid . shell comprises one or more enteric , acid - insoluble poly In another embodiment, the pharmaceutical composition 45 mers , a film - forming polymer, a plasticizer, an alkali -neu comprises a matrix fill comprising about 29 % by weight of tralizing agent, a solvent, and optionally , a coloring agent, a one or more fumarate esters (PSD : d90s100 um ); about 54 % flavoring , or a pharmaceutical excipient. by weight of a mixture of mono - and di - glycerides; about In another embodiment, the enteric soft capsule shell 3 % by weight polyvinylpyrrolidone ; about 10 % by weight comprises about 20 % to about 36 % by weight of at least one polyoxyl 40 hydrogenated castor oil , and about 5 % by 50 film - forming polymer, about 8 % to about 20 % by weight of weight lactic acid . In one aspect, the composition has at least one enteric , acid - insoluble polymer ; about 15 % to controlled release , delayed release , or extended release about 20 % by weight of at least one plasticizer, about 1 % to properties . In one aspect, the composition comprises one or about 5 % by weight of at least one alkali -neutralizing agent ; more FAEs in an amount of about 80 mg to about 460 mg. about 20 % to about 40 % by weight of a solvent; optionally , In one aspect, the one or more FAEs comprise about 90 mg 55 about 1 % to about 5 % by weight of an opacifying agent; and to about 110 mg. In one aspect , the composition comprises optionally , about 0 .05 % to about 1 % by weight of at least one or more FAEs in an amount of about 170 mg to about one coloring agent. 220 mg. In one aspect , the composition comprises one or In another embodiment, the soft capsule shell comprises more FAEs in an amount of about 340 mg to about 440 mg. about 30 % of at least one film - forming polymer; about 10 % In one aspect , the composition comprises one or more FAEs 60 by weight of at least one enteric , acid - insoluble polymer ; in an amount of about 80 mg FAE , about 85 mg FAE , about about 20 % by weight of at least one plasticizer ; about 1 % by 90 mg FAE , about 95 mg FAE , about 100 mg FAE , about weight of at least one alkali -neutralizing agent; about 37 % 105 mg FAE , about 110 mg FAE, about 115 mg FAE , about by weight of a solvent; and optionally , about 1 . 5 % by weight 120 mg FAE , about 125 mg FAE , about 130 mg FAE , about of an opacifying agent; and optionally , at least one coloring 135 mg FAE , about 140 mg FAE , about 145 mg FAE , about 65 agent. In one aspect, the soft capsule shell comprises gelatin , 150 mg FAE , about 155 mg FAE , about 160 mg FAE , about acrylic methacrylate copolymers , glycerol, triethyl citrate , 165 mg FAE , about 170 mg FAE , about 175 mg FAE , about ammonia , water , and titanium dioxide . US 9 ,814 ,692 B2 10 Another embodiment described herein is a method for coloring agent. In another aspect, the composition comprises manufacturing an oral soft capsule shell encapsulating a DMF, MMF, or a combination thereof. In another aspect , the matrix comprising a fumarate ester, the method comprising : matrix comprises DMF. In another aspect, the composition ( i ) providing a matrix fill composition comprising any of the comprises MMF. In one aspect, the soft capsule comprising composition described herein ; ( ii ) providing a soft capsule 5 a fumarate ester is resistant to dissolution at about pH 1 . 2 for shell composition comprising any of the composition at least about 2 hours . In another aspect , the soft capsule described herein ; ( iii ) casting the soft capsule shell into films comprising a fumarate ester begins dissolution at pH of using heat- controlled drums or surfaces ; and ( iv ) forming a soft capsule shell encapsulating the matrix fill composition about 6 . 8 within about 10 minutes . In one aspect, the soft using rotary die encapsulation technology . In one aspect, the 10 capsule has immediate release , controlled release , delayed soft capsule matrix comprises one or more fumarate esters release , or extended release properties . In another aspect, the produced by said method . soft capsule comprising a fumarate ester reduces the onset or Another embodiment described herein is a method for ameliorates the severity of any flushing or gastrointestinal manufacturing an oral soft capsule shell encapsulating a side effects . matrix comprising a fumarate ester , the method comprising : 155 Another embodiment described herein is a method for ( i) providing a matrix fill composition comprising : about treating , retarding the progression of, delaying the onset of, 10 % to about 64 % by weight of one or more fumarate esters prophylaxis of, amelioration of, or reducing the symptoms ( PSD : d90s100 um ); about 18 % to about 70 % by weightof of multiple sclerosis or psoriasis , comprising administering a mixture of mono - and diglycerides ; about 1 % to about to a subject in need thereof an oral pharmaceutical compo 10 % by weight polyvinylpyrrolidone ; about 2 % to about 20 sition comprising a controlled release soft capsule shell and 12 % by weight polyoxyl 40 hydrogenated castor oil, and matrix comprising a fumarate ester. In one aspect, the about 1 % to about 5 % by weight lactic acid ; ( ii ) providing pharmaceutical composition comprises a controlled release a soft capsule shell composition comprising : about 20 % to soft capsule comprising a formulation of fumarate ester. In about 36 % by weight of at least one film - forming polymer ; one aspect, the pharmaceutical composition comprises a about 8 % to about 20 % by weight of at least one enteric , 25 controlled release soft capsule comprising a formulation of acid - insoluble polymer , about 15 % to about 20 % by weight fumarate ester. In another aspect, the composition comprises of at least one plasticizer ; about 1 % to about 5 % by weight DMF , MMF, or a combination thereof. In another aspect , the of at least one alkali -neutralizing agent; about 20 % to about matrix comprises DMF. In another aspect , the composition 40 % by weight of a solvent; optionally , about 1 % to about comprises MMF. 5 % by weight of an opacifying agent; and optionally , about 30 Another embodiment described herein is a method for 0 .05 % to about 1 % by weight of at least one coloring agent; treating, retarding the progression of, delaying the onset of, ( iii ) casting the soft capsule shell into films using heat prophylaxis of, amelioration of, or reducing the symptoms controlled drums or surfaces; and ( iv ) forming a soft capsule of a general autoimmune or neurodegenerative disorder , shell encapsulating the matrix fill composition using rotary including but not limited to multiple sclerosis or psoriasis , die encapsulation technology. 35 comprising administering to a subject in need thereof an oral Another embodiment described herein is a soft capsule pharmaceutical composition comprising a controlled release comprising a shell encapsulating a fumarate ester matrix , formulation of a fumarate ester, wherein the subject achieves wherein the matrix comprises : about 10 % to about 64 % by a reduction of annualized relapse rate relative to baseline weight of one or more fumarate esters (PSD : d90s100 um ) ; without substantially experiencing one or more of flushing , about 18 % to about 70 % by weight of mono - and di- 40 abdominal pain , diarrhea , and nausea . In one aspect , the glycerides ; at least about 1 % to about 7 % by weight of pharmaceutical composition comprises any of the composi polyvinylpyrrolidone ; at least about 2 % to about 10 % by tions described herein . In another aspect, the composition weight of polyoxyl 40 hydrogenated castor oil , and at least comprises DMF, MMF, or a combination thereof. In another about 1 % to about 5 % by weight of lactic acid ; and wherein aspect , the matrix comprises DMF. In another aspect, the the soft capsule shell comprises : about 20 % to about 36 % by 45 composition comprises MMF. weight of at least one film - forming polymer ; about 8 % to Another embodiment described herein is an oral pharma about 20 % by weight of at least one enteric , acid - insoluble ceutical composition as described herein that is useful for polymer ; about 15 % to about 20 % by weight of at least one treating neurodegenerative disorders . In one aspect , the plasticizer; about 1 % to about 5 % by weight of at least one pharmaceutical composition is useful for treating multiple alkali - neutralizing agent; about 20 % to about 40 % by weight 50 sclerosis or psoriasis . In one embodiment described herein , of a solvent ; optionally, about 1 % to about 5 % by weight of subjects that are administered the oral pharmaceutical com an opacifying agent; and optionally , about 0 .05 % to about position as described herein exhibit a mean plasma monom 1 % by weight of at least one coloring agent. ethyl fumarate Tmor of from about 1. 5 hours to about 3 . 5 Another embodiment described herein is a soft capsule hours. comprising a shell encapsulating a fumarate ester matrix , 55 Another embodiment described herein is an oral pharma wherein the matrix comprises : about 29 % by weight of one ceutical composition useful for treating , retarding the pro or more fumarate esters (PSD : d90s100 um ); about 54 % by g ression of, delaying the onset of, prophylaxis of, amelio weight of a mixture of mono - and diglycerides ; about 3 % ration of, or reducing the symptoms of general autoimmune by weight polyvinylpyrrolidone ; about 10 % by weight poly - or neurodegenerative disorders . In one aspect, the compo oxyl 40 hydrogenated castor oil, and about 5 % by weight 60 sition comprises DMF, MMF, or a combination thereof. In lactic acid ; and wherein the soft capsule shell comprises : another aspect , the matrix comprises DMF. In another about 30 % by weight of at least one film - forming polymer ; aspect, the composition comprises MMF. about 10 % by weight of at least one enteric , acid - insoluble Another embodiment described herein is a method for polymer ; about 20 % by weight of at least one plasticizer; treating , retarding the progression of, delaying the onset of, about 1 % by weight of at least one alkali - neutralizing agent; 65 prophylaxis of, amelioration of, or reducing the symptoms about 37 % by weight of a solvent; optionally , about 1 . 5 % by of general autoimmune or neurodegenerative disorders . In weight of an opacifying agent; and optionally , at least one one aspect, the composition comprises DMF, MMF, or a US 9 ,814 ,692 B2 12 combination thereof. In another aspect, the matrix comprises cutaneous lupus, cutaneous sarcoidosis , diabetic retinopa DMF. In another aspect, the composition comprises MMF. thy, fibromyalgia , graft versus host disease , granuloma Another embodiment described herein is an oral pharma - annulare , granulomas including annulare , Grave ' s disease , ceutical composition comprising a controlled release com Hashimoto ' s thyroiditis, hepatitis C viral infection , herpes position comprising a formulation of a fumarate ester useful 5 simplex viral infection , human immunodeficiency viral for treating, retarding the progression of, delaying the onset infection , Huntington ' s disease, inflammatory bowel dis of, prophylaxis of, amelioration of , or reducing the symp - ease , irritable bowel disorder , ischemia , juvenile -onset dia toms of general autoimmune or neurodegenerative disor - betes mellitus, Krabbe disease, lichen planus, macular ders , including but not limited to , acute dermatitis , adrenal degeneration , mitochondrial encephalomyopathy , leukodystrophy , AGE - induced genome damage , Alexan - 10 monomelic amyotrophy, multiple sclerosis (MS ) , myocar der ' s disease , alopecia areata ( totalis and universalis ) , Alp - dial infarction , necrobiosis lipoidica , neurodegeneration er' s disease , Alzheimer ' s disease, amyotrophic lateral scle with brain iron accumulation , neurodermatitis , neuromyeli rosis , angina pectoris , arthritis , asthma, autoimmune tis optica , neuropathic pain , neurosarcoidosis , NF -KB medi diseases, balo concentric sclerosis , Behçet' s syndrome, bull - ated diseases, optic neuritis , organ transplantation rejection , ous pemphigoid , Canavan disease , cardiac insufficiency 15 paraneoplastic syndromes , Parkinson ' s disease , Pelizaeus including left ventricular insufficiency , central nervous sys - Merzbacher disease , pemphigus , pernicious anemia , pri tem vasculitis , Charcot -Marie - Tooth disease , childhood mary lateral sclerosis , progressive supranuclear palsy , pso ataxia with central nervous system hypomyelination , riasis , psoriatic arthritis , pyoderma gangrenosum , radiation chronic active (lupoid ) hepatitis , chronic dermatitis , chronic induced dermatitis , radicular pain , radiculopathic pain , rep idiopathic peripheral neuropathy, chronic obstructive pul- 20 erfusion injury , retinopathic pigmentosa, rheumatoid arthri monary disease , contact dermatitis , Crohn ' s disease and tis (RA ) , sarcoidosis , sarcoidosis , Schilder ' s disease, sciatic cutaneous Crohn ' s disease, cutaneous lupus, cutaneous sar - pain , sciatica , Sjögren ' s syndrome, subacute necrotizing coidosis , diabetic retinopathy , fibromyalgia , graft versus myelopathy , such as polyarthritis , Susac ' s syndrome, sys host disease, granuloma annulare , granulomas including temic lupus erythematosus (SLE ) , tumors, transverse myeli annulare , Grave ' s disease , Hashimoto ' s thyroiditis , hepatitis 25 tis , ulcerative colitis , or Zellweger syndrome comprising C viral infection , herpes simplex viral infection , human administering to a subject in need thereof an oral controlled immunodeficiency viral infection , Huntington ' s disease , release pharmaceutical composition comprising a fumarate inflammatory bowel disease , irritable bowel disorder , isch ester. In one embodiment described herein , the oral phar emia , juvenile -onset diabetes mellitus, Krabbe disease , maceutical composition comprises a soft capsule shell and lichen planus, macular degeneration , mitochondrial 30 matrix comprising a fumarate ester . In one aspect , the encephalomyopathy, monomelic amyotrophy, multiple scle - pharmaceutical composition comprises a controlled release rosis (MS ) , myocardial infarction , necrobiosis lipoidica , soft capsule comprising a formulation of a fumarate ester . In neurodegeneration with brain iron accumulation , neuroder - another aspect, the pharmaceutical composition is an imme matitis , neuromyelitis optica , neuropathic pain , neurosarcoi- diate release, delayed release , controlled release , or dosis , NF- KB mediated diseases, optic neuritis , organ trans - 35 extended release formulation of a fumarate ester. In another plantation rejection , paraneoplastic syndromes, Parkinson ' s aspect , the composition comprises DMF, MMF, or a com disease , Pelizaeus -Merzbacher disease , pemphigus , perni - bination thereof. In another aspect, the matrix comprises cious anemia , primary lateral sclerosis , progressive supra - DMF. In another aspect , the composition comprises MMF. nuclear palsy , psoriasis , psoriatic arthritis , pyoderma gan - Another embodiment described herein is an oral pharma grenosum , radiation induced dermatitis , radicular pain , 40 ceutical composition comprising a controlled release formu radiculopathic pain , reperfusion injury , retinopathic pigmen - lation of a fumarate ester . In one aspect , the composition is tosa , rheumatoid arthritis (RA ) , sarcoidosis , sarcoidosis , provided in a dosage form containing about 85 mg to about Schilder ' s disease , sciatic pain , sciatica , Sjögren ' s syn - 110 mg of one or more fumarate esters , wherein subjects drome, subacute necrotizing myelopathy, such as polyarthri administered the dose form four times daily exhibit one or tis , Susac ' s syndrome, systemic lupus erythematosus (SLE ) , 45 more pharmacokinetic parameters comprising : ( a ) a mean tumors , transverse myelitis , ulcerative colitis , or Zellweger plasma monomethyl fumarate Cmax ranging from about 0 . 4 syndrome. In one aspect, the composition comprises DMF, mg/ L to about 2 .41 mg/ L ; or (b ) a mean plasma monomethyl MMF, or a combination thereof. In another aspect, the fumarate AUCovers ranging from about 3 . 2 h ·mg / L to about matrix comprises DMF. In another aspect, the composition 11 . 2 hómg/ L . In another aspect , the composition is provided comprises MMF. 50 in a dosage form containing about 120 mg to about 180 mg Another embodiment described herein is a method for of one or more fumarate esters, wherein subjects adminis treating , retarding the progression of, delaying the onset of t ered the dose form exhibit one or more pharmacokinetic prophylaxis of, amelioration of, or reducing the symptoms parameters comprising : ( a ) a mean plasma monomethyl of general autoimmune or neurodegenerative disorders , fumarate Cmax ranging from about 0 . 4 mg/ L to about 2 . 41 including but not limited to , acute dermatitis , adrenal leu - 55 mg/ L ; ( b ) a mean plasmamonomethyl fumarate AUCO - 125 kodystrophy , AGE - induced genome damage, Alexander' s ranging from about 0 . 5 h ·mg / L to about 2 . 5 h ·mg / L ; or ( c ) disease , alopecia areata (totalis and universalis) , Alper' s a mean AUC - - - ranging from about 0 . 5 h ·mg / L to about 2 . 6 disease , Alzheimer' s disease , amyotrophic lateral sclerosis , h ·mg / L . In another aspect, the composition is provided in a angina pectoris , arthritis , asthma, autoimmune diseases , balo dosage form containing a total amount of about 170 mg to concentric sclerosis , Behçet ' s syndrome, bullous pemphig - 60 about 220 mg of one or more fumarate esters , wherein oid , Canavan disease , cardiac insufficiency including left subjects administered the dose form twice - daily exhibit one ventricular insufficiency, central nervous system vasculitis , or more pharmacokinetic parameters comprising : ( a ) a mean Charcot- Marie - Tooth disease , childhood ataxia with central plasma monomethyl fumarate Cmor ranging from about 1 . 0 nervous system hypomyelination , chronic active ( lupoid ) mg/ L to about 3 . 4 mg/ L ; ( b ) a mean plasma monomethyl hepatitis , chronic dermatitis , chronic idiopathic peripheral 65 fumarate AUCoverall ranging from about 4 .81 h ·mg / L to neuropathy , chronic obstructive pulmonary disease , contact about 11 . 2 h mg/ L . In another aspect, the composition is dermatitis , Crohn 's disease and cutaneous Crohn ' s disease , provided in a dosage form containing about 170 mgto about US 9 ,814 ,692 B2 13 14 220 mg of one or more fumarate esters , wherein subjects mg/ L to about 5 .2 mg/ L , ( b ) a mean plasma monomethyl administered the dose form exhibit one or more pharmama fumarate AUCO2 ranging from about 0 . 5 h ·mg / L to about cokinetic parameters comprising : (a ) a mean plasma 13 . 5 h ·mg / L , or ( c ) a mean AUCO - s ranging from about 0 . 5 monomethyl fumarate Cmax ranging from about 1 . 0 mg/ L to h ·mg / L to about 15 . 5 h ·mg / L . In another aspect, the capsule about 3 . 4 mg/ L ; ( b ) a mean plasma monomethyl fumarate 5 contains a total amount of about 80 mg to about 460 mg of AUCO - 124 ranging from about 1 . 0 h .mg / L to about 5 . 5 one or more fumarate esters , wherein subjects administered h ·mg / L ; or ( c ) a mean AUCO -> ranging from about 1 . 0 the one or more capsules exhibit one or more pharmacoki h•mg / L to about 5 . 6 h ·mg / L . In another aspect, the fumarate n etic parameters comprising : ( a ) a mean plasma monom ester formulation is encapsulated in a soft capsule . In ethyl fumarate Tmor of from about 1 . 5 hours to about 10 . 5 another aspect, the composition comprises DMF , MMF, or a 10 hours ; ( b ) a mean plasmamonomethyl fumarate Cmor rang combination thereof. In another aspect, the matrix comprises ing from about 0 . 4 mg/ L to about 5 . 2 mg/ L ; ( c ) a mean DMF. In another aspect, the composition comprises MMF. plasma monomethyl fumarate AUCO -2127 ranging from Another embodiment described herein is an oral pharma - about 0 . 5 h ·mg / L to about 13 . 5 h ·mg / L ; or ( d ) a mean ceutical composition comprising total amount of about 85 AUC . -- . ranging from about 0 .5 h .mg / L to about 15 . 5 mg to about 110 mg of one or more fumarate esters , wherein 15 h ·mg / L . subjects administered the capsule exhibit one or more phar - Another embodiment described herein is a pharmaceuti macokinetic parameters comprising : ( a ) a mean plasma cal composition as described herein , for oral administration monomethyl fumarate Timor of from about 1 . 5 hours to about to a subject having multiple sclerosis containing one ormore 3 . 5 hours ; ( b ) a mean plasma monomethyl fumarate Cmax fumarate ester compounds, or pharmaceutically acceptable ranging from about 0 . 4 mg/ L to about 2 . 41mg / L ; ( c ) a mean 20 salts thereof that metabolize to monomethyl fumarate , plasma monomethyl fumarate AUC0 - > 12h ranging from wherein said administering the composition provides one or about 0 . 5 h :mg / L to about 2 . 5 h .mg / L ; or ( d ) a mean more of the following pharmacokinetic parameters : ( a ) a AUCO- s ranging from about 0 . 5 h ·mg / L to about 2 . 6 mean plasma monomethyl fumarate Tmor of from about 1 . 5 h ·mg / L . In another aspect, the composition comprises about hours to about 3 . 5 hours ; ( b ) a mean plasma monomethyl 170 mg to about 220 mg of one or more fumarate esters , 25 fumarate Cmax ranging from about 0 . 4 mg/ L to about 3 . 4 wherein subjects administered the capsule exhibit one or mg/ L ; ( c ) a mean plasma monomethyl fumarate AUCoverall more pharmacokinetic parameters comprising : ( a ) a mean ranging from about 3 .2 h ·mg / L to about 11 . 2 h ·mg / L ; ( d ) a plasmamonomethyl fumarate Tar of from about 1 . 5 hours mean plasma monomethyl fumarate AUC0 - > 12h ranging to about 3 . 5 hours ; ( b ) a mean plasma monomethyl fumarate from about 0 . 5 h .mg / L to about 5 . 5 hómg/ L ; or ( e ) a mean Cmor ranging from about 1 . 0 mg/ L to about 3 . 4 mg / L ; ( c ) a 30 AUCO - s ranging from about 0 . 5 hómg/ L to about 5 .6 mean plasma monomethyl fumarate AUC . -> 12h ranging h ·mg / L . from about 1 .0 h .mg / L to about 5 . 5 h .mg / L ; or ( d ) a mean Another embodiment described herein is a method for AUCA ranging from about 1 . 0 h ·mg / L to about 5 . 6 treating , retarding the progression of, delaying the onset of, h ·mg / L . In one aspect, the composition comprises DMF, prophylaxis of, amelioration of, or reducing the symptoms MMF, or a combination thereof . In another aspect, the 35 of a general autoimmune or neurodegenerative disorder, matrix comprises DMF. In another aspect , the composition including but not limited to multiple sclerosis or psoriasis , comprises MMF. comprising administering to a subject in need thereof any Another embodiment described herein is a method for one of the compositions of described herein , containing one treating , retarding the progression of, delaying the onset of, or more fumarate ester compounds, or pharmaceutically prophylaxis of, amelioration of, or reducing the symptoms 40 acceptable salts thereof that metabolize to monomethyl of a general autoimmune or neurodegenerative disorder , fumarate , wherein said administering the composition pro including but not limited to multiple sclerosis or psoriasis , vides one or more of the following pharmacokinetic param comprising orally administering to a subject in need thereof eters : ( a ) a mean plasma monomethyl fumarate Tor of from a therapeutically effective amount of one or more fumarate about 1 . 5 hours to about 3 . 5 hours ; ( b ) a mean plasma esters comprising any of the compositions described herein 45 monomethyl fumarate Cmax ranging from about 0 . 4 mg/ L to and a therapeutically amount of one or more non - steroidal about 3 . 4 mg/ L ; ( c ) a mean plasma monomethyl fumarate anti - inflammatory drugs effective to reduce flushing. In one AUC vers ranging from about 3 . 2 hómg/ L to about 11 . 2 aspect, the one or more non - steroidal anti - inflammatory h ·mg / L ; ( d ) a mean plasma monomethyl fumarate drug is aspirin , ibuprofen , naproxene , diclofenac , ketopro - AUC _ 137, ranging from about 0 . 5 h ·mg / L to about 5 . 5 fen , celecoxib , or a combination thereof. 50 h ·mg / L ; or ( e ) a mean AUCO -> ranging from about 0 . 5 Another embodiment described herein is a once or twice h ·mg / L to about 5 .6 h ·mg / L . daily oral pharmaceutical composition comprising a delayed Another embodiment described herein is a pharmaceuti release , controlled release , or extended release formulation cal composition as described herein , for oral administration of a fumarate ester. In one aspect, the composition is to a subject having multiple sclerosis containing one or more provided in one or more dosage forms containing about 80 55 fumarate ester compounds , or pharmaceutically acceptable mg to about 460 mg of one or more fumarate esters , wherein salts thereof that metabolize to monomethyl fumarate , subjects administered the dose form once daily exhibit one wherein said administering the composition provides one or or more pharmacokinetic parameters comprising : ( a ) a mean more of the following pharmacokinetic parameters : ( a ) a plasma monomethyl fumarate Cmax ranging from about 0 . 4 mean plasma monomethyl fumarate Tmor of from about 1 . 5 mg/ L to about 5 . 2 mg/ L ; or ( b ) a mean plasma monomethyl 60 hours to about 10 .5 hours ; ( b ) a mean plasma monomethyl fumarate AUC0 - ranging from about 0 . 5 h ·mg / L to about fumarate Corranging from about 0 . 4 mg/ L to about 5 . 2 15 . 5 h ·mg / L . In another aspect, the composition is provided mg/ L ; ( c ) a maxmean plasma monomethyl fumarate AUC0 -> 12h in one or more dosage forms containing about 80 mg to ranging from about 0 . 5 h ·mg / L to about 13. 5 h ·mg / L ; or ( d ) about 460 mg of one or more fumarate esters , wherein a mean AUCo - > ranging from about 0 . 5 h ·mg / L to about subjects administered the dose form once daily exhibit one 65 15 . 5 h :mg / L . or more pharmacokinetic parameters comprising : (a ) a mean Another embodiment described herein is a method for plasma monomethyl fumarate Cmax ranging from about 0 . 4 treating, retarding the progression of, delaying the onset of, US 9 ,814 ,692 B2 15 16 prophylaxis of, amelioration of, or reducing the symptoms the method comprising the oral administration of a thera of a general autoimmune or neurodegenerative disorder , peutically effective amount of one or more fumarate esters including but not limited to multiple sclerosis or psoriasis , comprising any one of the pharmaceutical compositions comprising orally administering to a subject in need thereof described herein to a subject in need thereof, wherein the any one of the compositions described herein comprising 5 subject achieves a reduction annualized relapse rate relative one or more fumarate ester compounds, or pharmaceutically to baseline without substantially experiencing one or more acceptable salts thereof that metabolize to monomethyl of flushing , abdominal pain , diarrhea , and nausea . In one fumarate , wherein said administering the composition pro - aspect, the subject experiences one or more of flushing , vides one or more of the following pharmacokinetic param - abdominal pain , diarrhea , and nausea at an incidence rate of eters : ( a ) a mean plasma monomethyl fumarate Tmar of from 10 less than about 10 % . In another aspect, the subject is a child . about 1 . 5 hours to about 10 . 5 hours ; ( b ) a mean plasma In one aspect, the child is over 9 years of age . monomethyl fumarate Cmax ranging from about 0 . 4 mg/ L to Another embodiment described herein is a pharmaceuti about 5 . 2 mg/ L ; ( c ) a mean plasma monomethyl fumarate cal composition comprising any one of the pharmaceutical AUCoverall ranging from about 0 . 5 h ·mg / L to about 15 . 2 compositions described herein , for oral administration to a h ·mg / L ; ( d ) a mean plasma monomethyl fumarate 15 subject having a general autoimmune or neurodegenerative AUCO2 ranging from about 0 . 5 h ·mg / L to about 13 . 5 disorder, including but not limited to multiple sclerosis , h ·mg / L ; or ( e ) a mean AUC . - . ranging from about 0 . 5 comprising a therapeutically effective amount of one or h .mg / L to about 15 . 5 h .mg / L . In one aspect, the composition more fumarate esters , wherein the administration is suffi comprises DMF, MMF , or a combination thereof. In another cient to achieve a reduction of annualized relapse rate aspect , the matrix comprises DMF . In another aspect, the 20 relative to baseline in the subject without substantially composition comprises MMF. inducing one or more of flushing , abdominal pain , diarrhea , Another embodiment described herein is a pharmaceuti - and nausea in the subject; and wherein the administration cal composition comprising any one of the pharmaceutical does not require titration of the pharmaceutical composition . compositions described herein for oral administration to a In one aspect , the subject experiences one or more of subject having multiple sclerosis , comprising a therapeuti- 25 flushing , abdominal pain , diarrhea , and nausea at an inci cally effective amount of one or more fumarate esters , dence rate of less than about 10 % . In another aspect, the wherein the administration is sufficient to achieve a reduc subject is a child . In one aspect, the child is over 9 years of tion of about 0 .224 annualized relapse rate relative to age . baseline in the subject without substantially inducing one or Another embodiment described herein is a method for more of flushing , abdominal pain , diarrhea , and nausea in 30 treating, retarding the progression of, delaying the onset of, the subject. In one aspect , the subject experiences one or prophylaxis of , amelioration of, or reducing the symptoms more of flushing , abdominal pain , diarrhea , and nausea at a of a general autoimmune or neurodegenerative disorder, rate of less than about 10 % . In another aspect, the subject is including but not limited to multiple sclerosis , the method a child . In one aspect, the child is over 9 years of age . comprising the oral administration of a therapeutically effec Another embodiment described herein is a method for 35 tive amount of one or more fumarate esters comprising any treating , retarding the progression of, delaying the onset of, one of the pharmaceutical compositions described herein , to prophylaxis of , amelioration of , or reducing the symptoms a subject in need thereof , wherein the administration is of multiple sclerosis , the method comprising the oral admin - sufficient to achieve a reduction of annualized relapse rate istration of a therapeutically effective amount of one or more relative to baseline in the subject without substantially fumarate esters comprising any one of the pharmaceutical 40 inducing one or more of flushing , abdominal pain , diarrhea , compositions described herein , to a subject with multiple and nausea in the subject; and wherein the administration sclerosis , wherein the administration is sufficient to achieve does not require titration of the pharmaceutical composition . a reduction of about 0 .224 annualized relapse rate relative to Another embodiment described herein is a pharmaceuti baseline in the subject without substantially inducing one or cal composition comprising any of the pharmaceutical com more of flushing , abdominal pain , diarrhea , and nausea in 45 positions described herein for oral administration to a sub the subject. In one aspect, the subject experiences one or ject having a general autoimmune or neurodegenerative more of flushing, abdominal pain , diarrhea , and nausea at a disorder , including but not limited to multiple sclerosis , rate of less than about 10 % . In another aspect, the subject is comprising a therapeutically effective amount of one or a child . In one aspect, the child is over 9 years of age . more fumarate esters , wherein the administration is suffi Another embodiment described herein is a pharmaceuti - 50 cient to achieve a reduction of about 0 . 224 annualized cal composition comprising any one of the pharmaceutical relapse rate relative to baseline in the subject without compositions described herein for oral administration to a substantially inducing one or more of flushing, abdominal subject having multiple sclerosis , comprising a therapeuti - pain , diarrhea , and nausea in the subject and wherein the cally effective amount of one or more fumarate esters , administration does not require titration of the pharmaceu wherein the administration is sufficient to achieve a reduc - 55 tical composition . In one aspect, the subject experiences one tion of annualized relapse rate relative to baseline in the or more of flushing , abdominal pain , diarrhea , and nausea at subject without substantially inducing one or more of flush - a rate of less than about 10 % . In another aspect, the subject ing , abdominal pain , diarrhea , and nausea in the subject. In is a child . In one aspect , the child is over 9 years of age . one aspect, the subject experiences one or more of flushing , Another embodiment described herein is a method for abdominal pain , diarrhea , and nausea at a rate of less than 60 treating , retarding the progression of, delaying the onset of, about 10 % . In another aspect , the subject is a child . In one prophylaxis of, amelioration of, or reducing the symptoms aspect , the child is over 9 years of age . of a general autoimmune or neurodegenerative disorder, Another embodiment described herein is a method for including but not limited to multiple sclerosis , the method treating , retarding the progression of, delaying the onset of, comprising the oral administration of a therapeutically effec prophylaxis of, amelioration of, or reducing the symptoms 65 tive amount of one or more fumarate esters comprising any of a general autoimmune or neurodegenerative disorder, of the pharmaceutical compositions described herein to a including but not limited to multiple sclerosis or psoriasis , subject in need thereof , wherein the administration is suffi US 9 ,814 ,692 B2 17 18 cient to achieve a reduction of about 0 . 224 annualized prophylaxis of, amelioration of, or reducing the symptoms relapse rate relative to baseline in the subject without of a subject of less than 17 years of age having a general substantially inducing one or more of flushing , abdominal autoimmune or neurodegenerative disorder, including but pain , diarrhea , and nausea in the subject and wherein the not limited to multiple sclerosis or psoriasis , comprising administration does not require titration of the pharmaceu - 5 orally administering to a subject in need thereof having an tical composition . In one aspect , the subject experiences one age less than 17 a therapeutically effective amount of one or or more of flushing , abdominal pain , diarrhea , and nausea at more fumarate esters comprising any one of the pharma an incidence rate of less than about 10 % . In another aspect, ceutical compositions described herein . the subject is a child . In one aspect, the child is over 9 years Another embodiment described herein is a method for of age . 10 treating , retarding the progression of, delaying the onset of, Another embodiment described herein is a pharmaceuti - prophylaxis of , amelioration of, or reducing the symptoms cal composition comprising any one of the pharmaceutical of a general autoimmune or neurodegenerative disorder , compositions described herein , for oral administration to a including but not limited to multiple sclerosis or psoriasis , subject having a general autoimmune or neurodegenerative comprising orally administering to a subject in need thereof disorder, including but not limited to multiple sclerosis or 15 a therapeutically effective amount of a fumarate ester com psoriasis , comprising a therapeutically effective amount of prising any of the pharmaceutical compositions described one or more fumarate esters , wherein the subject achieves a herein and a therapeutically effective amount of a leukot reduction of annualized relapse rate relative to baseline riene receptor antagonist . In one aspect, the leukotriene without substantially experiencing one or more of flushing , receptor antagonist comprises montelukast or zafirlukast . abdominal pain , diarrhea , and nausea in the subject and 20 Another embodiment described herein is a pharmaceuti wherein the administration does not require titration of the cal composition comprising a matrix fill comprising any of pharmaceutical composition . the compositions described herein . In one aspect, the com Another embodiment described herein is a method for position is shown in any of the tables described herein . treating, retarding the progression of, delaying the onset of, Another embodiment described herein is a pharmaceuti prophylaxis of, amelioration of, or reducing the symptoms 25 cal composition for treating , retarding the progression of, of a general autoimmune or neurodegenerative disorder, delaying the onset of , prophylaxis of, amelioration of, or including but not limited to multiple sclerosis or psoriasis , reducing the symptoms of a general autoimmune or neuro the method comprising the oral administration of a thera - degenerative disorder , including but not limited to multiple peutically effective amount of one or more fumarate esters sclerosis or psoriasis , comprising a fumarate ester , wherein comprising any one of the pharmaceutical compositions 30 the pharmaceutical composition exhibits an in vitro disso described herein , to a subject in need thereof, wherein the lution rate ( % dissolution per minute ) at pH 6 . 8 , as shown in subject achieves a reduction of annualized relapse rate any of the Drawings described herein . relative to baseline without substantially experiencing one or Another embodiment described herein is a method for more of flushing , abdominal pain , diarrhea, and nausea in treating, retarding the progression of, delaying the onset of, the subject and wherein the administration does not require 35 prophylaxis of , amelioration of, or reducing the symptoms titration of the pharmaceutical composition . of a general autoimmune or neurodegenerative disorder , Another embodiment described herein is an oral pharma - including but not limited to multiple sclerosis or psoriasis , ceutical composition comprising any of the compositions comprising orally administering to a subject in need thereof described herein for administration to a subject having a a therapeutically effective amount of one or more fumarate general autoimmune or neurodegenerative disorder, includ - 40 esters comprising any of the pharmaceutical compositions ing but not limited to multiple sclerosis or psoriasis , com - described herein , wherein the composition exhibits an in prising a therapeutically effective amount of one or more vitro dissolution rate ( % dissolution per minute ) at pH 6 . 8 , fumarate esters , wherein the pharmaceutical composition is as shown in any of the Drawings described herein . stable at 25° C . and 60 % RH for at least 1 year. Another embodiment described herein is an oral pharma Another embodiment described herein is an oral pharma - 45 ceutical composition for treating, retarding the progression ceutical composition comprising any of the compositions of, delaying the onset of, prophylaxis of, amelioration of, or described herein comprising a therapeutically effective reducing the symptoms of general autoimmune or neurode amount of one or more fumarate esters for administration to generative disorders , including but not limited to multiple a subject diagnosed with multiple sclerosis or psoriasis . sclerosis or psoriasis , comprising one or more fumarate Another embodiment described herein is a method for 50 esters , wherein the pharmaceutical composition exhibits a treating , retarding the progression of, delaying the onset of, plasma monomethyl fumarate Cmax of about 1321. 3 - 618 . 9 prophylaxis of, amelioration of, or reducing the symptoms ng /mL . of a general autoimmune or neurodegenerative disorder , Another embodiment described herein is a method for including but not limited to multiple sclerosis or psoriasis , treating, retarding the progression of, delaying the onset of, comprising orally administering to a subject in need thereof 55 prophylaxis of, amelioration of , or reducing the symptoms a therapeutically effective amount of one or more fumarate of general autoimmune or neurodegenerative disorders , esters comprising any of the pharmaceutical compositions including but not limited to multiple sclerosis or psoriasis , described herein . comprising orally administering to a subject in need thereof Another embodiment described herein is a pharmaceuti - a therapeutically effective amount of one or more fumarate cal composition comprising any one of the compositions 60 esters comprising any of the pharmaceutical compositions described herein , for oral administration to a subject of less described herein , wherein the pharmaceutical composition than 17 years of age having a general autoimmune or exhibits a plasma monomethyl fumarate Cmax of about neurodegenerative disorder , including but not limited to 1321 . 3 618 . 9 ng /mL . ??? multiple sclerosis or psoriasis , comprising a therapeutically Another embodiment described herein is an oral pharma effective amount of one or more fumarate esters . 65 ceutical composition for treating, retarding the progression Another embodiment described herein is a method for of, delaying the onset of, prophylaxis of, amelioration of, or treating , retarding the progression of, delaying the onset of, reducing the symptoms of general autoimmune or neurode US 9 ,814 ,692 B2 19 20 generative disorders , including but not limited to multiple FAE ; about 180 mg to about 230 mg FAE ; about 200 mg to sclerosis or psoriasis , comprising one or more fumarate about 230 mg FAE ; about 270 mg to about 360 mg FAE ; esters , wherein the pharmaceutical composition exhibits a about 340 mg to about 440 mg FAE ; or about 400 to about plasma monomethyl fumarate Cmax as shown herein in 460 mg FAE . In another aspect, the matrix comprises about Drawing 15 . 5 90 mg to about 110 mg FAE . In another aspect, the matrix Another embodiment described herein is a method for comprises about 180 mg to about 230 mg FAE . In another treating , retarding the progression of , delaying the onset of, aspect, the matrix comprises about 200 mg to about 220 mg prophylaxis of, amelioration of, or reducing the symptoms FAE . In another aspect, the matrix comprises about 214 mg of general autoimmune or neurodegenerative disorders, FAE . In another aspect , the matrix comprises about 0 . 5 to including but not limited to multiple sclerosis or psoriasis , 10 about 3 . 5 mmol FAE . In another aspect , the matrix com comprising orally administering to a subject in need thereof prises about 0 . 6 to about 1 . 7 mmol FAE . In another aspect, a therapeutically effective amount of one or more fumarate the matrix comprises DMF, MMF, or a combination thereof. esters comprising any of the pharmaceutical compositions In another aspect, the matrix comprises DMF. In another described herein , wherein the pharmaceutical composition aspect, the matrix comprises MMF . exhibits a plasma monomethyl fumarate pharmacokinetic 15 Another embodiment described herein is a method of parameter as described herein . treating multiple sclerosis in a subject in need thereof Another embodiment described herein is an oral pharma- comprising orally administering to the subject one or more ceutical composition for treating , retarding the progression doses of a composition comprising one or more fumarate of, delaying the onset of, prophylaxis of, amelioration of, or esters in an amount of about 90 mg to about 110 mg FAE or reducing the symptoms of a general autoimmune or neuro - 20 about 170 mg to about 220 mg FAE , wherein the one or degenerative disorder, including but not limited to multiple more doses comprise a controlled release pharmaceutical sclerosis or psoriasis , comprising one or more fumarate composition that releases the contents at a physiological pH esters , wherein the pharmaceutical composition exhibits an of about pH 6 . 8 . in vitro dissolution rate at pH 6 .8 comprising about 10 % to Another embodiment described herein is a method of about 80 % dissolution after about 10 minutes to about 480 25 treating multiple sclerosis in a subject in need thereof minutes . comprising orally administering to the subject one or more Another embodiment described herein is a method for doses of one or more fumarate esters comprising about 90 treating, retarding the progression of , delaying the onset of, mg to about 110 mg FAE or about 170 mg to about 220 mg prophylaxis of, amelioration of, or reducing the symptoms FAE wherein the FAE comprises dimethyl fumarate . of general autoimmune or neurodegenerative disorders , 30 Another embodiment described herein is a method of including but not limited to multiple sclerosis or psoriasis , treating multiple sclerosis in a subject in need thereof comprising orally administering to a subject in need thereof comprising orally administering to the subject one or more a therapeutically effective amount of one or more fumarate doses of one or more fumarate esters comprising about 90 esters comprising any of the pharmaceutical compositions mg to about 110 mg FAE or about 170 mg to about 220 mg described herein , wherein the pharmaceutical composition is 35 FAE wherein the FAE comprises methyl hydrogen fumarate . administered without titration of the pharmaceutical com - Another embodiment described herein is a method of position and without substantially inducing one or more of treating multiple sclerosis in a subject in need thereof flushing , abdominal pain , diarrhea , and nausea in the sub - comprising orally administering to the subject one or more ject. doses of one or more fumarate esters wherein methyl Another embodiment described herein is an oral pharma - 40 hydrogen fumarate activates a nuclear erythroid 2 - related ceutical composition for treating , retarding the progression factor 2 ( nuclear factor erythroid - derived 2 - like 2 , Nrf2 ) of, delaying the onset of , prophylaxis of , amelioration of, or transcriptional pathway . In one aspect, the dose comprises reducing the symptoms of general autoimmune or neurode - an oral controlled release composition comprising: about generative disorders, comprising one or more fumarate 10 % to about 64 % by weight of one ormore fumarate esters esters , wherein the pharmaceutical composition is adminis - 45 ( FAE ; PSD : d90s100 um ) ; about 18 % to about 70 % by tered without titration of the pharmaceutical composition weight of a mixture of mono - and diglycerides ; about 3 % and without substantially inducing one or more of flushing , by weight of polyvinylpyrrolidone ; about 10 % by weight of abdominal pain , diarrhea , and nausea in the subject. polyoxyl 40 hydrogenated castor oil, and about 5 % by Another embodiment described herein is an oral pharma - weight of lactic acid . In another aspect, the dose comprises ceutical composition comprising a controlled release soft 50 one or more FAEs in an amount of about 80 mg to about 460 capsule shell encapsulating a matrix comprising: about 10 % mg. In another aspect, the dose comprises one or more FAEs to about 64 % by weight of one or more fumarate esters in an amount of about 85 mg to about 110 mg. In another ( FAE ; PSD : d90s100 um ) ; about 18 % to about 70 % by aspect , the dose comprises one or more FAEs in an amount weight of a mixture of mono - and diglycerides ; about 3 % of about 170 mg to about 220 mg. In another aspect, a daily by weight of polyvinylpyrrolidone ; about 10 % by weight of 55 total dose comprises one or more FAEs in an amount of polyoxyl 40 hydrogenated castor oil , and about 5 % by about 340 mg to about 440 mg. In another aspect , the weight of lactic acid . In one aspect , the matrix comprises fumarate ester comprises MMF, DMF , or a combination about 13 % to about 16 % ; about 27 % to about 32 % ; about thereof. In another aspect, the matrix comprises DMF. In 34 % , about 48 % , or about 53 % to about 64 % , each by another aspect, the fumarate ester comprises MMF. weight of one or more FAEs . In another aspect, the mixture 60 Another embodiment described herein is an oral con of mono - and di - glycerides is present in an amount of about trolled release pharmaceutical composition comprising a 66 % to about 69 % ; about 48 % to about 55 % ; or about 18 % soft capsule shell and a matrix , the matrix comprising about to about 29 % , each by weight. In another aspect , the one or 10 % to about 64 % by weight of one or more FAEs (PSD : more FAEs comprise about 80 mg to about 460 mg FAE . In d90s100 um ); about 18 % to about 70 % by weight of a another aspect , the matrix comprises about 80 mg to about 65 mixture ofmono - and diglycerides ; about 1 % to about 10 % 105 mg FAE , about 90 mg to about 110 mg FAE , about 95 by weight polyvinylpyrrolidone; about 2 % to about 10 % by mg to about 115 mg FAE , about 100 mg to about 120 mg weight polyoxyl 40 hydrogenated castor oil, and about 1 % US 9 ,814 ,692 B2 22 to about 5 % by weight lactic acid . In one aspect, the soft 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 capsule shell is a soft capsule comprising about 30 % by mg, about 100 mg, about 105 mg, about 108 mg, about 110 weight of gelatin ; about 10 % by weight of methylacrylic mg, about 115 mg, about 120 mg, about 180 mg, about 200 acid copolymer, about 18 % by weight of glycerol, about 1 % mg , about 210 mg, about 216 mg, about 220 mg, about 230 by weight of triethyl citrate ; about 1 . 5 % by weight of 5 mg, about 240 mg, about 360 mg, about 400 mg, about 420 ammonia ; and about 37 % by weight of water. mg, about 432 mg , about 440 mg, about 460 mg, or about Another embodiment described herein is a method of 480 mg of DMF or MMF; about 48 % by weight of a mixture treating multiple sclerosis in a subject in need thereof of mono - and diglycerides ; about 10 % by weight of poly comprising orally administering to the subject one or more vinylpyrrolidone ; about 3 % by weight of polyoxyl 40 hydro doses of an oral controlled release pharmaceutical compo - 10 genated castor oil , and about 5 % by weight of lactic acid . sition comprising a soft capsule shell and a matrix , the Another embodiment described herein is an oral con matrix comprising about 10 % to about 64 % by weight of one trolled release pharmaceutical composition dosage form or more fumarate esters (FAE ; PSD : d90s100 um ) ; about comprising a daily total amount of FAE of about 180 mg , 18 % to about 70 % by weight of a mixture of mono - and about 200 mg, about 210 mg, about 216 mg , about 220 mg, diglycerides ; about 1 % to about 10 % by weight polyvi- 15 about 230 mg, about 240 mg, about 360 mg, about 400 mg, nylpyrrolidone ; about 2 % to about 10 % by weight polyoxyl about 420 mg, about 432 mg, about 440 mg, about 460 mg, 40 hydrogenated castor oil , and about 1 % to about 5 % by or about 480 mg. weight lactic acid . Another embodiment described herein is an oral con Another embodiment described herein is an oral con - trolled release pharmaceutical composition dosage form trolled release pharmaceutical composition comprising a 20 comprising a daily total amount of DMF or MMF of about soft capsule shell and a matrix , the matrix comprising about 180 mg , about 200 mg , about 210 mg , about 216 mg, about 34 % by weight of FAE ; about 48 % by weight of a mixture 220 mg, about 230 mg, about 240 mg, about 360 mg, about of mono - and diglycerides ; about 10 % by weight of poly - 400 mg, about 420 mg, about 432 mg, about 440 mg, about vinylpyrrolidone ; about 3 % by weight of polyoxyl 40 hydro - 460 mg, or about 480 mg . genated castor oil , and about 5 % by weight of lactic acid . In 25 Another embodiment described herein is an oral pharma one aspect, the soft capsule shell is a soft capsule shell ceutical composition providing a daily total amount ofDMF comprising about 30 % by weight of gelatin ; about 10 % by or MMF of about 180 mg, about 200 mg, about 210 mg, weight of methylacrylic acid copolymer, about 18 % by about 216 mg, about 220 mg, about 230 mg, about 240 mg, weight of glycerol; about 1 % by weight of triethyl citrate ; about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 1. 5 % by weight of ammonia ; and about 37 % by 30 about 440 mg, about 460 mg , or about 480 mg DMF or weight of water. MMF; about 48 % by weight of a mixture of mono - and Another embodiment described herein is method of treat - diglycerides; about 10 % by weight of polyvinylpyrroli ing multiple sclerosis in a subject in need thereof comprising done ; about 3 % by weight of polyoxyl 40 hydrogenated orally administering to the subject one or more doses of an castor oil, and about 5 % by weight of lactic acid . oral controlled release pharmaceutical composition compris - 35 Another embodiment described herein is a method of ing a soft capsule shell and a matrix , the matrix comprising treating multiple sclerosis in a subject in need thereof about 34 % by weight of FAE ; about 48 % by weight of a comprising orally administering to the subject one or more mixture of mono - and diglycerides , about 10 % by weight of doses of a pharmaceutical composition providing a daily polyvinylpyrrolidone ; about 3 % by weight of polyoxyl 40 total amount of FAE of about 180 mg, about 200 mg, about hydrogenated castor oil , and about 5 % by weight of lactic 40 210 mg, about 216 mg , about 220 mg , about 230 mg, about acid . 240 mg, about 360 mg, about 400 mg, about 420 mg, about Another embodiment described herein is a method of 432 mg, about 440 mg, about 460 mg, or about 480 mg . treating multiple sclerosis in a subject in need thereof Another embodiment described herein is a method of comprising orally administering to the subject one or more treating multiple sclerosis in a subject in need thereof doses of an oral controlled release pharmaceutical compo - 45 comprising orally administering to the subject one or more sition comprising a soft capsule shell and a matrix , the doses of a pharmaceutical composition providing a daily matrix comprising about 34 % by weight of DMF or MMF ; total amount of DMF or MMF of about 180 mg, about 200 about 48 % by weight of a mixture of mono - and di- mg, about 210 mg, about 216 mg, about 220 mg, about 230 glycerides ; about 10 % by weight of polyvinylpyrrolidone ; mg, about 240 mg, about 360 mg, about 400 mg, about 420 about 3 % by weight of polyoxyl 40 hydrogenated castor oil , 50 mg , about 432 mg, about 440 mg, about 460 mg, or about and about 5 % by weight of lactic acid . 480 mg. Another embodiment described herein is an oral con - Another embodiment described herein is an oral pharma trolled release pharmaceutical composition comprising a ceutical composition comprising a controlled release soft soft capsule shell and a matrix , the matrix comprising about capsule shell and matrix comprising: about 10 % to about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 55 64 % of one or more fumarate esters ( FAE ; PSD : < 100 um ) ; mg, about 100 mg, about 105 mg, about 108 mg, about 110 about 18 % to about 70 % by weight of a mixture ofmono mg, about 115 mg , about 120 mg, about 180 mg, about 200 and di - glycerides , at least about 3 % by weight of polyvi mg, about 210 mg, about 216 mg, about 220 mg, about 230 nylpyrrolidone ; at least about 10 % by weight of polyoxyl 40 mg, about 240 mg, about 360 mg, about 400 mg, about 420 hydrogenated castor oil , and at least about 5 % by weight of mg, about 432 mg, about 440 mg , about 460 mg, or about 60 lactic acid . In one aspect, the composition comprises one or 480 mg of FAE ; about 48 % by weight of a mixture of mono - more FAEs in an amount of about 13 % to about 16 % by and di - glycerides; about 10 % by weight of polyvinylpyr - weight; about 27 % to about 32 % by weight; or about 48 % rolidone; about 3 % by weight of polyoxyl 40 hydrogenated to about 64 % by weight. In another aspect , the composition castor oil , and about 5 % by weight of lactic acid . comprises mono - and diglycerides in an amount of about Another embodiment described herein is an oral con - 65 66 % to about 69 % by weight; about 50 % to about 55 % by trolled release pharmaceutical composition comprising a weight ; or about 18 % to about 29 % by weight. In another soft capsule shell and a matrix , the matrix comprising about aspect, the composition comprises one or more FAEs in an US 9 ,814 ,692 B2 23 24 amount of about 80 mg to about 460 mg FAE . In another Another embodiment described herein is an oral con aspect , the composition comprises one or more FAEs in an trolled release pharmaceutical composition comprising a amount of about 80 mg to about 100 mg FAE ; about 90 mg soft capsule and a matrix , the matrix comprising about 10 % to about 110 mg FAE , about 100 mg to about 120 mg FAE ; to about 64 % by weight of one or more fumarate esters about 180 mg to about 220 mg FAE ; about 200 mg to about 5 (FAE ; PSD : d90s100 um ) ; about 18 % to about 70 % by 230 mg FAE ; or about 400 mg to about 460 mg FAE . In weight of a mixture of mono - and diglycerides ; about 1 % to about 10 % by weight polyvinylpyrrolidone ; about 2 % to another aspect, the composition comprises one or more about 10 % by weight polyoxyl 40 hydrogenated castor oil , FAEs in an amount of about 90 mg to about 110 mg FAE . and about 1 % to about 5 % by weight lactic acid . In one In another aspect, the composition comprises one or more 10 embodiment, the FAE is dimethyl fumarate . In one embodi FAEs in an amount of about 100 mg to about 120 mg FAE . ment, the soft capsule is a soft capsule shell comprising In another aspect, the composition comprises one or more about 30 % by weight of gelatin ; about 10 % by weight of FAEs in an amount of about 200 mg to about 220 mg FAE . methylacrylic acid copolymer, about 18 % by weight of In another aspect, the composition comprises one or more glycerol; about 1 % by weight of triethyl citrate ; about 1 . 5 % FAEs in an amount of about 210 mg to about 220 mg FAE* . 15 by weight of ammonia ; and about 37 % by weight of water. In another aspect , the composition comprises one or more Another embodiment described herein is a method of FAEs in an amount of about 214 mg FAE . In another aspect , treating multiple sclerosis in a subject in need thereof the composition comprises one or more FAEs in an amount comprising orally administering to the subject one or more of about 1 . 5 to about 1 . 7 mmol FAE . In another aspect , the doses of an oral controlled release pharmaceutical compo matrix comprises DMF, MMF, or a combination thereof. In 20 sition comprising a soft capsule shell and a matrix , the another aspect, the matrix comprises DMF. In another matrix comprising about 10 % to about64 % by weight of one aspect, the matrix comprises MMF. or more fumarate esters (FAE ; PSD : d90s100 um ); about Another embodiment described herein is a method of 18 % to about 70 % by weight of a mixture of mono - and treating multiple sclerosis in a subject in need thereof diglycerides; about 1 % to about 10 % by weight polyvi comprising orally administering to the subject one or more 25 nylpyrrolidone ; about 2 % to about 10 % by weight polyoxyl doses of one or more fumarate esters in an amount of about 40 hydrogenated castor oil , and about 1 % to about 5 % by 180 mg to about 220 mg FAE , wherein the one or more weight lactic acid . doses comprise a controlled release pharmaceutical compo Another embodiment described herein is an oral con sition that releases the contents at a physiological pH of trolled release pharmaceutical composition comprising a about pH 6 . 8 . 30 soft capsule shell and a matrix , the matrix comprising about Another embodiment described herein is a method of 34 % by weight of FAE ; about 48 % by weight of a mixture treating multiple sclerosis in a subject in need thereof of mono - and diglycerides ; about 10 % by weight of poly comprising orally administering to the subject one or more vinylpyrrolidone; about 3 % by weight of polyoxyl 40 hydro doses of one or more fumarate esters in an amount of about genated castor oil , and about 5 % by weight of lactic acid . In 180 mg to about 220 mg FAE , wherein the FAE comprises 35 one embodiment, the FAE is dimethyl fumarate . In one dimethyl fumarate . embodiment, the soft capsule is a soft capsule comprising Another embodiment described herein is a method of about 30 % by weight of gelatin ; about 10 % by weight of treating multiple sclerosis in a subject in need thereof methylacrylic acid copolymer ; about 18 % by weight of comprising orally administering to the subject one or more glycerol; about 1 % by weight of triethyl citrate ; about 1 . 5 % doses of one or more fumarate esters in an amount of about 40 by weight of ammonia ; and about 37 % by weight of water . 180 mg to about 220 mg FAE , wherein the FAE comprises Another embodiment described herein is a method of methyl hydrogen fumarate. treating multiple sclerosis in a subject in need thereof Another embodiment described herein is a method of comprising orally administering to the subject one or more treating multiple sclerosis in a subject in need thereof doses of an oral controlled release pharmaceutical compo comprising orally administering to the subject one or more 45 sition comprising a soft capsule shell and a matrix , the doses of one or more fumarate esters wherein methyl matrix comprising about 34 % by weight of FAE ; about 48 % hydrogen fumarate activates a nuclear erythroid 2 -related by weight of a mixture of mono - and diglycerides ; about factor 2 (nuclear factor erythroid - derived 2 -like 2 ; Nrf2 ) 10 % by weight of polyvinylpyrrolidone ; about 3 % by transcriptional pathway . In one aspect, the one or more doses weight of polyoxyl 40 hydrogenated castor oil , and about of fumarate esters comprise an oral controlled release com - 50 5 % by weight of lactic acid . position comprising : about 10 % to about 64 % by weight of Another embodiment described herein is a method of one or more fumarate esters ( FAE ; PSD : < 100 um ) ; about treating multiple sclerosis in a subject in need thereof 18 % to about 70 % by weight of a mixture of mono - and comprising orally administering to the subject one or more diglycerides; at least about 3 % by weight polyvinylpyrroli doses of an oral controlled release pharmaceutical compo done ; at least about 10 % by weight polyoxyl 40 hydroge - 55 sition comprising a soft capsule shell and a matrix , the nated castor oil , and at least about 5 % by weight lactic acid . matrix comprising about 34 % by weight of DMF or MMF; In another aspect, the dose comprises one or more FAEs in about 48 % by weight of a mixture of mono - and di an amount of about 80 mg to about 460 mg. In another glycerides ; about 10 % by weight of polyvinylpyrrolidone ; aspect , the dose comprises one or more FAEs in an amount about 3 % by weight of polyoxyl 40 hydrogenated castor oil , of about 85 mg to about 110 mg. In another aspect, the dose 60 and about 5 % by weight of lactic acid . comprises one or more FAEs in an amount of about 170 mg Another embodiment described herein is an oral con to about 220 mg. In another aspect , a daily total dose trolled release pharmaceutical composition comprising a comprises one or more FAEs in an amount of about 340 mg soft capsule and a matrix , the matrix comprising about 75 to about 440 mg . In another aspect, the FAE comprises mg, about 80 mg , about 85 mg, about 90 mg, about 95 mg, MMF, DMF, or a combination thereof. In another aspect, the 65 about 100 mg , about 105 mg , about 108 mg, about 110 mg, FAE comprises DMF. In another aspect , the FAE comprises about 115 mg, about 120 mg, about 180 mg , about 200 mg, MMF. about 210 mg, about 216 mg, about 220 mg, about 230 mg, US 9 , 814 ,692 B2 25 26 about 240 mg, about 360 mg, about 400 mg, about 420 mg, doses of a pharmaceutical composition providing a daily about 432 mg, about 440 mg, about 460 mg, or about 480 mg total amount of FAE of about 180 mg, about 200 mg, about of FAE and about 48 % by weight of a mixture of mono - and 210 mg, about 216 mg, about 220 mg, about 230 mg, about di - glycerides ; about 10 % by weight of polyvinylpyrroli - 240 mg, about 360 mg, about 400 mg, about 420 mg, about done ; about 3 % by weight of polyoxyl 40 hydrogenated 5 432 mg, about 440 mg, about 460 mg, or about 480 mg. In castor oil , and about 5 % by weight of lactic acid . In one one embodiment, the pharmaceutical composition com embodiment, the soft capsule is a soft capsule comprising prises about 34 % by weight of FAE ; about 48 % by weight about 30 % by weight of gelatin ; about 10 % by weight of of a mixture of mono - and diglycerides ; about 10 % by methylacrylic acid copolymer ; about 18 % by weight of weight of polyvinylpyrrolidone ; about 3 % by weight of glycerol; about 1 % by weight of triethyl citrate ; about 1 . 5 % 10 polyoxyl 40 hydrogenated castor oil , and about 5 % by by weight of ammonia ; and about 37 % by weight of water . weight of lactic acid . Another embodiment described herein is an oral con - Another embodiment described herein is a method of trolled release pharmaceutical composition comprising a treating multiple sclerosis in a subject in need thereof soft capsule and a matrix , the matrix comprising about 75 comprising orally administering to the subject one or more mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, 15 doses of a pharmaceutical composition providing a daily about 100 mg, about 105 mg, about 108 mg , about 110 mg, total amount of DMF or MMF of about 180 mg, about 200 about 115 mg, about 120 mg, about 180 mg, about 200 mg, mg, about 210 mg, about 216 mg, about 220 mg, about 230 about 210 mg, about 216 mg, about 220 mg, about 230 mg, mg, about 240 mg, about 360 mg, about 400 mg, about 420 about 240 mg, about 360 mg, about 400 mg, about 420 mg , mg , about 432 mg, about 440 mg, about 460 mg, or about about 432 mg, about 440 mg, about 460 mg, or about 480 mg 20 480 mg . In one embodiment , the pharmaceutical composi of DMF or MMF and about 48 % by weight of a mixture of tion comprises about 34 % by weight of DMF or MMF ; mono - and diglycerides ; about 10 % by weight of polyvi- about 48 % by weight of a mixture of mono - and di nylpyrrolidone ; about 3 % by weight of polyoxyl 40 hydro glycerides ; about 10 % by weight of polyvinylpyrrolidone ; genated castor oil , and about 5 % by weight of lactic acid . In about 3 % by weight of polyoxyl 40 hydrogenated castor oil , one embodiment, the soft capsule is a soft capsule compris - 25 and about 5 % by weight of lactic acid . ing about 30 % by weight of gelatin ; about 10 % by weight of Another embodiment described herein is an oral pharma methylacrylic acid copolymer ; about 18 % by weight of ceutical composition for treating multiple sclerosis in a glycerol; about 1 % by weight of triethyl citrate; about 1 . 5 % subject in need thereof comprising one or more fumarate by weight of ammonia ; and about 37 % by weight of water. esters comprising DMF, MMF , or a combination thereof. Another embodiment described herein is an oral con - 30 Another embodiment described herein is an oral pharma trolled release pharmaceutical composition dosage forms ceutical composition for treating multiple sclerosis in a comprising a daily total amount of FAE of about 180 mg, subject in need thereof comprising one or more fumarate about 200 mg, about 210 mg, about 216 mg, about 220 mg, esters comprising DMF. about 230 mg, about 240 mg, about 360 mg, about 400 mg, Another embodiment described herein is an oral pharma about 420 mg, about 432 mg, about 440 mg, about 460 mg, 35 ceutical composition for treating multiple sclerosis in a or about 480 mg. subject in need thereof comprising one or more fumarate Another embodiment described herein is an oral con esters comprising MMF. trolled release pharmaceutical composition dosage form Another embodiment described herein is any of the fore comprising a daily total amount of DMF or MMF of about going compositions or methods, wherein the fumarate ester 180 mg, about 200 mg, about 210 mg, about 216 mg, about 40 comprises a therapeutically effective amount ofDMF , MMF , 220 mg, about 230 mg, about 240 mg, about 360 mg, about or a combination thereof. 400 mg, about 420 mg, about 432 mg, about 440 mg, about Another embodiment described herein is any of the fore 460 mg, or about 480 mg. going compositions or methods, wherein the fumarate ester Another embodiment described herein is an oral pharma comprises a therapeutically effective amount of DMF. ceutical compositions providing a daily total amount of FAE 45 Another embodiment described herein is any of the fore of about 180 mg, about 190 mg, about 200 mg, about 210 going compositions or methods , wherein the fumarate ester mg, about 216 mg, about 220 mg, about 230 mg, about 240 comprises a therapeutically effective amount of MMF. mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg , about 460 mg, or about BRIEF DESCRIPTION OF THE DRAWINGS 480 mg FAE ; about 48 % by weight of a mixture of mono - 50 and diglycerides ; about 10 % by weight of polyvinylpyr - Further features of the present disclosure will become rolidone ; about 3 % by weight of polyoxyl 40 hydrogenated more apparent with the following detailed description when castor oil , and about 5 % by weight of lactic acid . taken with reference to the accompanying drawings , each Another embodiment described herein is an oral pharma - according to an aspect of the present disclosure : ceutical compositions providing a daily total amount of 55 FIG . 1 . Scheme for manufacturing enteric soft capsules DMF or MMF of about 180 mg, about 190 mg, about 200 comprising a DMF matrix . mg, about 210 mg, about 216 mg, about 220 mg, about 230 FIG . 2 . Dissolution of enteric soft capsules comprising mg, about 240 mg, about 360 mg, about 380 mg, about 400 two DMF formulations . mg, about 420 mg, about 432 mg, about 440 mg, about 460 FIG . 3 . DMF enteric soft capsule stability . mg , or about 480 mg DMF or MMF ; about 48 % by weight 60 FIG . 4 . DMF release in enteric soft capsules. of a mixture of mono - and diglycerides ; about 10 % by FIG . 5 . Surfactant affects DMF release rate . weight of polyvinylpyrrolidone; about 3 % by weight of FIG . 6 . Polyvinylpyrrolidone concentration affects DMF polyoxyl 40 hydrogenated castor oil, and about 5 % by release rate . weight of lactic acid . FIG . 7 . DMF enteric soft capsules are amenable to Another embodiment described herein is a method of 65 controlled or extended release. treating multiple sclerosis in a subject in need thereof FIG . 8 . DMF particle size affects release rate . comprising orally administering to the subject one or more FIG . 9 . Two- stage dissolution of application batches . US 9 ,814 ,692 B2 27 28 FIG . 10 . Two - stage dissolution of GMP batch compared ceutical composition is a liquid encapsulated within a hard to application batches . capsule shell. In another embodiment, the soft capsule is a FIG . 11. Effects of Povidone K30 and PEG 600 on DMF soft capsule or an enteric soft capsule coated with an enteric release rate . coating and one or more subcoatings or top coatings . In FIG . 12 . Two- stage dissolution of 120 mg DMF enteric 5 another embodiment described herein , the composition is soft capsule . encapsulated in a hard capsule or an enteric hard capsule . In FIG . 13 . DMF enteric soft capsule stability at T , and after another embodiment described herein , the composition is 3 - and 6 -month conditions. encapsulated in a hard capsule comprising an enteric coating FIG . 14 . Two - stage dissolution ofmonomethyl fumarate and one or more subcoatings or top coatings. In another enteric soft capsules . 10 FIG . 15 . Mean plasma concentration of MMF over time embodiment described herein , the fumarate ester is in the following dose administration . form of solid microparticles of defined size within a com FIG . 16 . Two - stage dissolution of dimethyl fumarate and position comprising a lipid or lipophilic vehicle . In some monomethyl fumarate enteric soft capsules . aspects described herein , the lipid or lipophilic vehicle may FIG . 17 . Release of fumarate ester in soybean oil from 15 comprise one or more hydrophilic polymers or species , but enteric soft capsules under acidic conditions (pH 1 . 2 ) . as described herein , the vehicle is considered a lipid or FIG . 18 . Release of fumarate ester in soybean and vegveo lipophilic vehicle . etable oil from enteric soft capsules under acidic conditions As used herein , the terms “ fumarate ester ” or “ FAE ” (pH 1 . 2 ) . refers to any pharmacologically active mono - or dialkyl FIG . 19 . Release of fumarate ester in mono - and di- 20 fumarate ester, such as monomethyl fumarate, dimethyl glycerides from enteric soft capsules under acidic conditions fumarate , or other fumarate esters, acids, salts , pro - drugs of ( pH 1 . 2 ) . monomethyl fumarate , derivatives thereof, combinations or FIG . 20 . Two -stage dissolution of fumarate ester in soft mixtures of any of the foregoing . Fumarate ester as used capsules coated with an enteric coating . herein also comprises prodrugs that are metabolized to FIG . 21 . Two - stage dissolution of fumarate ester in soft 25 monomethyl fumarate after administration to a subject. capsules and enteric soft capsules coated with an enteric The terms " active ingredient” or “ active pharmaceutical coating ingredient” as used herein refer to a pharmaceutical agent, FIG . 22 . Comparison of data from FIG . 21 with enteric active ingredient, compound , or substance , compositions , or soft capsule containing dimethyl fumarate . mixtures thereof, that provide a pharmacological , often FIG . 23 . Two - stage dissolution of fumarate ester in a soft 30 beneficial, effect. capsule and an enteric soft capsule coated with an enteric coating with and without precoating . The term “ dose ” as used herein denotes any form of the FIG . 24 . Mean plasma monomethyl fumarate concentra active ingredient formulation that contains an amount suf tions for Test samples T1, T2 , T3 , and the Reference as a ficient to produce a therapeutic effect with a single admin function of time after dosing (see Examples 31- 33 ) . Panels 35 istration . A and B show the same data , with B having a logarithmic The term " dosage” as used herein refers to the adminis y -axis . tering of a specific amount, number , and frequency of doses FIG . 25 . Mean plasma monomethyl fumarate concentra - over aa specifiedspecimen perperiod of time, typically 1 day . tions for Test samples T4 , T5 , T6 , and the Reference as a The term " dosage form ” as used herein refers to any function of time after dosing ( see Examples 31- 33 ) . Panels 40 pharmaceutical composition described herein in a form that A and B show the same data , with B having a logarithmic can be administered to a subject. The dosage form used y - axis . herein is for oral administration . Exemplary dosage forms described herein include capsules , hard capsules , soft cap DETAILED DESCRIPTION sules, enteric soft capsules , coated soft capsules, suspen 45 sions , solutions emulsions , or the like. Described herein are pharmaceutical compositions of The term " soft capsule ” or " soft gel capsule ” as used fumarate esters , such as dimethyl fumarate , monomethyl herein refers to a soft capsule comprising one or more fumarate , pro - drugs of monomethyl fumarate , other phar - film - forming polymers that is capable of encapsulating a macologically active fumarate esters , or combinations liquid " matrix ” or “ fill ” comprising pharmaceutically thereof. 50 acceptable excipients and one or more active pharmaceutical The pharmaceutical compositions described herein pro - ingredients . The term soft capsule can encompass enteric vide compositions of fumarate esters , dialkyl fumarates, soft capsules as described herein . mono - alkyl fumarates , such as dimethyl fumarate , monom - The term “ enteric soft capsule " as used herein refers to a ethyl fumarate , or combinations thereof, and methods for soft capsule comprising one or more enteric polymers in the preparation thereof . Also described herein are compositions 55 shell or a soft capsule thathas been coated with one or more and methods for manufacturing controlled , delayed , or enteric coatings that are applied to the external surface of the extended release fumarate esters , dimethyl fumarate , capsule as described herein . The coated soft capsule may monomethyl fumarate , or combinations thereof as capsule have one or more subcoatings applied prior to the applica dosage forms. In one embodiment described herein , the tion of the enteric coating . fumarate ester pharmaceutical composition is a liquid . In 60 The terms “ matrix ,” “ fill, ” or “ matrix fill” as used herein one aspect, the liquid is a single - phase , flowable liquid . The refer to a composition comprising one or more active liquid can be lipid , lipophilic , hydrophilic , or combinations pharmaceutical ingredients that is encapsulated within a thereof. In one aspect, the liquid is non -aqueous . In another capsule . Often the matrix comprises a vehicle , one or more aspect, the liquid is aqueous. In one embodiment described active pharmaceutical ingredients, and one or more phar herein , the fumarate ester pharmaceutical composition is a 65 maceutically acceptable excipients . In one aspect described liquid encapsulated within a soft capsule shell . In another herein the matrix is a liquid and comprises a lipid or embodiment described herein , the fumarate ester pharma- lipophilic liquid comprising one or more fumarate esters . US 9 ,814 ,692 B2 29 30 The terms “ active pharmaceutical ingredient load ” or The term “ AUC . -- " as used herein refers to area under “ drug load ” as used herein refers to the quantity (mass ) of the blood ( plasma, serum , or whole blood ) concentration the active pharmaceutical ingredient comprised in a single versus time curve from time zero to time tau ( T ) over a soft capsule fill . dosing interval at steady state , where tau is the length of the The terms “ formulation ” or “ composition ” as used herein 5 dosing interval, and is expressed in units of h ·mg / L or refers to the drug in combination with pharmaceutically hºng/ mL , as applicable . For example , the term AUC0- > 12 as acceptable excipients . This term includes orally adminis used herein refers to the area under the concentration versus trable formulations as well as formulations administrable by time curve from 0 to 12 hours . The term " AUCOO > " as used herein refers to the area other means . 10 under the blood (plasma , serum , or whole blood ) concen The term " titration ” as used herein refers to the incre tration versus time curve from time 0 hours to infinity , and mental increase in drug dosage to a level that provides the is expressed in units of h ·mg / L or h ·ng /mL , as applicable . optimal therapeutic effect. The term “ AUCoveral as used herein refers to the com The term “ controlled release ” as used herein encompasses bined area under the blood ( plasma, serum , or whole blood ) the terms “ immediate release ," " modified releaseelease , , " " sussus 15 concentration versus time curve, and is expressed in units of tained release, " " extended release, " and " delayed release. ” h ·mg / L (or h?ng /mL ) for at least one or more doses of the The terms " extended release " or " sustained release ” as pharmaceutical compositions described herein . In one used herein refers to a composition that releases an active aspect, the “ AUCoverali” refers to the combined area under ingredient according to a desired profile over an extended the blood concentration versus time curve for at least two period under physiological conditions or in an in vitro test . 20 doses of the pharmaceutical compositions described herein . By " extended period ” it is meant a continuous period of time The terms " bioequivalence ” or “ bioequivalent" as used of at least about 1 hour; about 2 hours ; about 4 hours ; about herein refer to a drug product or dosage form that has highly 6 hours ; about 8 hours ; about 10 hours ; about 12 hours ; similar release and systemic absorption as compared to a about 14 hours ; about 16 hours ; about 18 hours ; about 20 reference drug . The U . S . Food , Drug and Cosmetic Act (21 hours about 24 hours; or even longer; specifically , over a 25 U . S . C . $ 505 (1 ) ( 8 ) ( B ) ( i ) provides that a drug is bioequiva period of about 18 hours under physiological conditions or lent to a reference listed drug (RLD ) if : “ the rate and extent in an in vitro assay . of absorption of the drug do not show a significant difference The term " modified release ” as used herein refers to a from the rate and extent of absorption of the listed drug composition that releases an active ingredient at a slower when administered at the same molar dose of the therapeutic rate than does an immediate release formulation under 30 ingredient under similar experimental conditions in either a physiological conditions or in an in vitro test. single dose or multiple doses . . . . " The term " delayed ” release ” as used herein refers to a The phrase " enhanced bioavailability ” as used herein composition that releases an active ingredient after a period refers to the increased proportion of an active pharmaceu of time, for example minutes or hours, such that the active tical ingredient that enters the systemic circulation when ingredient is not released initially . A delayed release com - 35 introduced into the body as compared to a reference active position may provide , for example , the release of a drug or pharmaceutical’ s bioavailability . Bioavailability can be active ingredient from a dosage form , after a certain period , determined by comparing the rate and extent of absorption under physiological conditions or in an in vitro test. of a test drug with a reference drug when administered at the The term mean “ particle size distribution ” ( PSD ) as used same molar dose of the active therapeutic ingredient under herein refers to the mean particle size from a statistical 40 similar experimental conditions in either a single dose or distribution of a range of particle sizes as described herein . multiple doses. Typical pharmacokinetic parameters can be The distribution may be a Gaussian , normal distribution , or used to demonstrate enhanced bioavailability compared to a non - normal distribution . the reference . The terms such as “ d90 , " " d50 ,” and “ d10 ” refer to the The term “ treating ” refers to administering a therapy in an percentage ( e . g . , 90 % , 50 % , or 10 % , respectively ) of par - 45 amount, manner, or mode effective ( e . g . , a therapeutic effect ) ticle sizes that are less than a specified size , range, or to improve a condition , symptom , disorder, or parameter distribution . For example , " d90s90 um " as specified means associated with a disorder , or a likelihood thereof. that 90 % of the particle sizes within a distribution of The term “ prophylaxis ” refers to preventing or reducing particles are less than or equal to 90 um . the progression of a disorder , either to a statistically signifi The term " Cmax" as used herein refers to the maximum 50 cant degree or to a degree detectable to one skilled in the art. observed blood (plasma , serum , or whole blood ) concentra - The term " substantially ” as used herein means to a great tion or the maximum blood concentration calculated or or significant extent, but not completely . estimated from a concentration to time curve , and is As used herein , all percentages ( % ) refer to weight expressed in units of mg /L or ng/ mL , as applicable . percent ( w / w ) unless noted otherwise . The term “ Cmin ” as used herein refers to the minimum 55 The term “ about” as used herein refers to any values , observed blood (plasma , serum , or whole blood ) concentra - including both integers and fractional components that are tion or the minimum blood concentration calculated or within a variation of up to + 10 % of the value modified by the estimated from a concentration to time curve , and is term “ about .” expressed in units of mg/ L or ng /mL , as applicable. As used herein , “ a ” or “ an” means one or more unless The term "C O " as used herein refers to the blood 60 otherwise specified . ( plasma , serum , or whole blood ) concentration of the drug Terms such as “ include , ” “ including, " " contain ,” “ con within the dosing interval, is calculated as AUC / dosing taining, " " having, " and the like mean " comprising. " interval, and is expressed in units of mg / L or ng /mL , as The term “ or ” can be conjunctive or disjunctive . applicable . One embodiment described herein is a liquid pharmaceu The term “ Tmax" as used herein refers to the time after 65 tical composition of one or more fumarate esters . Particles administration at which Cmor occurs , and is expressed in or micronized powders of one or more fumarate esters can units of hours ( h ) or minutes (min ), as applicable . be suspended or solvated in various solutions. The solutions US 9 ,814 ,692 B2 31 32 can comprise lipid or lipophilic liquids or hydrophilic liq - using dual solvent/ anti - solvent rapid precipitation tech uids . Such liquids can be encapsulated in capsules , such as niques. See, Handbook of Pharmaceutical Granulation hard or soft capsules . In one embodiment, the pharmaceu Technology , CRC Press , 3rd Edition , 2010 , which is incor tical composition comprises a non -aqueous , single- phase , porated by reference herein for teachings related to gener flowable liquid . In one embodiment , the pharmaceutical 5 ating pharmaceutical particles . In one aspect described composition comprises a liquid comprising one or more herein , fumarate ester particles of a specified size distribu lipid liquids, lipophilic liquids, hydrophilic liquids, or a tion are produce using a milling technique . combination thereof. In one embodiment, the pharmaceuti - In another embodiment , the pharmaceutical composition cal composition comprises a liquid comprising one or more comprises liquid matrix fills for fumarate esters , such as lipid liquids, lipophilic liquids, or a combination thereof. In 10 dimethyl fumarate , monomethyl fumarate , prodrugs thereof, one embodiment, the pharmaceutical composition com - or derivatives thereof, based on lipids or lipophilic vehicles prises a liquid comprising one or more lipophilic liquids, or hydrophilic vehicles . Some of the described matrices hydrophilic liquids, or a combination thereof. In one have a hydrophobic ( lipophilic ) surface in contact with the embodiment, the pharmaceutical composition comprises a hydrophilic soft capsule shell to minimize any potential liquid comprising one or more lipid liquids. 15 shell - fill interactions , such as when soft capsules are filled One embodiment described herein , is a controlled release with hydrophilic vehicles . pharmaceutical composition comprising one or more fumar- Described herein are methods for manufacturing liquid ate esters . Another embodiment is a controlled release matrix fills comprising fumarate esters, such as dimethyl pharmaceutical composition comprising a soft capsule shell fumarate , monomethyl fumarate, prodrugs thereof, or encapsulating a liquid matrix fill comprising one or more 20 derivatives thereof , in a controlled release soft capsule in the fumarate esters . Another embodiment is a controlled release form of a suspension , where part or all of the fumarate ester pharmaceutical composition comprising a hard capsule shell is suspended within the matrix . Also provided are compo encapsulating a liquid matrix fill comprising one or more sitions and formulations where the fumarate ester is incor fumarate esters . porated into a one -phase or two - phase matrix . Another embodiment is a controlled release pharmaceu - 25 Also described herein are methods for manufacturing tical composition comprising a capsule shell encapsulating a liquid matrix fills comprising fumarate esters or derivatives matrix fill comprising one or more fumarate esters , wherein thereof, in a delayed release soft capsule in the form of a the capsule shell comprises one or more subcoatings, coat - suspension , where part or all of the fumarate ester is ings , or topcoatings. Suitable coatings may be adherence suspended within the matrix . coatings , enteric coatings, moisture barriers , air or gas 30 Described herein are methods for manufacturing liquid barriers, polymer coatings, colorings, flavors , writings , or matrix fills comprising fumarate esters or derivatives combinations thereof. thereof, in an extended release soft capsule in the form of a In one embodiment, the pharmaceutical composition has suspension , where part or all of the fumarate ester is controlled release properties. suspended within the matrix . In another embodiment, the matrix fill provides controlled 35 Another embodiment described herein is a controlled , release properties . Such controlled release matrix fills are delayed , or extended release capsule having a shell and a described in International Patent Application Publication matrix fill , wherein the matrix fill includes a lipid or lipo No . WO 2005 /009409 ; U . S . Patent Application Publication philic liquid vehicle comprising a suspension of solid par No. US 2006 /0115527 ; U . S . Pat. Nos. 8 ,293 ,270 ; and 8, 333, ticles of one or more fumarate esters such as dimethyl 989 , each of which is incorporated by reference herein for 40 fumarate , monomethyl fumarate , prodrugs thereof, or such teachings . In one aspect, the matrix is configured to derivatives thereof. In another embodiment, the lipid or provide controlled release , extended release, sustained lipophilic vehicle comprises an oil , a vegetable oil, fatty release , delayed release, or combinations thereof. acid , fatty acid ester , or a combination thereof. In one In another embodiment, the matrix comprises a lipid or embodiment, the matrix fill is a single phase lipid or lipophilic vehicle that provides a suspension of fumarate 45 lipophilic liquid at room temperature and prevents sublima ester microparticles having defined sizes. In one aspect , a tion of the fumarate ester. In another embodiment, the lipid capsule comprising a lipid or lipophilic vehicle comprising or lipophilic liquid vehicle comprises one or more oils , suspension of one or more fumarate ester microparticles mono / diglycerides , polyoxyl hydrogenated castor oils , poly provides controlled release delivery of the fumarate ester. In vinylpyrrolidones , or a combination thereof. In another one embodiment, the capsule is a soft capsule . In another 50 embodiment, the lipid or lipophilic liquid vehicle comprises embodiment, the capsule is a hard capsule . In another an oil . In another embodiment, the lipid or lipophilic vehicle embodiment, the capsule is coated with one or more sub comprises mono /diglycerides , polyoxylhydrogenated castor coatings , one or more enteric coatings , and one or more oils , polyvinylpyrrolidones, or a combination thereof. topcoating moisture barriers . Exemplary lipid or lipophilic vehicles comprise mineral The fumarate ester particles described herein ( e . g . , dim - 55 oil; light mineral oil ; natural oils ( e . g . , vegetable , corn , ethyl fumarate or monomethyl fumarate , or prodrugs of canola , sunflower , soybean , olive, coconut , cocoa, peanut , monomethyl fumarate ) may be generated by any particle almond , cottonseed , persic , sesame, squalane , castor, cod size reduction or particle growth methodology known to one liver ) hydrogenated vegetable oil ; partially hydrogenated having ordinary skill the art. Exemplary and non - limiting oils ; beeswax ; polyethoxylated beeswax ; paraffin ; normal methods may comprise a “ top - down ” reduction in particle 60 waxes; medium chain medium chain monoglycerides , size including mechanical micronization techniques , diglycerides and triglycerides ; higher aliphatic alcohols ; wherein a larger particle is crushed , bashed , or ground into higher aliphatic acids ; long chain fatty acids; saturated or a smaller particle through techniques , such as jet milling , unsaturated fatty acids ; hydrogenated fatty acids; fatty acid ball milling , or high pressure homogenization ; or particle glycerides ; polyoxyethylated oleic glycerides ; monoglycer engineering techniques such as cryogenic spraying or crystal 65 ides and diglycerides ; mono - , bi- or tri- substituted glycer engineering. In addition , " bottom - up ” processing may be ides; glycerol mono - oleate esters ; glycerol mono - caprate ; used to build a suitable size of particles as described herein glyceryl monocaprylate ; propylene glycol dicaprylate; pro US 9 ,814 ,692 B2 33 34 pylene glycol monolaurate ; glyceryl palmitostearate ; glyc - tan monopalmitate , sorbitan monostearate , stearic acid , tro eryl behenate ; diethyleneglycol palmitostearate ; polyethyl - lamine , emulsifying wax , or combinations thereof. eneglycol stearate ; polyoxyethyleneglycol palmitostearate ; In another embodiment , the matrix comprises a neutral glyceryl mono palmitostearate ; cetyl palmitate ; polyethyl - izing agent . Without being bound to any theory , the neutral eneglycol palmitostearate ; dimethylpolysiloxane ; mono - or 5 izing agent it thought to stabilize the fumarate ester in the di- glyceryl behenate ; fatty alcohols associated with poly matrix fill by preventing hydrolysis . In addition , without ethoxylate fatty alcohols ; cetyl alcohol; octyl dodecanol; being bound by any theory , the neutralizing agent may myristyl alcohol; isopropyl myristate , isopropyl palmitate , stabilize soft capsule shells comprising enteric polymers stearic acid , or stearyl alcohol, inter alia , or combinations such as acrylate methacrylate by forming salts with the thereof. In one embodiment , the liquid matrix comprises " methylacrylate moieties from the capsule shell . In one solid particles of fumarate ester suspended in a lipid or aspect, the neutralizing agent comprises an organic acid , lipophilic vehicle ofvegetable oil, fatty acid , fatty acid ester, ester , or salt. In another aspect, the neutralizing agent or a combination thereof. In one embodiment, the lipid or comprises at least one of lactate , fumarate , caprylate , lipophilic vehicle is a liquid at room temperature (e . g ., 25° 16 caprate , oleate , maleate , succinate , tartrate , citrate , gluta C . ) or phisiological temperature ( e . g . , 37° C . ) . In one mate , gluconate , esters or salts thereof , or combinations embodiment, the lipid or lipophilic vehicle is soybean oil. In thereof. In one aspect, the neutralizing agent is lactic acid . another embodiment, the lipid or lipophilic vehicle com - In another embodiment, the matrix includes a hydrophilic prises medium chain monoglycerides and diglycerides . internal phase and a lipid or lipophilic external phase . The In one embodiment, the matrix comprises a solvent or 20 hydrophilic internal phase can comprise polypropylene gly solubility enhancing agent . Exemplary solvents or solubility col or polyethylene glycolof molecular weight ranging from enhancing agents useful for the matrix fills described herein about 200 to about 8000 (My , number average molecular include Capmul® MCM , Cremophor RH 40 , Captex® weight ) . In another embodiment, the internal phase com 355 , Croscarmellose , Crospovidone , Crospovidone CL , prises hydroalcoholic solutions of cellulose derivatives , Crospovidone CL - F , Crospovidone CL - M , Imwitor® 742 , 25 polyacrylates , polyvinyl polymers , or combinations thereof. Kollidon® CL , Kollidon® CL - F , Kollidon® CL - M , Labra - In one embodiment, the internal phase comprises polymers facTM Lipophile WL 1349 , Labrafil® M2125CS , Labrasol® , such as methylcellulose , hydroxypropylmethylcellulose , Lutrol® F 68 , MaisineTM 35 - 1 , mannitol, Miglyol® 812 , polymethylmethacrylate , or polyvinylpyrrolidone (PVP ). In Pearlitol® Flash , Peceol® , polyethylene glycol 400 , poly ethylene glycol 600 , polyethylene glycol 3350 , Plurol® 30 one« th embodiment , the internal phase of the matrix state is Oleique CC 497 , Povidone K 17 , Povidone K 30 , propylene " fluid ” or “ structured . ” A “ fluid ” internal phase , as used glycol, or combinations thereof. In one embodiment, the herein , means a completely flowable liquid whose globules lipid or lipophilic vehicle comprises medium chain mono can aggregate to make a larger globule . A " structured ” and diglycerides (e . g. , Capmul® MCM ) and polyoxyl 40 internal phase , as used herein , means a solid , semisolid , or hydrogenated castor oil ( e . g . , macrogolglycerol hydrox - 3535 18a gel whose shape is relatively stable and does not usually ystearate ; Cremophor RH 40 ). aggregate to form a large globule . A structured internal In another embodiment, the matrix comprises a one or phase can provide controlled drug release and stabilize the more hydrophilic solvents or suspension agents . The matrix physical state of the matrix . Without being bound to any can polyvinylpyrrolidone , polyethylene glycols of molecu - theory , the structured nature of the matrix impedes solvation lar weight ranging from about 200 to about 8000 (My 40 or diffusion of the fumarate ester out of the matrix . In number averagemolecular weight) , or combinations thereof. another embodiment, the external phase comprises a veg In one embodiment, the matrix comprises polyvinylpyrroli - etable oil , hydrogenated vegetable oil , fatty acid , fatty acid done K30 ( e . g . , Povidone K30 ) . In another embodiment, the ester , wax , or a combination thereof. In another embodi matrix comprises polyethylene glycol 400 and poly polyvi- ment , fumarate ester is dispersed in the internal phase as a nylpyrrolidone K30 . 45 suspension form . In another embodiment, the matrix fill comprises a release In another embodiment , the matrix fill is an emulsion regulator such as a fatty acid salt, fatty acid ester, or fatty type, where the fumarate ester is distributed in one or both acid polyoxyethylene derivative . The release regulator can of the external (lipophilic ) and internal (hydrophilic ) phases . also be a surfactant having a hydrophilic /lipophilic balance The external phase of the emulsion matrix fill comprises (HLB ) value between about 2 and about 40 . The HLB 50 linic characteristic of surfactants can be determined in accordance 30 lipid or lipophilic vehicles similar to those described herein . with “ Physical Pharmacy : Physical Chemical Principles in The fumarate ester can be dispersed in the internal phase as the Pharmaceutical Sciences, ” Fourth Edition , pp . 371- 373 , a solution or as a suspension . For example , one portion of A . Martin , Ed ., Lippincott Williams & Wilkins , Philadelphia the fumarate ester in the form of a powder is incorporated in ( 1993 ), which is incorporated by reference herein for such 55 the internal phase, while another portion is dispersed in the teachings . external phase as solid particles . An emulsion - type matrix In another embodiment, thematrix comprises emulsifying may comprise a surfactant or combination of surfactants or solubilizing agents such as acacia , cholesterol, dietha having HLB values ranging from about 2 to about 40 , nolamine , glyceryl monostearate , lanolin alcohols , lecithin , including all integers within the specified range . In one mono - and di - glycerides, monoethanolamines , oleic acids, 60 aspect , the HLB range comprises from about 8 to about 20 , oleyl alcohols , poloxamer, polyoxyethylene 50 stearate , including all integers within the specified range . polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil , In one embodiment, the pharmaceutical composition polyoxyl 10 oleyl ether , polyoxyl 20 cetostearyl ether, described herein comprises a soft capsule comprising a polyoxyl 40 stearate , polysorbate 20 , polysorbate 40 , poly - matrix comprising a lipid or lipophilic vehicle that provides sorbate 60 , polysorbate 80 , propylene glycol diacetate , pro - 65 a solution , suspension , or combination thereof of a fumarate pylene glycol monostearate , sodium lauryl sulfate , sodium ester . In one embodiment described herein , the fumarate stearate , sorbitan monolaurate , sorbitan monooleate , sorbi- ester is a mono - or di - alkyl fumarate of Formula I : US 9 , 814 ,692 B2 35 36 cation Publication Nos. US 2014 /0275048 ; US 2014 / 0275205 ; US 2014 /0275250 ; US 2015 /0190360 ; US 2014 / R2 057918 ; US 2014 / 348914 ; US 2014 /350018 ; US 2014 / R ', 056973 ; US 2014 /0348915 ; and US 2015 /0252013 , each of 5 which is incorporated by reference herein for such teachings. In one embodiment, the prodrug comprises one or more of N , N -diethylcarbamoyl ) methyl methyl( 2E )but - 2 -ene - 1, 4 wherein R and R2, which may be the same or different, dioate; methyl[ N -benzylcarbamoyl ] methyl ( 2E )but - 2 -ene - 1 , independently represent linear, branched , or cyclic , satu 4 - dioate ; methyl 2 -morpholin - 4 - yl- 2 - oxoethyl ( 2E )but - 2 rated or unsaturated C1 . 30 alkyl radical , which may be " ene - 1 , 4 - dioate ; ( N - butylcarbamoyl) methyl methyl( 2E )but optionally substituted with halogen (C1 , F , I, Br) , hydroxy, 2 -ene - 1 ,4 -dioate ; [N -( 2 -methoxyethyl )carbamoyl ] methyl C1- 4 alkoxy, nitro , or cyano for preparing a pharmaceutical methyl ( 2E ) but- 2 - ene - 1 , 4 - dioate ; methyl ( N - ( 1 , 3 , 4 - thiadi composition as described herein . azol- 2yl) carbamoyl )methyl ( 2E )but - Zene - 1, 4 -dioate ; ( N ,N The C1- 20 alkyl radicals , C1- 8 alkyl radicals , and C4-5 alkyl dimethylcarbamoyl) methyl methyl (2E )but - 2 - ene - 1, 4 - dio radicals are , for example , methyl, ethyl , n -propyl , isopropyl, ate ; ( N -methoxy - N -methylcarbamoyl ) methyl methyl( 2E ) n -butyl , sec -butyl , t- butyl , pentyl, cyclopentyl, 2 -ethyl but- 2 - ene - 1 ,4 - dioate ; bis - ( 2 -methoxyethylamino ) hexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, carbamoyl] methyl methyl( 2E )but - 2 - ene - 1 ,4 -dioate ; [N allyl, 2 -hydroxyethyl , 2 or 3 -hydroxy propyl, 2 -methoxy (methoxycarbonyl ) carbamoyl ]methyl methyl( 2E )but - 2ene ethyl, methoxy methyl or 2 - or 3 -methoxy propyl. In one 20 1 , 4 - dioate ; methyl 2 - oxo - 2 -piperazinylethyl ( 2E ) but- 2 - ene aspect , at least one of R or R2 is a C . alkyl, especially 20 1 , 4 - dioate ; methyl 2 -oxo - 2 - ( 2 - oxo ( 1 , 3 -oxazolidin - 3yl) ethyl methyl or ethyl. In another aspect, R and RP are the same (2E ) but- 2ene - 1, 4 - dioate ; { N - [ 2 - ( dimethylamino ) ethyl ] or different Cl- s alkyl radicals such as methyl, ethyl, n - pro carbamoyl }methyl methyl( 2E )but - 2ene - 1 , 4 -dioate ; ethoxy pyl, or t -butyl . In one aspect, R and R are the same or carbonyloxyethyl methyl (2E ) but- 2 - ene - 1 , 4 - dioate ; methyl different C - 5 alkyl radicals such as methyl and ethyl. In one 25 (methylethoxycarbonyl oxy ethyl ( 2E )but - 2 - ene - 1 , 4 - dioate ; aspect, R1 and R2 are identical and are methyl or ethyl. In 25 ( cyclohexyloxycarbonyloxy ) ethyl methyl ( 2E ) but- 2 - ene - 1 , one aspect , the fumarate ester is monomethyl fumarate , 4 -dioate ; methyl ( 2 -methylpropanoyloxy ) ethyl (2E )but - 2 dimethyl fumarate , methyl ethyl fumarate , or diethyl fumar ene - 1, 4 - dioate ; methyl phenylcarbonyloxyethyl (2E )but - 2 ate . In one aspect , the fumarate ester is monomethyl fumar ene- 1 , 4 - dioate ; cyclohexylcarbonyloxybutyl methyl (2E ) ate , dimethyl fumarate , or a combination thereof. In oneIn 30 but - 2 - ene- 1 , 4 - dioate ; [ ( 2E ) - 3 - (methoxycarbonyl ) prop - 2 aspect , the fumarate ester is monomethyl fumarate . In 30 enoyloxylethyl methyl (2E ) but- 2 - ene - 1 , 4 - dioate ; methyl another aspect, the fumarate ester is dimethyl fumarate . 2 -methyl - 1 - phenylcarbonyloxypropyl (2E )but - 2 - ene - 1 ,4 In one embodiment , the fumarate ester is : dioate ; ( cyclohexyloxycarbonyloxy ) ethyl methyl ( 2E ) but- 2 ene - 1 , 4 - dioate ; 3 - { { [ (2E ) - 3 - (methoxycarbonyl ) prop - 2 35 enoyloxy ]methyl } oxycarbonyl) ( 3S ) - 3 - aminopropanoic acid ; 3 - { { [ ( 2E ) - 3 - (methoxycarbonyl ) prop - 2 - enoyloxy ] CH3. methyl } oxycarbonyl) ( 2S )- 2 - aminopropanoic acid ; HC Y 3 - { {[ ( 2E )- 3 -( methoxycarbonyl ) prop -2 -enoyloxy ] methyl } oxycarbonyl) (3S ) - 3 - ( 2 -aminoacetylamino ) pro 40 panoic acid ; 3 - {{ [( 2E ) - 3 - (methoxycarbonyl ) prop - 2 -enoy loxy ]methyl }oxycarbonyl ) (2S ) - 2 - aminopropanoic acid ; In one embodiment, the fumarate ester is : 3 - { [( 2E ) -3 - (methoxycarbonyl ) prop - 2enoyloxy ]ethoxycar bonyloxy } ( 2S ) - 2 - aminopropanoic acid ; methyl ( 2 -mor pholinoethyl) fumarate ; methyl ( 3 -morpholinopropyl ) fumar 45 ate ; methyl (4 -morpholinobutyl ) fumarate ; methyl HO ( 5 -morpholinopentyl ) fumarate ; methyl (6 -morpholino hexyl) fumarate ; ( E ) - 2 , 2 - ( ( 2 - ( 4 -methoxy - 4 -oxobut - 2 - enoyl) oxy ) ethyl ) azanediyl) diacetic acid ; methyl ( 2 - (methyl ( 2 (methyl sulfonyl) ethyl) amino ) ethyl) fumarate ; 50 2 -( dimethylamino )propyl methyl fumarate ; (E ) -2 -( ( 4 In one embodiment, the fumarate ester is : methoxy - 4 -oxobut - 2 -enoyl ) oxy ) - N , N , N - trimethylethan aminium ; 2 - ( 4 ,4 -difluoropiperidin - 1 - yl) ethylmethyl fumar ate ; 1- (dimethylamino )propan - 2 -yl methyl fumarate ;methyl ( 2 -thiomorpholinoethyl ) fumarate ; methyl (2 - (phenylamino ) HO 55 ethyl) fumarate ; 2 -( dimethylamino ) -2 -methyl propyl methyl fumarate ; methyl ( 2 - (methylsulfonyl ) ethyl) fumarate ; 2 - ( 1 , 1 -dioxidothiomorpholino ) ethyl methyl fumarate ; 2 - ( benzyl (methyl ) amino )ethyl methyl fumarate ; 2 - ( 2 , 5 - dioxopyrroli din - 1- yl) ethyl methyl fumarate; methyl (2 - (piperidin - 1 -yl ) wherein R comprises any C1- 20 alkyl, any C1- 20 acid , any 60 ethyl) fumarate ; methyl ( 2 -morpholinoethyl ) fumarate ; 2 - ( 1 , C1- 20 ether , any C1- 20 ester , any C1- 20 amino, any C1- 20 4 -dioxa - 8 -azaspiro [4 .5 ]decan - 8 -yl ) ethyl methyl fumarate ; amide, or any C1- 20 heterocycle . methyl ( 2 - ( pyrrolidin - 1 - yl) ethyl) fumarate ; 2 - ( dimethyl In another embodiment described herein , the fumarate amino )ethyl methyl fumarate ; 2 - (diethylamino )ethyl methyl ester is a prodrug of monomethyl fumarate . In one aspect the fumarate ; or 2 - diethylamino ) - 2 - oxoethyl methyl fumarate , monomethyl fumarate prodrug is dimethyl fumarate . Exem - 65 or pharmaceutically acceptable salts thereof. In one embodi plary monomethyl fumarate prodrugs are described in U . S . ment , the prodrug is ( N , N - diethylcarbamoyl) methyl methyl Pat. Nos . 8 ,669 , 281 and 9 , 090 ,558 and U . S . Patent Appli - (2E ) but- 2 - ene - 1 , 4 - dioate , or a salt thereof. In another US 9 ,814 ,692 B2 37 38 embodiment, the prodrug is 2 - (2 , 5 -dioxopyrrolidin - 1 - yl) In one embodiment, the fumarate ester -to -matrix fill ratio ethyl methyl fumarate , or a salt thereof. range ( e . g ., the ratio of the fumarate ester weight to the In one embodiment, the pharmaceutical compositions weight of the other components of the matrix fill or vehicle ) described herein comprise pharmaceutically acceptable salts comprises from about 1 : 50 to about 1 : 1 by weight, including of the fumarate ester active pharmaceutical ingredient. The 5 all ratios within the specified range . In another embodiment , term " pharmaceutically acceptable salts” of an active ingre - the fumarate ester - to -matrix ratio range comprises from dient includes alkali metal salts such as, sodium or potas - about 1 : 10 to about 1 : 1 by weight, including all ratios within sium salts , alkaline earth metal salts such as , for example , the specified range . In one aspect, the fumarate ester - to calcium and magnesium salts , and salts with organic or matrix ratio comprises about 1 : 9 to about 1 : 1 by weight, inorganic acid such as, for example , hydrochloric acid , 10 including all ratios within the specified range . In another hydrobromic acid , nitric acid , sulfuric acid , phosphoric acid , aspect, the fumarate ester- to -matrix ratio range comprises citric acid , formic acid , maleic acid , succinic acid , tartaric from about 1 : 5 to about 1 : 1 by weight, including all ratios acid , methanesulphonic acid , toluenesulphonic acid , inter within the specified range . In another aspect , the fumarate alia . In another embodiment, the active ingredientmay also ester - to -matrix ratio range comprises from about 1 : 3 to be in the form of pharmaceutically acceptable uncharged or 15 about 1 : 1 . 4 by weight , including all ratios within the speci charged molecules , molecular complexes , solvates , or anhy - fied range . In another aspect, the fumarate ester - to -matrix drates thereof, and , if relevant, single isomers , enantiomers , ratio is about 1 : 5 ; about 1 : 4 ; about 1 : 3 ; about 1 : 2 ; about 1 : 1 ; racemic mixtures , or mixtures thereof. In another embodi- or about 0 . 5 : 1 . In other aspects , the fumarate ester - to -matrix ment, the active pharmaceutical ingredient may be in any of 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 ; its crystalline, polymorphous, semi- crystalline, amorphous 20 1 : 1. 4 ; 1 : 1. 35; 1 : 1. 2, or about 1: 1. 2 . or polyamorphous forms, or mixtures thereof. In one embodiment, the active ingredient comprises about The fumarate esters described herein can be prepared by 1 % to about 70 % of the matrix , including all integers and processes known in the art . See, e . g . , EPO 312 697 and U . S . fractions within the specified range . In another embodiment, Patent Application Publication Nos. US 2013 / 0295169 ; US the active ingredient comprises about 70 % ; about 60 % ; 2014 /0179779 ; US 2014 / 0200363 ; and US 2014 / 0364604 , 25 about 50 % ; about 40 % , about 30 % ; about 20 % ; about 15 % ; each of which is incorporated by reference herein for such about 10 % ; about 5 % ; about 2 % ; or about 1 % of the matrix teachings . fill . In one aspect, the active ingredient comprises about 64 % In one embodiment, the pharmaceutical composition of the matrix . In another embodiment, the active ingredient comprises an active ingredient or drug . In one embodiment, comprises about 57 % of the matrix . In another embodiment, the active ingredient or drug is a pharmacologically active 30 the active ingredient comprises about 50 % of the matrix . In fumarate ester. In one embodiment described herein , the another embodiment, the active ingredient comprises about active ingredient is a monoalkyl fumarate . In one embodi- 34 % of the matrix . In another embodiment, the active ment described herein , the active ingredient is a dialkyl ingredient comprises about 32 % of the matrix . In another fumarate . In one embodiment described herein , the active embodiment, the active ingredient comprises about 30 % of ingredient is a fumarate ester or combination of fumarate 35 the matrix . In another embodiment, the active ingredient esters . In one embodiment described herein , the active comprises about 28 % of the matrix . In another embodiment , ingredient is dimethyl fumarate . In another embodiment the active ingredient comprises about 25 % of the matrix . described herein , the active ingredient is monomethyl In one embodiment, the lipid or lipophilic liquid vehicle , fumarate (methyl hydrogen fumarate ) . In another embodi - including soluble components other than the fumarate ester , ment described herein , the active ingredient is a combination 40 comprises about 50 % to about 88 % of the matrix by weight, of dimethyl fumarate and monomethyl fumarate . In another including all integers and fractions within the specified embodiment described herein , the active ingredient is a range . In one embodiment the lipid or lipophilic liquid combination of dimethyl fumarate , monomethyl fumarate , vehicle comprise about 60 % of the matrix by weight. and other pharmacologically active fumarate esters , acids, In one embodiment , the solid fumarate ester particles are salts , or derivatives thereof . In another embodiment , the 45 milled or micronized . In one embodiment , the fumarate ester active ingredient or drug comprises dimethyl fumarate , comprises a particle size range of about 1 um to about 500 monomethyl fumarate , other pharmacologically active um , including all integers and fractions within the specified fumarate esters , acids , or salts , derivatives thereof, or com - range . In one aspect, the micronized solid fumarate ester binations thereof. In another embodiment, the active ingre - particles have a particle size of about 1 um , 2 um , about 5 dient comprises dimethyl fumarate , monomethyl fumarate , 50 um , about 10 um , about 15 um , about 20 um , about 25 um , or derivatives thereof, combined with aspirin , ibuprofen , about 30 um , about 35 um , about 40 um , about 45 um , about naproxene, diclofenac , ketoprofen , celecoxib , other non 50 um , about 55 um , about 60 um , about 65 um , about 70 steroidal anti- inflamatory active drugs (NSAIDs ) , or com um , about 75 um , about 80 um , about 85 um , about 90 um , binations thereof. In one embodiment, the pharmaceutical about 95 um , about 100 um , about 105 um , about 110 um , composition comprises a fumarate ester combined with 55 about 115 um , about 120 um , about 125 um , about 130 um , aspirin . about 135 um , about 140 um , about 145 um , about 150 um , In another embodiment, the pharmaceutical composition about 155 um , about 160 um , about 165 um , about 170 um , comprises a fumarate ester combined with one or more about 175 um , about 180 um , about 185 um , about 190 um , leukotriene receptor antagonists . In another embodiment, about 195 um , about 200 um , about 205 um , about 210 um , the pharmaceutical composition comprises a fumarate ester 60 about 215 um , about 220 um , about 225 um , about 230 um , combined with montelukast ( Singulair® ) or zafirlukast ( Ac about 235 um , about 240 um , about 245 um , about 250 um , colate® ) . In another embodiment, the pharmaceutical com - about 255 um , about 260 um , about 265 um , about 270 um , position comprises a fumarate ester combined with mon about 275 um , about 280 um , about 285 um , about 290 um , telukast or zafirlukast and an NSAID . In another about 295 um , about 300 um , about 305 um , about 310 um , embodiment, the pharmaceutical composition comprises a 65 about 315 um , about 320 um , about 325 um , about 330 um , fumarate ester combined with montelukast or zafirlukast and about 335 um , about 340 um , about 345 um , about 350 um , aspirin . about 355 um , about 360 um , about 365 um , about 370 um , US 9 ,814 ,692 B2 39 40 about 375 um , about 380 um , about 385 um , about 390 um , a d90 of s to about 150 um , a d10 of s to about 10 um and about 395 um , about 400 um , about 405 um , about 410 um , a d90 of s to about 100 um . In one aspect, the solid particles about 415 um , about 420 um , about 425 um , about 430 um , of fumarate ester have a particle size distribution with a d10 about 435 um , about 440 um , about 445 um , about 450 um , of s to about 10 um and a d90 of s to about 100 um , a d10 about 455 um , about 460 um , about 465 um , about 470 um , 5 of s to about 20 um and a d90 of s to about 100 um , a d10 about 475 um , about 480 um , about 485 um , about 490 um , of s to about 30 um and a d90 of s to about 100 um , a d10 about 495 um , about 500 um , or even larger. In another of s to about 40 um and a d90 of s to about 100 um , a d10 aspect , the solid particles of fumarate ester comprise a of s to about 50 um and a d90 of s to about 100 um , a d10 distribution of particle sizes, comprising particles of any of of s to about 60 um and a d90 of s to about 100 um , a d10 the foregoing particle sizes . 10 of s to about 70 um and a d90 of s to about 100 um , a d10 In another embodiment, the solid fumarate ester particles of s to about 80 um and a d90 of s to about 100 um . have mean particle size distributions (PSD ) ranging from In another embodiment, the solid particles of fumarate about 20 um to about 300 um , including all integers and ester comprise multiple distributions of particle sizes . In one fractions within the specified range . In one aspect, the solid aspect , the solid particles of fumarate ester may comprise a particles of fumarate ester comprise mean particle size 15 plurality of independently combined mean particle size distributions of about 20 um , about 30 um , about 40 um , distributions , wherein each independent mean particle size about 50 um , about 60 um , about 70 um , about 80 um , about distribution ranges from about 20 um to about 300 um , 90 um , about 100 um , about 120 um , about 140 um , about including all integers and fractions within the specified 160 um , about 180 um , about 190 um , about 200 um , about range . In another aspect, the plurality of mean particle size 220 um , about 240 um , about 260 um , about 280 um , or 20 distributions can comprise a mean particle size distribution about 300 um . In one aspect, the solid particles of fumarate of about 261 um , a mean particle size distribution of about ester have a mean particle size distribution of about 260 um . 168 um , a mean particle size distribution of about 148 um , In one aspect, the solid particles of fumarate ester have a a mean particle size distribution of about 100 um , a mean mean particle size distribution of about 170 um . In one particle size distribution of about 90 um , a mean particle size aspect , the solid particles of fumarate ester have a mean 25 distribution of about 80 um , or a mean particle size distri particle size distribution of about 140 um . In one aspect , the bution of about 26 um . In another aspect, the plurality of solid particles of fumarate ester have a mean particle size mean particle size distributions can comprise combinations distribution of about 100 um . In one aspect, the solid of independent mean particle size distributions, wherein particles of fumarate ester have a mean particle size distri- each independently combined mean particle size distribution bution of about 90 um . In one aspect , the solid particles of 30 is about 261 um , about 168 um , about 148 um , about 100 fumarate ester have a mean particle size distribution of about um ; about 90 um , about 80 um , or about 26 um . In another 80 um . In one aspect, the solid particles of fumarate ester aspect, the solid particles of fumarate ester comprise a have a mean particle size distribution of about 25 um . combination of independently combined mean particle size In another embodiment, the solid fumarate ester particles distributions of about 30 um to about 260 um in a single have a particle size distribution with a d90 of less than or 35 matrix fill. Any of the foregoing particle size distributions equal to about 500 um . In one aspect , the particle size may be combined to provide the desired controlled release distribution of solid particles of fumarate ester have a d90 of profile . s to about 20 um , about 30 um , about 40 um , about 50 um , The forgoing sizes of fumarate ester particles may be about 60 um , about 70 um , about 80 um , about 90 um , about determined using standard techniques known to one of 100 um , about 120 um , about 140 um , about 160 um , about 40 ordinary skill in the art . The exemplary techniques that can 180 um , about 190 um , about 200 um , about 220 um , about be used for measuring the size of fumarate ester particles 240 um , about 260 um , about 280 um , about 300 um , or may include laser diffraction analysis , light scattering ( e . g . , about 400 um . In one aspect, the solid particles of fumarate dynamic light scattering ) , microscopic particle image analy ester have a particle size distribution with a d90 of s about sis , elutriation , or aerosol mass spectrometry . The sample of 260 um ( d905260 um ) . In one aspect , the solid particles of 45 fumarate ester particles may be measured as a dry sample or fumarate ester have a particle size distribution with a d90 of a wet sample . Any commercially available instrument for s about 170 um (d90s170 um ) . In one aspect, the solid measuring particle sizes may be used , including instruments particles of fumarate ester have a particle size distribution from Cilas ; Brookhaven Instruments Corporation ; Malvern with a d90 of s about 140 um ( d90s140 um ) . In one aspect , Instruments ; Horiba Scientific ; or Wyatt following the rec the solid particles of fumarate ester have a particle size 50 ommended operating procedures according to the manufac distribution with a d90 of s about 100 um ( d90s100 um ). In turer ' s instructions . one aspect , the solid particles of fumarate ester have a The measured particle sizes using the techniques particle size distribution with a d90 of s about 90 um described herein may be expressed as a derived diameter (d90s90 um ). In one aspect, the solid particles of fumarate with a normal distribution or non - normal distribution with a ester have a particle size distribution with a d90 of s about 55 mean , median ( e . g ., mass median diameter ) , and mode of 80 um (d90s80 um ). In one aspect , the solid particles of particle diameter sizes. The particle size distribution may be fumarate ester have a particle size distribution with a d90 of expressed as a diameter number distribution , a surface area s about 25 um (d90s25 um ) . distribution , or a particle volume distribution . The mean of In another embodiment, the solid fumarate ester particles the particle size distribution may be calculated and have a mean particle size distribution comprising a range of 60 expressed in various ways , such as the volume mean diam particle sizes with a d10 of s10 um and a d90 of s500 um . eter ( D [ 4 , 3 ] or d22 ) , mean surface area diameter ( D [ 3 , 2 ] or In one aspect , the solid particles of fumarate ester have a dzz) or the mean number particle diameter ( D [ 1 , 0 ] or dio ) . particle size distribution with a d10 of sto about 10 um and Because the particle size distribution values vary depending a d90 of s to about 400 um , a d10 of s to about 10 um and on the measurement methodology and how the distribution a d90 of s to about 300 um , a d10 of s to about 10 um and 65 is expressed , the comparison of different mean particle size a d90 of s to about 250 um , a d10 of s to about 10 um and distributions must be calculated by the samemethodology in a d90 of s to about 200 um , a d10 of s to about 10 um and order to yield an accurate comparison . For example , a US 9 ,814 ,692 B2 42 sample with a measured and calculated volume mean diam ceutically acceptable excipients. In another aspect, the eter must be compared with a second sample having a matrix comprises oils , polyvinylpyrrolidones, and surfac measured and calculated volume mean diameter , ideally tants . In one aspect, the surfactant comprises polysorbate 80 measured using the same measuring instrument under the or polyoxyl 40 hydrogenated castor oil . In another aspect, same conditions . Thus, the specific particle size distributions 5 the matrix comprises, a mixture of mono - and diglycerides, described herein are not intended to be limited to any one polyvinylpyrrolidone , polyoxyl 40 hydrogenated castor oil , type of method for measuring or calculating a particle size and solid particles of one or more fumarate esters. In another distribution ( e . g . , a diameter number distribution , a surface area distribution , or a particle volume distribution ), but aspect, the matrix comprises one or more oils, and solid rather indicate particle size values and distributions thereof 10 particles of one or more fumarate esters . In another aspect, for each method of measuring particle sizes described the solid particles of one or more fumarate esters are soluble herein . in the matrix fill . Another embodiment described herein is a method for In one embodiment , the matrix comprises the composition manufacturing a fill for a controlled release pharmaceutical shown in Table 1 including all possible iterations of the composition comprising particles of fumarate esters such as 15 specified ranges that provide 100 % total weight percentage . dimethyl fumarate, monomethyl fumarate , or combinations thereof of defined sizes. In one aspect , the particles are of a TABLE 1 similar size distribution . In another aspect, the fumarate Exemplary Matrix Fill Composition ester particles comprise varied size distributions . In another aspect, the fumarate ester particles comprise several size 20 Ingredient mg/ capsule % weight distributions . In another aspect, the fumarate ester particles Fumarate Ester ( PSD : d90 s 100 um ) 200 - 215 32 - 35 comprise a mixture of smaller and larger size distributions . Lipid or lipophilic vehicle 370 - 425 60 - 70 Without being bound to any theory , smaller particles are Excipients 0 -50 0 - 8 generally solubilized and released more rapidly than larger 625 mg 100 % particles . The release rate can be adjusted to achieve a 25 TOTAL specific therapeutic window over a defined period and produce controlled release, delayed release , or extended In one embodiment, the matrix comprises about 29 % by release compositions by combining multiple fumarate ester weight of fumarate ester (PSD : d90s100 um ); about 50 % by particle sizes or size distributions . weight of a mixture of mono - and diglycerides; at least Another embodiment described herein is a method for 30 about 1- 15 % by weight of polyvinylpyrrolidone ; at least manufacturing a pharmaceutical composition comprising about 2 - 10 % by weight of polyoxyl 40 hydrogenated castor fumarate ester ( s ) where the fumarate ester does not sublime oil, and at least about 0 - 5 % by weight of lactic acid , during processing, manufacturing , after production , or dur including all iterations of the specified ranges . In one aspect, ing storage . Soft capsules comprising fumarate ester in the the composition prevents sublimation of the FAE during matrix fills described herein are stable for months or years . 35 processing and manufacturing . In one aspect, the composi Without being bound to any theory , it is believed that tion reduces the onset of symptoms of gastrointestinal side suspending solid fumarate ester in a lipid or lipophilic effects . In another aspect , the composition is stable for at vehicle prevents or retards sublimation and stabilizes the least 6 months at 25° C . and 60 % relative humidity . In one fumarate ester. In one aspect, the pharmaceutical composi- aspect , the composition is stable for at least 24 months . tions described herein are stable at 25° C . and 60 % relative 40 In one embodiment, the composition comprises one of humidity (RH ) for about 1 month , about 2 months , about 3 those shown in Table 2 including all possible iterations of months, about 4 months, about 5 months, about 6 months , the specified ranges that provide 100 % total weight percent about 9 months , about 10 months , about 11 months, about 12 age . months, about 18 months , about 24 months, or even longer . In another aspect, the pharmaceutical compositions 45 TABLE 2 described herein are stable for at least 1 year , or longer at 25° C . and 60 % RH . In another aspect , the pharmaceutical Exemplary Matrix Fill Compositions compositions described herein are stable for at least 2 years , Ingredient mg/ capsule % weight or longer at 25° C . and 60 % RH . Fumarate ester PSD : d90 s 100 um 200 - 215 32 - 35 Another embodiment described herein is a method for 50 Mono - and diglycerides 125 - 315 20 - 50 preparing a pharmaceutical matrix comprising a fumarate Polyvinyl pyrrolidone 5 - 32 0 .75 - 5 ester . An exemplary scheme of a manufacturing process is Polyoxyl 40 Hydrogenated castor oil 12 .5 - 75 2 - 12 shown in FIG . 1 . The methodmethod comprisescomprises applying heat toto the LacticLactic acid 0 - 32 0 - 5 matrix components during mixing or prior to mixing at TOTAL 625 100 % about the melting point of the matrix fill composition ; and 55 Fumarate ester PSD : d90 s 100 um 200 - 215 32 - 35 then mixing the fumarate ester with the lipid or lipophilic Soybean oil 410 - 425 65 - 70 matrix ingredients using mechanical or ultrasonic forces to form the matrix fill. The matrix fill is flowable such that it TOTAL 625 100 % can be encapsulated using a rotary die encapsulation machine . In one embodiment, the matrix components are 60 In another embodiment , the matrix fill comprises about heated to a temperature in the range of from about 25° C . to 32 % to 35 % of fumarate ester (PSD : d90s100 um ) ; about about 70° C . In another embodiment, the matrix components 20 % to about 50 % of a mixture of mono - and diglycerides ; are heated to a temperature in the range of from about 25° at least about 0 .75 - 5 % polyvinylpyrrolidone ; at least about C . to about 30° C . 2 - 12 % polyoxyl 40 hydrogenated castor oil ; and at least In one embodiment, the matrix comprises a lipid or 65 about 0 - 5 % lactic acid , including each integer within each of lipophilic vehicle , solid particles of one or more fumarate the specified ranges . In one embodiment , the lactic acid is esters, an optional neutralizing agent, and optional pharma optional . In another embodiment , the matrix fill comprises US 9 ,814 ,692 B2 43 44 about 32 % to 35 % of fumarate ester ( PSD : d90s100 um ) and the weight (in grams) needed by a 0 . 5 - inch diameter probe about 65 % to about 70 % of soybean oil, including each to deflect the surface of a gel 4 mm without breaking it . The integer within each of the specified ranges. In another result is expressed as “ Bloom ” or “ Bloom strength .” The embodiment, the lactic acid is optionally added to the soft capsules described herein utilize gelatins with Bloom soybean oil matrix . In one aspect, the composition prevents 5 strengths in the range of about 20 Bloom to about 400 sublimation of the FAE during processing and manufactur Bloom , including each integer within the specified range. In ing . In another aspect, the composition reduces the onset of one embodiment, Bloom strengths for soft capsules symptoms of any gastrointestinal side effects . In another described herein are about 50 Bloom to about 250 Bloom aspect , the composition is stable for at least 6 months at 25° including each integer within the specified range . In some C . and 60 % relative humidity . In another aspect, the com - 10 embodiments , the gelatin Bloom strength is about 50 Bloom , position is stable for at least 24 months at 25° C . and 60 % about 80 Bloom , about 100 Bloom , about 120 Bloom , about relative humidity . In another aspect, the composition is 150 Bloom , about 180 Bloom , about 200 Bloom , or about liquid at room temperature. 250 Bloom . In one embodiment, the gelatin Bloom strength In one embodiment, the fumarate ester pharmaceutical is 100 Bloom . In another embodiment, the gelatin Bloom composition comprises a capsule dosage form . In one 15 strength is 150 Bloom . In another embodiment , the gelatin embodiment, the fumarate ester pharmaceutical composition Bloom strength is 195 Bloom . In another embodiment, the comprises a soft capsule encapsulating a matrix fill com - gelatin Bloom strength is 200 Bloom . prising a liquid lipid or lipophilic fill comprising one ormore Plasticizers that are useful for creating soft capsules as fumarate esters . described herein are glycerol, sorbitol, partially dehydrated In one embodiment described herein , the soft capsule 20 sorbitol ( a blend of D - sorbitol, 1 , 4 - sorbitan , mannitol, and shell has the composition of Table 3 , including all possible water ; e . g ., Sorbitol Special® (SPI Pharma) ; Anidrisorb® or iterations of the specified ranges that provide 100 % for the Polysorb® , (Roquette ) ) , maltitol (hydrogenated corn syrup ; total weight percentage , including or excluding optional e . g ., Lycasin® , Roquette ) , corn syrup , xylitol, mannitol, colorings , opacifiers , flavorings, or other excipients . propylene glycol , low molecular weight polyethylene gly 25 cols, poly - alcohols with 3 to 6 carbon atoms, or a combi TABLE 3 nation thereof. Plasticizers typically comprise about 10 - 30 % of the totalwet mass of a shell, including each integer within Exemplary Soft Gelatin Capsule Composition the specified range . The weight ratio between the film Weight forming polymer , plasticizer, and solvent is adjusted so that Component Exemplary Component Percentage ( % ) the gel mass is flowable and not too viscous, and can be made into soft capsules using rotary die encapsulation Film - forming polymer Gelatin , 150 - 200 Bloom 20 - 48 Plasticizer Glycerol, sorbitol 10 - 30 methods . Solvent Water 20 - 70 In one embodiment described herein , the soft capsule Opacifier ( optional ) Titanium dioxide 0 - 1 . 5 35 Shellshell hashas the exemplary composition shown in Table 4 . Coloring agent ( optional) Various 0 - 0 . 1 Excipients (optional ) Various 0 - 5 TABLE 4 TOTAL 100 % Exemplary Soft Capsule Shell Composition Film - former polymers that are useful for creating soft 40 Component Percent weight ( % ) capsules are gelatin , hydroxypropylmethylcellulose Film forming polymer ( e . g ., gelatin ) 20 - 50 (HPMC ) or carrageenan ( e . g . , iota carrageenan and kappa Plasticizer ( e. g ., glycerol, sorbitol , 15 - 30 carrageenan ) . In one embodiment described herein , the combinations thereof) film - forming polymer is gelatin . Solvent ( e . g ., water ) q. s. (e . g. , 20 -40 % ) Examples of gelatin compositionsompositions that areare useruluseful lorfor 45 TOTAL 100 % creating soft capsule shells as described herein comprise Final pH ~ 4 - 7 acid bone gelatin , pig skin gelatin , chicken skin gelatin , fish Ratio total plasticizer to gelatin 20 :43 ( 0 .46 : 1 ) gelatin , acid hide gelatin , gelatin hydrolysate , lime bone Water content in dried soft capsule shell : 8 - 15 % gelatin , or combinations thereof. Gelatins that are useful for creating soft capsules described herein can be classified as 50 In one embodiment, the weight percentage range of either Type A or Type B gelatin . Type A gelatin is derived film - forming polymer of the soft capsule described herein is from the acid hydrolysis of collagen ( e . g . , acid bone gelatin about 20 % to about 50 % , including all integers within the or pig skin gelatin ), while Type B gelatin ( e . g . , lime bone specified range . In one aspect, the film - forming polymer gelatin ) is derived from the alkaline hydrolysis of collagen . weight percentage is about 38 % . In another aspect, the Traditionally , bovine bones and skins are used as raw 55 film - forming 1 polymer weight percentage is about 42 % . In materials for manufacturing Type A and Type B gelatin , another aspect, the film - forming polymer weight percentage while porcine skins are used extensively for manufacturing is about 44 % . Type A gelatin . In addition , at neutral pH values , Type A In one embodiment, the weight percentage range of gelatins ( acid processed gelatins ) are typically net cationic plasticizer is about 15 % to about 30 % , including all itera ( e . g . , isoelectric point of about 7 - 9 ) and Type B gelatins 60 tions of integers with the specified range . In one aspect, the (alkali processed gelatins ) are typically net anionic ( e . g ., plasticizer weight percentage is about 24 % . In another isoelectric point of about 4 . 5 - 5 . 3 ) . Type A gelatin typically aspect, the plasticizer weight percentage is about 22 % . In has higher plasticity and elasticity than type B gelatin ; type another aspect, the plasticizer weight percentage is about B gelatin typically has higher gel strength than type A 20 % . gelatin . 65 In one embodiment, the solvent comprises about 20 % to The strength of gelatin compositions is typically defined about 40 % of the soft capsule composition , including all by their Bloom strength or grade . The Bloom test determines integers and fractions within the specified range . In one US 9 , 814 ,692 B2 45 46 embodiment, the solvent is water . The quantity of water in 730 ; and 6 , 482, 516 , each of which are incorporated by the composition varies depending on the quantities of the reference herein for such teachings . other ingredients . For example , the quantity of plasticizer, Another embodiment described herein includes a process opacifier, colorant, flavoring , or other excipients can change of manufacturing soft capsules comprising any of the phar the percentage of water present in the composition . In one 5 maceutical composition as described herein . The process embodiment, the weight percentage of water is as much as includes preparing a gel mass composition comprising a suffices to bring the total weight percentage to 100 % (i . e ., film - forming , water - soluble polymer, an appropriate plasti quantum sufficiat ; q . s . ) . In another embodiment , the water cizer, and solvent; casting the gel mass into filmsor ribbons comprises about 20 % , about 25 % , about 30 % , about 35 % , or using heat- controlled drums or surfaces; and manufacturing about 40 % of the enteric soft capsule composition . In 10 a soft capsule comprising a matrix fill using rotary die another embodiment, water comprises about 30 % to about 40 % of the enteric soft capsule composition . In one embodi technology. The thickness of the films or ribbons that form ment, water comprises about 34 % of the composition . the soft capsule shell is from about 0 .010 inches ( ~ 0 . 254 In one embodiment, the final moisture (water ) content of mm ) to about 0 . 050 inches ( ~ 1 . 27 mm ), including all the soft capsule after manufacturing and drying is from 15 integers within the specified range . The shell thickness can about 8 % to about 15 % , including all integers and fractions be about 0 .010 inch ( - 0 . 254 mm ), about 0 .015 inch (~ 0 .381 within the specified range . In another embodiment, the mm ) , about 0 .02 in ( - 0 . 508 mm ) , about 0 .03 in ( ~ 0 . 762 moisture content is about 8 % to about 12 % , including all mm ) , about 0 . 04 in ( 1 . 02 mm ), or about 0 . 05 in ( ~ 1 .27 integers and fractions within the specified range . In one mm ). In one embodiment, the thickness is about 0 .02 inches aspect , the final moisture contentontent is about 12100 %% . Inin one 20 ( - 0 .508 mm ) to about 0 . 040 inches ( ~ 1 .02 mm ) . In one aspect, the final moisture content is about 11 % . In one embodiment, the shell thickness is about 0 .028 inches aspect, the final moisture content is about 10 % . In one ( 20 .711 mm ) . In another embodiment, the shell thickness is aspect , the final moisture content is about 9 % . In another about 0 .033 inches ( ~ 0 .838 mm ) . In another embodiment , aspect, the final moisture content is about 8 % . the shell thickness is about 0 .038 inches ( ~ 0 . 965 mm ) . In In one embodiment, the weight percentage ratio range of 25 another embodiment, the shell thickness is about 0 . 035 plasticizer to film - forming polymer is about 0 .33 : 1 to about inches ( ~ 0 .889 mm ). In another embodiment, the shell 0 56 : 1 including all iterations of iterations of ratios with the thickness is about 0 .038 inches ( ~ 0 . 965 mm ) . In another specified range . In one embodiment, the weight percentage embodiment, the shell thickness is about 0 .040 inches (~ 1. 02 ratio range of plasticizer to film - forming polymer is about mm ) . 0 .38 : 1 . In one embodiment, the weight percentage ratio 30 In one embodiment described herein , the soft capsule range of plasticizer to film - forming polymer is about 0 .42 : 1 . shell described herein , encapsulates a matrix fill as described In one embodiment, the weight percentage ratio range of herein . In another embodiment described herein , the soft plasticizer to film - forming polymer is about 0 . 46 : 1. In one capsule shell and encapsulated matrix fill comprises an outer embodiment, the weight percentage ratio range of plasticizer dimension from about 2 oval to about 30 oval including all to film - forming polymer is about 0 .52 : 1 . 35 iterations of capsule size within the specified range ( e . g . , 2 In one embodiment described herein , the soft capsule oval, 3 oval, 4 oval, 5 oval, 6 oval, 7 oval, 8 oval , 10 oval, comprises about 42 % of at least one film - forming polymer ; 12 oval, 16 oval, 20 , or 30 oval) . In another embodiment about 24 % of at least one plasticizer; and about 34 % water . described herein , the soft capsule shell and encapsulated In another embodiment, the soft capsule shell has the matrix fill comprises an outer dimension from about 2 round exemplary composition shown in Table 5 . 40 to about 28 round including all iterations of capsule size within the specified range ( e . g ., 2 round , 3 round , 4 round , TABLE 5 5 round , 6 round , 7 round , 8 round , 10 round , 12 round , 16 round, 20 round or 28 round ) . In another embodiment Exemplary Soft Capsule Shell Composition described herein , the soft capsule shell and encapsulated 45 matrix fill comprises an outer dimension from about 2 Component PerceiPercent weight ( % ) oblong to about 22 oblong including all iterations of capsule Gelatin , 150 Bloom , Lime Bone 42 size within the specified range ( e . g ., 2 oblong , 3 oblong , 4 Sorbitol (e . g . , Polysorb® 85 /70 /00 ; Roquette ) 24 oblong , 5 oblong , 6 oblong, 7 oblong , 8 oblong , 10 oblong , Water 34 11 , oblong, 12 oblong, 14 oblong, 16 oblong, 20 oblong , or TOTAL 100 % 50 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 Publish In another embodiment, the soft gel capsule shell has the ing Company, London , UK , 1st Edition , 2013 , which is exemplary composition shown in Table 6 . incorporated by reference herein for such teachings . 55 In another embodiment, the fumarate ester pharmaceuti TABLE 6 cal composition can comprise an enteric soft capsule shell Exemplary Soft Gel Capsule Shell Composition comprising a matrix comprising a fumarate ester. Enteric soft capsules , e . g . , soft capsules having enteric polymers Component Percent weight ( % ) integrated into the capsule shell, are described in Interna Gelatin , 195 Bloom , Lime Bone 42 60 tional Patent Application Publication No. WO 2004 / 030658 ; Sorbitol ( e . g . , Polysorb ® 85 / 70 /00 ; Roquette ) 24 U . S . Patent Application Publication No. US 2006 / 0165778 ; Water 34 and U . S . Pat. No. 8 ,685 , 445 , each of which is incorporated by reference herein for such teachings. The enteric soft TOTAL 100 % capsule shell may comprise one or more film forming 65 polymers , one or more enteric acid - insoluble polymers , one In one aspect, soft capsules are made using a rotary die or more plasticizers , one or more alkali -neutralizing agents , apparatus as described in U . S . Pat . Nos . 5 ,459 ,983 ; 5 ,146 , one or more solvents , optionally one or more colorants , and US 9 ,814 ,692 B2 47 48 optionally one or more flavorings or other conventionally ethylene diamine. The amount of alkali is adjusted to give a accepted pharmaceutical excipients or additives. final pH value of the gelmass less than or equal to about pH Film - forming polymers that are useful for creating enteric 9 . 0 . In one embodiment, the final pH does not exceed 8 . 5 . soft capsules are gelatin or hydroxypropylmethylcellulose The volatile alkali -neutralizing agent, ammonia is preferred . ( HPMC ) . In one aspect of the enteric soft capsule shell 5 The film - forming polymer can then be combined with the described herein , the film - forming polymer is gelatin . plasticizer and solvent and then blended with the acid Examples of enteric , acid - insoluble polymers are acrylic insoluble gel to make a final homogeneous mix in a heat and methacrylate acid copolymers , cellulose acetate phtha late (CAP ) , cellulose acetate butyrate , hydroxypropylmeth controlled vessel with degassing by vacuum . The fugitive ylcellulose phthalate (HPMCP ), algenic acid salts such as 10 ammonia evaporates during degassing . Using the foregoing sodium or potassium alginate , or shellac . Poly (methacylic process , the alkali concentrations do not require heating or acid - co -methyl methacrylate ) anionic copolymers based on neutralizing with acid in order to neutralize the gel mass . methacrylic acid and methyl methacrylate are particularly In another embodiment described herein , the enteric soft stable and are preferred in some embodiments . Poly (meth ) capsule shell is made using an aqueous dispersion of the acrylates (methacrylic acid copolymer ), available under the 15 acid - insoluble polymer by adding an alkali -neutralizing trade name EUDRAGIT® (Evonik Industries AG , Essen , agent such as ammonium , sodium , or potassium hydroxides , Germany ) , are provided as powder or aqueous dispersions. other alkalis , or a combination thereof that will cause the In another aspect, the methacrylic acid copolymer comprises enteric acid -insoluble polymer to dissolve. The plasticizer EUDRAGIT® L 30 D - 55 ; EUDRAGIT® L 100 - 55 ; wetted , film -forming polymer can then be mixed with the EUDRAGIT® L 100 ; EUDRAGIT® L 12 .5 ; EUDRAGIT® 20 solution of the acid -insoluble polymer . In one embodiment, S 100 : EUDRAGIT® S 12 . 5 ; EUDRAGIT® FS 30 D ; enteric acid - insoluble polymers in the form of salts of the EUDRAGIT® E 100 ; EUDRAGIT® E 12 . 5 ; EUDRAGIT® bases or alkalis as described herein are dissolved directly in E PO ; EUDRAGIT® RL 100 ; EUDRAGIT® RL PO ; water and mixed with the plasticizer- wetted , film - forming EUDRAGIT® RL 3030 D ; EUDRAGIT®EUDRAGIT® RL 12 .. 50 ; polymer. EUDRAGIT® RS 100 ; EUDRAGIT® RS PO ; 25 In one embodiment described herein , enteric acid - in EUDRAGIT® RS 30 D ; EUDRAGIT® RS 12 . 5 ; soluble polymers in the form of salts of the bases or alkalis EUDRAGIT® NE 30 D ; EUDRAGIT® NE 40 D ; described herein are dissolved directly in water and mixed EUDRAGIT® NM 30 D ; other poly (methacrylate poly - with the plasticizer -wetted , film - forming polymer. In mers ; or a mixture thereof. In one aspect, the enteric polymer is EUDRAGIT® L 100 , a methacrylic acid copolymer, Type 30 another embodiment described herein , an aqueous disper A . Acid - insoluble polymer specifications are detailed in the sion of the acid - insoluble polymer or polymers is used , United States Pharmacopoeia and in various monographs . which obviates the need for the addition of the alkali In another embodiment described herein , the enteric poly neutralizing agent described herein . mer in the enteric soft capsule shell comprises poly (meth In one embodiment, the enteric soft capsule shell has the acylic acid - co - ethyl acrylate ) 1 : 1 leg . EUDRAGIT® L 35 composition of Table 7 , including all possible iterations of the specified ranges that provide 100 % for the total weight polymer100 - 55 ) . comprisesIn one embodiment poly (ethyl acrylatedescribed - co herein-methyl , the methacry enteric - percentage , including or excluding the optional, excipients , late ) 2 : 1 ( e . g . , EUDRAGIT® NE 40 D ) . In another embodi - opacifiers , colorants , and flavorings . ment described herein , the enteric polymer comprises poly (methyl acrylate -co -methyl methacrylate -co -methacrylic 40 TABLE 7 acid ) 7 : 3 : 1 ( e . g . , EUDRAGIT® FS 30 D ) . In another embodiment described herein , the enteric polymer com Enteric Soft Capsule Shell Composition prises a combination of poly (methacylic acid - co - ethyl acry Composition late ) 1 : 1 and poly (methyl acrylate - co -methyl methacrylate Component Exemplary Component Range ( % ) co -methacrylic acid ) 7 :3 :1 . In another embodiment, the 45 FilmFilm - form lymer Gelatin 20 - 36 enteric polymer comprises a combination of poly (meth Enteric , acid -insoluble Methacrylic Acid Copolymer 8 - 20 acylic acid - co - ethyl acrylate ) 1 : 1 and poly (ethyl acrylate polymer Plasticizer Glycerol, sorbitol, 15 - 22 co -methyl methacrylate ) 2 : 1. In another embodiment, the Triethyl citrate enteric polymer comprises a combination of poly (meth Alkali- neutralizing agents NH ,OH ( 30 % ), NaOH 1 - 5 acylic acid -co - ethyl acrylate ) 1 : 1, poly ( ethyl acrylate - co - 50 Solvent Water 20 - 40 methyl methacrylate ) 2 : 1, and poly (methyl acrylate- co Opacifier (optional ) Titanium Dioxide 0 - 7 .5 methyl methacrylate - co -methacrylic acid ) 7 : 3 : 1 . Colorant (optional ) Various 0 - 1 Flavoring (optional ) Various 0 - 2 In another embodiment, plasticizers that are useful for Excipients (optional ) Various 0 - 5 creating enteric soft capsules as described herein are glyc erol, sorbitol, Sorbitol Special® , maltitol , corn syrup , pro - 55 pylene glycol, poly - alcohols with 3 to 6 carbon atoms , In one embodiment, the enteric soft capsule shell com polyethylene glycol, citric acid , citric acid esters, such as prises a composition of about 30 % film forming polymer, triethyl citrate , or combinations thereof. The weight ratio about 10 % enteric , acid - insoluble polymer , about 20 % plas between the film -forming polymer , the enteric acid - in - ticizer; about 1 % alkali- neutralizing agent; and about 37 % soluble polymer, and plasticizer is adjusted so that the gel 60 solvent. mass is flowable and not too viscous, and can be made into In another embodiment , the weight percentage range of soft capsules using rotary die encapsulation methods. total polymer content (i . e . , film forming polymer and enteric In one embodiment, enteric soft capsule shell composi - acid - insoluble polymer) of the enteric soft capsule described tions are made by dissolving the enteric acid -insoluble herein is about 30 % to about 45 % , including all integers and polymer in an aqueous solution of an alkali -neutralizing 65 fractions within the specified range. In one aspect, the total agent such as ammonia , sodium hydroxide , potassium polymer weight percentage is about 40 % . In another aspect , hydroxide, or liquid amines such as tri -ethanol amine or the total polymer weight percentage is about 42 % . In another US 9 ,814 ,692 B2 49 50 aspect , the total polymer weight percentage is about 45 % . In ( 0 . 5 ) . In another aspect , the weight ratio range of total another aspect , the total polymer weight percentage is about plasticizer to total polymer is about 19 . 3 : 40 . 4 ( - 0 .477 ) . 38 % . In one embodiment, the solvent comprises about 20 % to In one embodiment, the weight percentage range of total about 40 % of the enteric soft capsule composition , including plasticizer is about 15 % to about 22 % , including all integers 5 all integers and fractions within the specified range . In one and fractions within the specified range. In one aspect , the total plasticizer weight percentage is about 19 % . In another embodiment, the solvent is water . The quantity of water in aspect, the total plasticizer weight percentage is about the composition varies depending on the quantities of the 17 . 7 % . In another aspect, the total plasticizer weight per other ingredients . For example , the quantity of opacifier , centage is about 18 . 9 % . In another aspect , the total plasti - 10 colorant , flavoring, or other excipients can change the per cizer weight percentage is about 19. 3 % . centage of water present in the composition . In one embodi In one embodiment , the alkali - neutralizing agent is ment, the weight percentage of water is as much as suffices ammonia (ammonium hydroxide; 30 % w / v ) that is added to to bring the total weight percentage to 100 % ( i. e ., quantum comprise a weight percentage of about 1 % to about 5 % of sufficiat ; q . s .) . In another embodiment, the water comprises the total enteric soft capsule composition . In one aspect, 155 abouta 20 % , about 25 % , about 30 % , about 35 % , or about 30 % w / v ammonia is added to comprise a weight percentage 40 % of the enteric soft capsule composition . In another of about 2 % . In another aspect , 30 % w / v ammonia is added embodiment, water comprises about 33 % to about 40 % OI to comprise a weight percentage of about 1 . 7 % . In one the enteric soft capsule composition . In one embodiment , aspect, ammonia is added to provide a final pH of about 9 water comprises about 37 % of the composition . in the enteric soft capsule composition . In another aspect, 20 In one embodiment, the final moisture (water ) content of ammonia is added to provide a final pH of about 8 . 5 in the the enteric soft capsule is from about 8 % to about 15 % , enteric soft capsule composition . In another aspect, after the including all integers and fractions within the specified capsules are filled and dried , the ammonia concentration is range . In another embodiment, the moisture content is about substantially reduced , owing to the fugitive nature of the 8 % to about 12 % , including all integers and fractions within volatile alkali -neutralizing agent. In another aspect , practi - 25 the specified range . In one aspect, the finalmoisture content cally all of the ammonia is evaporated except for ammonium is about 8 % . In one aspect, the final moisture content is ions comprising salts with other moieties in the composition . about 9 % . In one aspect, the final moisture content is about In one embodiment, the weight ratio range of film forming 10 % . In one aspect , the final moisture content is about 11 % . polymer to enteric acid - insoluble polymer ( i . e ., film form - In another aspect, the final moisture content is about 12 % . ing : enteric ) is about 25 : 75 ( - 0 .33 ) to about 40 :60 ( - 0 .67 ) 30 In one embodiment, the enteric soft capsule shell has the (i . e ., 20 .33 - 0 .67 ) , including all ratios within the specified exemplary composition shown in Table 8 . range . In one aspect , the ratio of film forming polymer to enteric acid - insoluble polymer is about 30 : 70 ( - 0 . 43 ) . In TABLE 8 another aspect , the ratio of film forming polymer to enteric acid - insoluble polymer is about 28 : 72 ( ~ 0 . 38 ) . 35 - Exemplary Enteric Soft Capsule Shell Composition In one embodiment, the weight ratio of total plasticizer to Component Percent weight ( % ) film forming polymer is about 20 : 40 to 21 : 30 ( i . e . , 0 . 5 - 0 . 7 ) , including all ratios within the specified range. In one aspect, Gelatin 29 . 2 the weight ratio of total plasticizer to film forming polymer MethacrylicL 100 ) Acid Copolymer ( EUDRAGIT ® 11. 2 is about 20 : 40 ( - 0 . 5 ) . In another aspect, the weight ratio of 40 Glycerol or Sorbitol 18 . 0 total plasticizer to film forming polymer is about 21: 30 Triethyl citrate 1 . 3 Ammonium hydroxide 1 . 7 ( - 0 . 7 ) . In another aspect, the weight ratio of total plasticizer Titanium dioxide 1 . 5 to film forming polymer is about 19 : 29 ( - 0 .65 ) . In another Water 37 . 1 aspect, the weight ratio of total plasticizer to film forming TOTAL 100 % polymer is about 19. 3 :29 . 2 ( ~ 0 .66 ) . Final pH 8 . 5 - 9 . 0 In one embodiment, the weight ratio of total plasticizer to Total polymer % weight (gelatin + enteric ) 40 . 4 % enteric acid - insoluble polymer is about 1 : 1 to about 2 : 1 Gelatin % wt of total polymer ( gelatin + enteric ) 72 . 4 % ( ~ 1 - 2 ), including all ratios within the specified range . In one Enteric % wt of total polymer ( gelatin + enteric ) 27 . 6 % aspect , the weight ratio of total plasticizer to enteric acid Ratio of Enteric to Gelatin 11. 2 :29 . 2 ( 0 . 38 ) Total plasticizer % weight ( glycerol + triethyl 19 . 3 % insoluble polymer is about 11 : 10 (~ 1. 1 ). In another aspect , 50 citrate ) the weight ratio of total plasticizer to enteric acid - insoluble Ratio of total plasticizer to total polymer 19 . 3 : 40 . 4 ( 0 .48 ) polymer is about 14 : 10 ( ~ 1 . 4 ). In another aspect, the weight Ratio total plasticizer to gelatin 19. 3 : 29 . 2 (0 .66 ) ratio of total plasticizer to enteric acid - insoluble polymer is Ratio total plasticizer to enteric 19 . 3 : 11. 2 ( 1 .73 ) about 17 :10 ( ~ 1. 7) . In another aspect, the weight ratio of Water content in dried enteric soft capsule : 8 - 15 % total plasticizer to enteric acid - insoluble polymer is about 55 20 : 10 ( ~ 2 ) . In another aspect, the weight ratio of total In one embodiment, the enteric soft capsule shell com plasticizer to enteric acid - insoluble polymer is about 19 . 3 : prises about 30 % gelatin ; about 10 % poly (methyl ) acrylate 11 . 2 ( - 1. 73 ) . copolymer ; about 18 % glycerol; about 1 % triethyl citrate ; In one embodiment, the weight ratio range of total plas - about 1 . 5 % ammonia ; about 37 % water; and about 1 . 5 % ticizer to total polymer ( film forming and enteric acid - 60 titanium dioxide. insoluble polymer ) is about 18 :45 to about 20 :40 (i . e . In another embodiment, the enteric soft capsule is ~ 0 . 40 - 0 . 5 ) , including all ratios within the specified range . In described in U . S . patent application Ser. No . 14 / 744 , 057 , one aspect, the weight ratio range of total plasticizer to total which is incorporated by reference herein for such teachings . polymer is about 18 : 45 ( - 0 . 40 ) . In another aspect , the One embodiment described herein provides an enteric weight ratio range of total plasticizer to total polymer is 65 acid - insoluble polymer dispersed within the film - forming about 19 :40 ( - 0 .475 ) . In another aspect, the weight ratio polymer gelmass that provides the total soft gel composition range of total plasticizer to total polymer is about 20 :40 with enteric acid -insoluble properties , at relatively low con US 9 ,814 ,692 B2 51 52 centrations of the enteric acid - insoluble polymer ( e . g . , from TABLE 9 about 8 % to about 20 % of the total wet gel mass composi tion ) and without the need of excessive amounts of alkali , Exemplary Enteric Coating Composition thus avoiding denaturation or degradation of the film - form Weight ing polymer that can weaken the integrity of the enteric soft 5 Component Exemplary Component Percentage ( % ) capsule shell. Enteric Polymer( s ) Methacrylic acid copolymers , 5 - 90 Films of the enteric soft capsule shell do not dissolve or polyvinyl acetate phthalates, disintegrate in acids, such as 0 . 1 N hydrochloric acid or polyvinyl phthalate , cellulose simulated gastric fluid ( ca . pH 1 . 2 ) , despite the fact that the acetate phthalates , cellulose majority of the shell ingredients ( i . e ., greater than 50 % ) 10 acetate trimellitate , cellulose acetate succinate , hydroxypropyl normally dissolve in , or are miscible with , acids. Enteric soft methylcellulose , carboxymethyl capsules made using the compositions described herein cellulose remain intact in hydrochloric acid or simulated gastric fluid Plasticizer (s ) Triethyl citrate , tributyl citrate , 0 - 25 for at least two hours . The capsules readily release the polyethylene glycols , propylene glycol , triacetin , dibutyl contents upon shifting the pH of the solution to ca . 6 . 8 , such 15 phthalate , tripropionin , ethyl acid as that of simulated intestinal fluid . phtalate , butyl acid phthalate , In another embodiment, the final enteric capsule compo ethyl acid adipate , fats and sition provides films of increased strength without substan waxes mixed with esters , tially compromising film elasticity. Moreover, films made glycerin Neutralizing agent Ammonia , NaOH , sodium 0 - 5 from the enteric soft capsule compositions as described 20 bicarbonate herein are sealed at normal temperature range typically used Solubilizers Sodium lauryl sulfate , sodium lauroyl sarcosinate sodium for making traditional soft gel capsules . In one aspect , dodecyl sulfate , polysorbate 20 , enteric soft capsules are made using a rotary die apparatus polysorbate 80 , other detergents as described herein . and surfactants Another embodiment described herein includes a process 25 Solvent( s ) Water , ethanol, isopropanol, 50 - 80 of manufacturing enteric soft capsules comprising the phar acetone Excipients Emulsifiers, pore - forming 0 - 20 maceutical composition as described herein . The process agents , anti - adherents , includes preparing a gel mass composition comprising a surfactants , pigments , colorants , film - forming , water - soluble polymer and an enteric acid antifoam , antioxidants , waxes, insoluble polymer and mixing with appropriate plasticizers 30 magnesium stearate , micronized and solvent ; casting the gel mass into films or ribbons using amorphous silica , kaolin , talc, heat - controlled drums or surfaces, and manufacturing a soft capsule comprising a matrix fill using rotary die technology . Enteric polymers useful for enteric coatings include pH The thickness of the films that form the enteric capsule and dependent polymers that are less soluble in an aqueous the dimensions of the capsules are similar to those described 35 media with acidic pH and more soluble in an aqueousmedia herein . In one embodiment described herein , enteric soft capsules with basic pH . In one embodiment, the enteric of pH are " traditional” soft capsules coated with an enteric coating . dependent material dissolves or rapidly disperses at a pH In another embodiment described herein , enteric soft cap level above pH 5. 0 , above pH 5 . 5 , or above pH 6 .0 . sules are soft capsules having enteric polymers embedded 40 Exemplary enteric polymers useful for coats include within the capsule shell ( e . g ., an enteric soft capsule ) and are cellulose acetate phthalate , hydroxypropylmethyl cellulose coated with an enteric coating . Without being bound to any phthalate , hydroxypropyl methylcellulose acetate succinate , theory , it is believed that enteric coatings, in addition to polyvinyl acetate phthalate , cellulose acetate trimellitate , providing acid - resistance or pH -dependently release , also carboxymethylcellulose , methacrylic acid copolymers such prevent the influx of water or other solvents into soft 45 as, Eudragit L (polymethacrylic acid , methylmethacrylate , capsules or soft capsules having enteric polymers imbedded 1 : 1 ratio ) , or Eudragit S (polymethacrylic acid , methylmeth in the shell wall that solubilize the fumarate ester and acrylate , 1 : 2 ratio ) , shellac , zein , or combinations thereof. facilitate diffusion of the fumarate ester out of the capsule . Suitable plasticizers include acetyl triethyl citrate, dibutyl Experiments described herein demonstrate that soft capsules phthalate , tributyl citrate , triethyl citrate , acetyl tributyl with enteric polymers embedded within the shell wall con - 50 citrate , propylene glycol, triacetin , polyethylene glycol, taining dimethyl fumarate do not substantially release the diethyl phthalate , or combinations thereof. dimethyl fumarate under acidic media . When monomethyl Suitable solubilizers include sodium lauryl sulfate , fumarate is substituted for dimethyl fumarate in similar sodium lauroyl sarcosinate sodium dodecyl sulfate , polysor capsules , however , monomethyl fumarate is released from bate 20 , polysorbate 80 , other detergents or surfactants, or enteric soft capsules in acidic media . FIGS . 16 - 19 . Without 55 combinations thereof. being bound to any theory , it is though that the increased Anti - adherent agents serve to prevent potential agglom solubility ofMMF contributes to the release of this molecule eration in acid media . Suitable anti- adherents include talc , by facilitating solvent influx through the capsule shell and magnesium stearate , calcium stearate , stearic acid , hydro resulting in diffusion of the monomethyl fumarate out of the genated vegetable oils , polyethylene glycols , fumed silica , capsule . Enteric coatings on soft capsules or soft capsules 60 silicon dioxide , or combinations thereof. comprising enteric polymers embedded within the capsule Pore - forming agents serve to create pores or channels in shell abrogate the influx of solvent and impede the release of the enteric coating after administration to a human . Suitable the monomethyl fumarate active pharmaceutical ingredient. pore - forming agents include sodium chloride, potassium FIGS. 20 - 23 . chloride, sucrose , sorbitol, mannitol, polyethylene glycols In one embodiment described herein , soft capsules are 65 (PEG ) , propylene glycol, hydroxypropyl cellulose , hydroxy coated with an enteric coating comprising the exemplary propylmethylcellulose , polyvinyl alcohols , methacrylic acid composition shown in Table 9 . copolymers , poloxamers , or combinations thereof. US 9 ,814 ,692 B2 53 54 Many conventional coating excipients are described in the about 100 % by weight. Such compositions are hereby dis art . See e . g ., Rowe et al. , Eds . Handbook of Pharmaceutical closed as if they were expressly disclosed herein . Excipients , 7th ed . Royal Pharmaceutical Society , UK In one embodiment , the pharmaceutical compositions ( 2012 ) . described herein provide a dosage form of one or more In one embodiment described herein , the enteric coating 5 fumarate esters , or prodrugs thereof, for administration to a comprises methacrylic acid and ethyl acrylate copolymer subject. The dosage form can be administered , for example , ( e .g ., EUDRAGIT® L100 -55 , Evonik ) , talc , triethyl citrate , to a subject, or a subject in need thereof. In one aspect, the sodium bicarbonate , colloidal silica , sodium lauryl sulfate , subject is a mammal, or a mammal in need thereof. In one and water . aspect, the subject is a human , or human in need thereof. In In one embodiment, adjusting the amount of enteric 10 one aspect, the human or human in need thereof is a medical coating and the ratio of polymer to other components allows patient. In one aspect , the human subject is a child (~ 0 - 9 for tuning the release profile of the dosage form . years old ) or an adolescent ( - 10 - 17 years old ) . In one aspect , Subcoats can be applied to the soft capsules prior to the subject is from about ( to about 9 years of age . In another coating to prevent shell - coat interactions and improve coat - aspect, the human subject is from about 10 years to about 17 ing adhesion to the capsule . Exemplary subcoatings can 15 years of age . In another aspect , the human subject is over 17 comprise polyvinylpyrrolidone , polyvinyl alcohols , hydrox - years of age . In another aspect, the human subject is an adult propyl methylcellulose, polyethylene glycol, oils , or com - (218 years of age ). binations thereof. The dosage form can be administered , for example , 1x , Coatings , top coatings , or subcoatings are applied to the 2x , 3x , 4x , 5x , 6x , or even more times per day . One or more soft capsules using various methods know in the art . The 20 dosage forms can be administered, for example , for 1, 2 , 3 , coatings are typically prepared as suspensions and sprayed 4 , 5 , 6 , 7 days , or even longer . One or more dosage forms can on capsules in perforated coating pans through one or more be administered , for example , for 1 , 2 , 3 , 4 weeks , or even spray nozzles at a specific temperature. Coating solutions or longer. One or more dosage forms can be administered , for dispersion may be applied at spray rates between 100 and example , for 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 months , 1 year , 400 g /min . The spray rate may be proportionately higher for 25 2 , years , 3 years , 4 years , 5 years, over 5 years , a decade , coatings with higher solid content and lower for more dilute multiple decades , or even longer. One or more dosage forms dispersions. In one embodiment, capsules are coated using a can be administered at a regular interval until the subject or pan coater. After the enteric coating suspension is applied , subject in need thereof , does not require treatment , prophy the coated capsules are dried in the pan coater for a period laxis , or amelioration of any disease or condition including of time at a specific temperature . 30 but not limited to , general autoimmune or neurodegenerative Another embodiment described herein comprises a sub - disorders . coating that is applied prior to applying an enteric coating . In one embodiment, the pharmaceutical composition In one embodiment, the subcoating comprises hydroxpropyl described herein is administered in multiple doses simulta methylcellulose , methylcellulose , ethylcellulose , or a com neously . For example , two or more identical doses are bination thereof. 35 administered at one time. In another embodiment, two or Another embodiment described herein comprises a mois - more different doses are administered at one time. Such dual ture barrier that is applied as a top coating on the enteric or different simultaneous doses can be used to provide an coating . In one embodiment the moisture barrier comprises effective amount of the pharmaceutical composition to a one or more polyvinyl alcohols and appropriate pharmaceu - subject in need thereof. tically acceptable excipients . In one embodiment the mois - 40 In another embodiment , the pharmaceutical compositions ture barrier comprises polyvinyl alcohol, sodium lauryl described herein may be used to treat, prevent, retard the sulfate , glyceryl mono - caprylate -caprate , and talc . In one progression of, delay the onset , ameliorate , reduce the aspect , the moisture barrier aids in preserving the cosmetic symptoms of, or prophylaxis of general autoimmune or appearance of the dosage forms by preventing dimpling , neurodegenerative disorders . Neurodegenerative disorders , sticking , or other processing or storage induced blemishes . 45 as used herein , include multiple sclerosis (MS ) , which Another embodiment described herein , the fumarate ester includes relapsing remitting multiple sclerosis (RRMS ) , pharmaceutical composition can comprise an enteric hard secondary progressive multiple sclerosis (SPMS ) , primary capsule shell comprising a matrix comprising a fumarate progressive multiple sclerosis (PPMS ) , progressive relaps ester. ing multiple sclerosis ( PPVMS) , amyotrophic lateral sclero Another embodiment described herein , the fumarate ester 50 sis ( ALS) , psoriasis , psoriatic arthritis , Alzheimer ' s disease , pharmaceutical composition can comprise a hard capsule Parkinson ' s disease , or any combination thereof. shell comprising a matrix comprising a fumarate ester . In one embodiment described herein , other conditions, The pharmaceutical compositions described herein can disorders , or diseases are controlled by administration of contain a matrix fill that is liquid , semisolid , or solid . fumarate esters . The administration of pharmaceutical com Capsules prepared as described herein can contain hydro - 55 positions comprising fumarate esters , as described herein , phobic solutions or suspensions, such as vegetable oils , may be used for treating, preventing, retarding the progres shortening , waxes , or combinations thereof. The matrix fill sion of, delaying the onset, ameliorating , reducing the symp can be formulated to prevent interaction with the capsule toms of, or prophylaxis of general autoimmune or neurode shell components and release the pharmaceutical composi - generative disorders, including but not limited to , acute tion at a specified rate . 60 dermatitis , adrenal leukodystrophy, AGE - induced genome One embodiment described herein , is a pharmaceutical damage, Alexander ' s disease, alopecia areata ( totalis and composition comprising a matrix fill formulation compris - universalis ) , Alper ' s disease , Alzheimer ' s disease , amyo ing any of the formulations shown in the Tables or Examples trophic lateral sclerosis , angina pectoris , arthritis , asthma , described herein . Any of the components in the formulations autoimmune diseases , balo concentric sclerosis , Behçet ' s described herein , shown in the Tables , or illustrated in the 65 syndrome, bullous pemphigoid , Canavan disease , cardiac Examples can be increased , decreased , combined , substi - insufficiency including left ventricular insufficiency, central tuted , or omitted to provide for a formulation comprising nervous system vasculitis , Charcot- Marie - Tooth disease , US 9 ,814 ,692 B2 55 56 childhood ataxia with central nervous system hypomyelina e . g ., including but not limited to one dose of a twice , thrice tion , chronic active ( lupoid ) hepatitis , chronic dermatitis , or quadrice daily regimen . In another embodiment, any of chronic idiopathic peripheral neuropathy , chronic obstruc- the foregoing doses comprise a total daily dosage. In another tive pulmonary disease, contact dermatitis , Crohn ' s disease embodiment, any of the foregoing doses may be adminis and cutaneous Crohn ' s disease , cutaneous lupus , cutaneous 5 tered simultaneously , such as two 95 mg FAE or two 100 mg sarcoidosis , diabetic retinopathy, fibromyalgia , graft versus FAE , to provide 190 mg or 200 mg FAE for a particular host disease , granuloma annulare , granulomas including dosing period . annulare , Grave ' s disease , Hashimoto ' s thyroiditis , hepatitis In another embodiment described herein , the fumarate C viral infection , herpes simplex viral infection , human ester (FAE ) dosage form can comprise , but is not limited to immunodeficiency viral infection , Huntington ' s disease , 10 about 50 mg FAE , about 52 mg FAE , about 54 mg FAE , inflammatory bowel disease , irritable bowel disorder , isch - about 56 mg FAE , about 58 mg FAE , about 60 mg FAE , emia , juvenile - onset diabetes mellitus, Krabbe disease , about 62 mg FAE , about 64 mg FAE , about 66 mg FAE , lichen planus , macular degeneration , mitochondrial about 68 mg FAE , about 70 mg FAE , about 72 mg FAE , encephalomyopathy , monomelic amyotrophy, multiple scle about 74 mg FAE , about 76 mg FAE , about 78 mg FAE , rosis (MS ) , myocardial infarction , necrobiosis lipoidica , 15 about 80 mg FAE , about 82 mg FAE , about 84 mg FAE , neurodegeneration with brain iron accumulation , neuroder - about 86 mg FAE , about 88 mg FAE , about 90 mg FAE , matitis , neuromyelitis optica , neuropathic pain , neurosarcoi about 92 mg FAE , about 94 mg FAE , about 96 mg FAE , dosis , NF -KB mediated diseases, optic neuritis , organ trans - about 98 mg FAE , about 100 mg FAE , about 102 mg FAE , plantation rejection , paraneoplastic syndromes , Parkinson ' s about 104 mg FAE , about 106 mg FAE , about 108 mg FAE , disease , Pelizaeus -Merzbacher disease , pemphigus , perni - 20 about 110 mg FAE , about 112 mg FAE , about 114 mg FAE , cious anemia , primary lateral sclerosis , progressive supra - about 116 mg FAE , about 118 mg FAE , about 120 mg FAE , nuclear palsy , psoriasis , psoriatic arthritis , pyoderma gan - about 122 mg FAE , about 124 mg FAE , about 126 mg FAE , grenosum , radiation - induced dermatitis , radicular pain , about 128 mg FAE , about 130 mg FAE , about 132 mg FAE , radiculopathic pain , reperfusion injury, retinopathic pigmen - about 134 mg FAE , about 136 mg FAE , about 138 mg FAE , tosa , rheumatoid arthritis (RA ), sarcoidosis , sarcoidosis , 25 about 140 mg FAE , about 142 mg FAE , about 144 mg FAE , Schilder ' s disease , sciatic pain , sciatica , Sjögren ' s syn - about 146 mg FAE , about 148 mg FAE , about 150 mg FAE , drome, subacute necrotizing myelopathy, such as polyarthri about 152 mg FAE , about 154 mg FAE , about 156 mg FAE , tis , Susac ' s syndrome, systemic lupus erythematosus (SLE ) , about 158 mg FAE , about 160 mg FAE , about 162 mg FAE , tumors , transverse myelitis , ulcerative colitis , or Zellweger about 164 mg FAE , about 166 mg FAE , about 168 mg FAE , syndrome. 30 about 170 mg FAE , about 172 mg FAE , about 174 mg FAE , One embodiment described herein comprises a method about 176 mg FAE , about 178 mg FAE , about 180 mg FAE , for orally administering a dosage form that provides a total about 182 mg FAE , about 184 mg FAE , about 186 mg FAE , amount of fumarate ester of about 20 mg to about 1000 mg about 188 mg FAE , about 190 mg FAE , about 192 mg FAE , ( e . g . , ~ 20 - 1000 mg) , including all integers and fractions about 194 mg FAE , about 196 mg FAE , about 198 mg FAE , within the specified range . 35 about 200 mg FAE , about 202 mg FAE , about 204 mg FAE , In one embodiment described herein , the fumarate ester about 206 mg FAE , about 208 mg FAE , about 210 mg FAE , (FAE ) dosage form can comprise , but is not limited to about about 212 mg FAE , about 214 mg FAE , about 215 mg FAE , 50 mg FAE , about 55 mg FAE , about 60 mg FAE , about 65 about 216 mg FAE , about 218 mg FAE , about 220 mg FAE , mg FAE , about 70 mg FAE , about 75 mg FAE , about 80 mg about 222 mg FAE , about 224 mg FAE , about 226 mg FAE , FAE , about 85 mg FAE , about 90 mg FAE , about 95 mg 40 about 228 mg FAE , about 230 mg FAE , about 232 mg FAE , FAE , about 100 mg FAE , about 105 mg FAE , about 110 mg about 234 mg FAE , about 236 mg FAE , about 238 mg FAE , FAE , about 115 mg FAE , about 120 mg FAE , about 125 mgOl) about 240 mg FAE , about 242mg FAE , about 244 mg FAE , FAE , about 130 mg FAE , about 135 mg FAE , about 140 mg about 246 mg FAE , about 248 mg FAE , about 250 mg FAE , FAE , about 145 mg FAE , about 150 mg FAE , about 155 mg about 252 mg FAE , about 254 mg FAE , about 256 mg FAE , FAE , about 160 mg FAE , about 165 mg FAE , about 170 mg 45 about 258 mg FAE , about 260 mg FAE , about 262 mg FAE , FAE , about 175 mg FAE , about 180 mg FAE , about 185 mg about 264 mg FAE , about 266 mg FAE , about 268 mg FAE , FAE, about 190 mg FAE, about 195 mg FAE , about 200 mg about 270 mg FAE , about 272 mg FAE , about 274 mg FAE , FAE, about 205 mg FAE, about 210 mg FAE , about 215 mg about 276 mg FAE , about 278 mg FAE , about 280 mg FAE , FAE , about 220 mg FAE , about 225 mg FAE , about 230 mg about 282 mg FAE , about 284 mg FAE , about 286 mg FAE , FAE , about 235 mg FAE , about 240 mg FAE , about 245 mg 50 about 288 mg FAE , about 290 mg FAE , about 292 mg FAE , FAE , about 250 mg FAE , about 255 mg FAE , about 260 mg about 294 mg FAE , about 296 mg FAE , about 298 mg FAE , FAE , about 265 mg FAE , about 270 mg FAE , about 275 mg about 300 mg FAE , about 302mg FAE , about 304 mg FAE , FAE , about 280 mg FAE , about 285 mg FAE , about 290 mg about 306 mg FAE , about 308 mg FAE , about 310 mg FAE , FAE , about 295 mg FAE , about 300 mg FAE , about 305 mg about 312 mg FAE , about 314 mg FAE , about 316 mg FAE , FAE , about 310 mg FAE , about 315 mg FAE , about 320 mg 55 about 318 mg FAE , about 320 mg FAE , about 322 mg FAE , FAE , about 325 mg FAE , about 330 mg FAE , about 335 mg about 324 mg FAE , about 326 mg FAE , about 328 mg FAE , FAE , about 340 mg FAE , about 345 mg FAE , about 350 mg about 330 mg FAE , about 332 mg FAE , about 334 mg FAE , FAE , about 355 mg FAE , about 360 mg FAE , about 365 mg about 336 mg FAE , about 338 mg FAE , about 340 mg FAE , FAE , about 370 mg FAE , about 375 mg FAE , about 380 mg about 342 mg FAE , about 344 mg FAE , about 346 mg FAE , FAE , about 385 mg FAE , about 390 mg FAE , about 395 mg 60 about 348 mg FAE , about 350 mg FAE , about 352 mg FAE , FAE , about 400 mg FAE , about 405 mg FAE , about 410 mg about 354 mg FAE , about 356 mg FAE , about 358 mg FAE , FAE , about 415 mg FAE , about 420 mg FAE , about 425 mg about 360 mg FAE , about 362 mg FAE , about 364 mg FAE , FAE , about 430 mg FAE , about 435 mg FAE , about 440 mg about 366 mg FAE , about 368 mg FAE , about 370 mg FAE , FAE , about 445 mg FAE , about 450 mg FAE , about 455 mg about 372 mg FAE , about 374 mg FAE , about 376 mg FAE , FAE , about 460 mg FAE , about 465 mg FAE , about 470 mg 65 about 378 mg FAE , about 380 mg FAE , about 382 mg FAE , FAE , about 475 mg FAE , or about 480 mg FAE . In one about 384 mg FAE , about 386 mg FAE , about 388 mg FAE , embodiment, the foregoing doses comprise a partial dosage , about 390 mg FAE , about 392 mg FAE , about 394 mg FAE , US 9 , 814 ,692 B2 57 58 about 396 mg FAE , about 398 mg FAE , about 400 mg FAE , FAE , about 94 mg FAE , about 96 mg FAE , about 98 mg about 402 mg FAE , about 404 mg FAE , about 406 mg FAE , FAE , about 100 mg FAE , about 102 mg FAE , about 104 mg about 408 mg FAE , about 410 mg FAE , about 412 mg FAE , FAE , about 106 mg FAE , about 108 mg FAE , about 110 mg about 414 mg FAE , about 416 mg FAE , about 418 mg FAE , FAE , about 112 mg FAE , about 114 mg FAE , about 116 mg about 420 mg FAE , about 422 mg FAE , about 424 mg FAE , 5 FAE , about 118 mg FAE , about 120 mg FAE , about 122 mg about 426 mg FAE , about 428 mg FAE , about 430 mg FAE , FAE , about 124 mg FAE , about 126 mg FAE , about 128 mg about 432 mg FAE , about 434 mg FAE , about 436 mg FAE , FAE , about 130 mg FAE , about 132 mg FAE , about 134 mg about 438 mg FAE , about 440 mg FAE , about 442 mg FAE , FAE , about 136 mg FAE , about 138 mg FAE , about 140 mg about 444 mg FAE , about 446 mg FAE , about 448 mg FAE , FAE , about 142 mg FAE , about 144 mg FAE , about 146 mg about 450 mg FAE , about 452 mg FAE , about 454 mg FAE , 10 FAE , about 148 mg FAE , about 150 mg FAE , about 152 mg about 456 mg FAE , about 458 mg FAE , about 460 mg FAE , FAE , about 154 mg FAE , about 156 mg FAE , about 158 mg about 462 mg FAE , about 464 mg FAE , about 466 mg FAE , FAE , about 160 mg FAE , about 162 mg FAE , about 164 mg about 468 mg FAE , about 470 mg FAE , about 472 mg FAE , FAE , about 166 mg FAE , about 168 mg FAE , about 170 mg about 474 mg FAE , about 476 mg FAE , about 478 mg FAE , FAE , about 172 mg FAE , about 174 mg FAE , about 176 mg or about 480 mg FAE . In one embodiment , the foregoing 15 FAE , about 178 mg FAE , about 180 mg FAE , about 182 mg doses comprise a partial dosage , e . g . , including but not FAE , about 184 mg FAE , about 186 mg FAE , about 188 mg limited to one dose of a twice thrice , or quadrice daily FAE , about 190 mg FAE , about 192 mg FAE , about 194 mg regimen . In another embodiment, any of the foregoing doses FAE , about 196 mg FAE , about 198 mg FAE , about 200 mg comprise a total daily dosage . In another embodiment, any F AE , about 202 mg FAE , about 204 mg FAE , about 206 mg of the foregoing doses may be administered simultaneously , 20 FAE , about 208 mg FAE , about 210 mg FAE , about 212 mg such as two 95 mg FAE or two 100 mg FAE , to provide 190 FAE , about 214 mg FAE , about 215 mg FAE , about 216 mg mg or 200 mg FAE for a particular dosing period . FAE , about 218 mg FAE , about 220 mg FAE , about 222 mg In one embodiment, the daily dosage is about 80 mg FAE FAE , about 224 mg FAE , about 226 mg FAE , about 228 mg to about 460 mg FAE including all integers and fractions FAE , about 230 mg FAE , about 232 mg FAE , about 234 mg within the specified range . In another embodiment, the daily 25 FAE , about 236 mg FAE , about 238 mg FAE , about 240 mg dosage is about 90 mg FAE to about 110 mg FAE , including FAE , about 242 mg FAE , about 244 mg FAE , about 246 mg all integers and fractions within the specified range . In FAE , about 248 mg FAE , about 250 mg FAE , about 252 mg another embodiment, the daily dosage is about 95 mg FAE FAE , about 254 mg FAE , about 256 mg FAE , about 258 mg to about 100 mg FAE , including all integers and fractions FAE , about 260 mg FAE , about 262 mg FAE , about 264 mg within the specified range . In another embodiment, the daily 30 FAE , about 266 mg FAE , about 268 mg FAE , about 270 mg dosage is about 90 mg FAE to about 220 mg FAE , including FAE , about 272 mg FAE , about 274 mg FAE , about 276 mg all integers and fractions within the specified range . In FAE , about 278 mg FAE , about 280 mg FAE , about 282 mg another embodiment, the daily dosage is about 100 mg FAE FAE , about 284 mg FAE , about 286 mg FAE , about 288 mg to about 200 mg FAE , including all integers and fractions FAE , about 290 mg FAE , about 292 mg FAE , about 294 mg within the specified range . In another embodiment , the daily 35 FAE , about 296 mg FAE , about 298 mg FAE , about 300 mg dosage is about 100 mg FAE to about 220 mg FAE , FAE , about 302 mg FAE , about 304 mg FAE , about 306 mg including all integers and fractions within the specified FAE , about 308 mg FAE , about 310 mg FAE , about 312 mg range . In another embodiment, the daily dosage is about 170 FAE , about 314 mg FAE , about 316 mg FAE , about 318 mg mg FAE to about 200 mg FAE , including all integers and FAE , about 320 mg FAE , about 322 mg FAE , about 324 mg fractions within the specified range. In another embodiment , 40 FAE , about 326 mg FAE , about 328 mg FAE , about 330 mg the daily dosage is about 180 mg FAE to about 200 mg FAE , FAE , about 332 mg FAE , about 334 mg FAE , about 336 mg including all integers and fractions within the specified FAE , about 338 mg FAE , about 340 mg FAE , about 342 mg range . In another embodiment, the daily dosage is about 190 FAE , about 344 mg FAE , about 346 mg FAE , about 348 mg mg FAE to about 200 mg FAE , including all integers and FAE , about 350 mg FAE , about 352 mg FAE , about 354 mg fractions within the specified range . In one embodiment, the 45 FAE , about 356 mg FAE , about 358 mg FAE , about 360 mg daily dosage is about 200 mg FAE to about 220 mg FAE , FAE , about 362 mg FAE , about 364 mg FAE , about 366 mg including all integers and fractions within the specified FAE , about 368 mg FAE , about 370 mg FAE , about 372 mg range. In another embodiment, the daily dosage is about 380 FAE , about 374 mg FAE , about 376 mg FAE , about 378 mg mg FAE to about 400 mg FAE , including all integers and FAE , about 380 mg FAE , about 382 mg FAE , about 384 mg fractions within the specified range . In another embodiment, 50 FAE , about 386 mg FAE , about 388 mg FAE , about 390 mg the daily dosage is about 320 mg FAE to about 460 mg FAE , FAE , about 392 mg FAE , about 394 mg FAE , about 396 mg including all integers and fractions within the specified FAE , about 398 mg FAE , about 400 mg FAE , about 402 mg range . In another embodiment, the daily dosage is about 400 FAE , about 404 mg FAE , about 406 mg FAE , about 408 mg mg FAE to about 460 mg FAE , including all integers and FAE , about 410 mg FAE , about 412 mg FAE , about 414 mg fractions within the specified range . In another embodiment, 55 FAE , about 416 mg FAE , about 418 mg FAE , about 420 mg the daily dosage is about 460 mg FAE . The total daily dose FAE , about 422 mg FAE, about 424 mg FAE , about 426 mg may be administered in any number of individual dosage FAE , about 428 mg FAE , about 430 mg FAE , about 432 mg forms that cumulatively total the daily dose . For example , FAE , about 434 mg FAE, about 436 mg FAE , about 438 mg four 95 mg FAE dosage forms may be administered in a FAE , about 440 mg FAE , about 442 mg FAE , about 444 mg regimen of two dosage forms in the morning and two in the 60 FAE , about 446 mg FAE , about 448 mg FAE , about 450 mg evening for a total daily dose of 380 mg FAE . Alternatively , FAE , about 452 mg FAE , about 454 mg FAE , about 456 mg four 95 mg FAE dosage forms may be administered QID FAE , about 458 mg FAE , about 460 mg FAE , about 462 mg ( e . g . , every six hours ) for a total daily dose of 380 mg FAE . FAE , about 464 mg FAE , about 466 mg FAE , about 468 mg In another embodiment, the daily dosage can comprise , FAE , about 470 mg FAE , about 472 mg FAE , about 474 mg but is not limited to , a total amount of FAE of about 80 mg 65 FAE , about 476 mg FAE , about 478 mg FAE , or about 480 FAE , about 82 mg FAE , about 84 mg FAE , about 86 mg mg FAE . The daily dosage can contain a total amount of FAE , about 88 mg FAE , about 90 mg FAE , about 92 mg fumarate ester effective for treatment of retarding the pro US 9 ,814 ,692 B2 59 60 gression of, prophylaxis of delaying the onset of, ameliora - mg FAE to about 230 mg FAE , about 120 mg FAE to about tion of, or reducing symptoms of multiple sclerosis or 240 mg FAE , about 120 mg FAE to about 400 mg FAE , psoriasis or other neurodegenerative disorders . In one about 120 mg FAE to about 420mg FAE , about 120 mg FAE aspect, the daily dosage is about 380 mg FAE to about 420 to about 430 mg FAE , about 120 mg FAE to about 440 mg mg FAE . In another aspect , the daily dosage is about 380 mg 5 FAE , about 120 mg FAE to about 460 mg FAE , about 120 FAE to about 400 mg FAE . In another aspect, the daily mg FAE to about 480 mg FAE , about 180 mg FAE to about dosage is about 380 mg FAE . In another aspect , the daily 200 mg FAE , about 190 mg FAE to about 200 mg FAE , dosage is about 400 mg FAE . about 190 mg FAE to about 380 mg FAE , about 190 mg FAE In one embodiment, the amount of fumarate ester can to about 400 mg FAE , about 200 mg FAE to about 210 mg comprise about 80 mg to about 500 mg ( e . g ., 80 - 500 mg ) of 10 FAE , about 200 mg FAE to about 220 mg FAE , about 200 fumarate ester , including all integers and fractions within the mg FAE to about 230 mg FAE , about 200 mg FAE to about specified range . In one embodiment, the amount can com - 240 mg FAE , about 200 mg FAE to about 400 mg FAE , prise , but is not limited to , about 80 mg to about 480 mg about 200 mg FAE to about 420 mg FAE , about 200 mg FAE FAE , including all integers and fractions within the specified to about 430 mg FAE , about 200 mg FAE to about 440 mg range . In one embodiment, the amount of fumarate ester can 15 FAE , about 200 mg FAE to about 460 mg FAE , about 200 comprise about 80 mg FAE to about 85 mg FAE , about 85 mg FAE to about 480 mg FAE , about 210 mg FAE to about mg FAE to about 90 mg FAE , about 85 mg FAE to about 100 220 mg FAE , about 210 mg FAE to about 230 mg FAE , mg FAE , about 90 mg FAE to about 95 mg FAE , about 90 about 210 mg FAE to about 240 mg FAE , about 210 mg FAE mg FAE to about 100 mg FAE , about 90 mg FAE to about to about 400 mg FAE , about 210 mg FAE to about 420 mg 105 mg FAE , about 90 mg FAE to about 110 mg FAE , about 20 FAE , about 210 mg FAE to about 430 mg FAE , about 210 90 mg FAE to about 115 mg FAE , about 90 mg FAE to about mg FAE to about 440 mg FAE , about 210 mg FAE to about 120 mg FAE , about 95 mg FAE to about 100 mg FAE , about 460 mg FAE , about 210 mg FAE to about 480 mg FAE , 95 mg FAE to about 110 mg FAE , about 95 mg FAE to about about 220 mg FAE to about 230 mg FAE , about 220 mg FAE 120 mg FAE , about 95 mg FAE to about 190 mg FAE , about to about 240 mg FAE , about 220 mg FAE to about 400 mg 95 mg FAE to about 200 mg FAE , about 100 mg FAE to 25 FAE , about 220 mg FAE to about 420 mg FAE , about 220 about 105 mg FAE , about 100 mg FAE to about 110 mg mg FAE to about 430 mg FAE , about 220 mg FAE to about FAE , about 100 mg FAE to about 115 mg FAE , about 100 440 mg FAE , about 220 mg FAE to about 460 mg FAE , mg FAE to about 120 mg FAE , about 100 mg FAE to about about 220 mg FAE to about 480 mg FAE , about 230 mg FAE 180 mg FAE , about 100 mg FAE to about 190 mg FAE , to about 240 mg FAE , about 230 mg FAE to about 400 mg about 100 mg FAE to about 200 mg FAE , about 100 mg FAE 30 FAE , about 230 mg FAE to about 420 mg FAE , about 230 to about 210 mg FAE , about 100 mg FAE to about 220 mg mg FAE to about 430 mg FAE , about 230 mg FAE to about FAE , about 100 mg FAE to about 230 mg FAE , about 100 440 mg FAE , about 230 mg FAE to about 460 mg FAE , mg FAE to about 240 mg FAE , about 100 mg FAE to about about 230 mg FAE to about 480 mg FAE , about 240 mg FAE 400 mg FAE , about 100 mg FAE to about 420 mg FAE , to about 400 mg FAE , about 240 mg FAE to about 420 mg about 100 mg FAE to about 430 mg FAE , about 100 mg FAE 35 FAE , about 240 mg FAE to about 430 mg FAE , about 240 to about 440 mg FAE , about 100 mg FAE to about 460 mg mg FAE to about 440 mg FAE , about 240 mg FAE to about FAE , about 100 mg FAE to about 480 mg FAE , about 105 460 mg FAE , about 240 mg FAE to about 480 mg FAE , mg FAE to about 110 mg FAE , about 105 mg FAE to about about 380 mg FAE to about 400 mg FAE , about 380 mg FAE 115 mg FAE , about 105 mg FAE to about 120 mg FAE , to about 420 mg FAE , about 400 mg FAE to about 410 mg about 105 mg FAE to about 200 mg FAE , about 105 mg FAE 40 FAE , about 400 mg FAE to about 420 mg FAE , about 400 to about 210 mg FAE , about 105 mg FAE to about 220 mg mg FAE to about 430 mg FAE , about 400 mg FAE to about FAE , about 105 mg FAE to about 230 mg FAE , about 105 440 mg FAE , about 400 mg FAE to about 460 mg FAE , mg FAE to about 240 mg FAE , about 105 mg FAE to about about 400 mg FAE to about 480 mg FAE , about 420 mg FAE 400 mg FAE , about 105 mg FAE to about 420 mg FAE , to about 430 mg FAE , about 420 mg FAE to about 440 mg about 105 mg FAE to about 430 mg FAE , about 105 mg FAE 45 FAE , about 420 mg FAE to about 460 mg FAE , about 420 to about 440 mg FAE , about 105 mg FAE to about 460 mg mg FAE to about 480 mg FAE , about 430 mg FAE to about FAE , about 105 mg FAE to about 480 mg FAE , about 110 440 mg FAE , about 430 mg FAE to about 460 mg FAE , mg FAE to about 115 mg FAE , about 110 mg FAE to about about 430 mg FAE to about 480 mg FAE , about 440 mg FAE 120 mg FAE , about 110 mg FAE to about 200 mg FAE , to about 460 mg FAE , about 440 mg FAE to about 480 mg about 110 mg FAE to about 210 mg FAE , about 110 mg FAE 50 FAE , or about 460 mg FAE to about 480 mg FAE , including to about 220 mg FAE , about 110 mg FAE to about 230 mg all integers and fractions within the specified ranges . FAE , about 110 mg FAE to about 240 mg FAE , about 110 In one embodiment described herein , the pharmaceutical mg FAE to about 400 mg FAE , about 110 mg FAE to about composition comprises from about 80 mg FAE to about 119 420 mg FAE , about 120 mg FAE to about 430 mg FAE , FAE including each integer within the specified range . In about 110 mg FAE to about 440 mg FAE , about 110 mg FAE 55 one embodiment described herein , the pharmaceutical com to about 460 mg FAE , about 110 mg FAE to about 480 mg position comprises about 80 mg FAE , about 81 mg FAE , FAE , about 115 mg FAE to about 120 mg FAE , about 115 about 82 mg FAE , about 893 mg FAE , about 84 mg FAE , mg FAE to about 200 mg FAE , about 115 mg FAE to about about 85 mg FAE , about 86 mg FAE , about 87 mg FAE , 210 mg FAE , about 115 mg FAE to about 220 mg FAE , about 88 mg FAE , about 89 mg FAE , about 90 mg FAE , about 115 mg FAE to about 230 mg FAE , about 115 mg FAE 60 about 91 mg FAE , about 92 mg FAE , about 93 mg FAE , to about 240 mg FAE , about 115 mg FAE to about 400 mg about 94 mg FAE , about 95 mg FAE , about 96 mg FAE , FAE , about 115 mg FAE to about 420 mg FAE , about 115 about 97 mg FAE , about 98 mg FAE , about 99 mg FAE , mg FAE to about 430 mg FAE , about 115 mg FAE to about about 100 mg FAE , about 101mg FAE , about 102 mg FAE , 440 mg FAE , about 115 mg FAE to about 460 mg FAE , about 103 mg FAE , about 104 mg FAE , about 105 mg FAE , about 115 mg FAE to about 480 mg FAE , about 120 mg FAE 65 about 106 mg FAE , about 107 mg FAE , about 108 mg FAE , to about 200 mg FAE , about 120 mg FAE to about 210 mg about 109 mg FAE , about 110 mg FAE , about 111 mg FAE , FAE , about 120 mg FAE to about 220 mg FAE , about 120 about 112 mg FAE , about 113 mg FAE , about 114 mg FAE , US 9 ,814 ,692 B2 62 about 115 mg FAE , about 116 mg FAE , about 117 mg FAE , In one embodiment, the amount of fumarate ester can about 118 mg FAE , or about 119 mg FAE . comprise about 85 mg to about 100 mg FAE , about 85 mg In one embodiment described herein , the pharmaceutical to about 110 mg FAE , about 85 mg to about 115 mg FAE , composition comprises from about 180 mg FAE to about about 90 mg to about 100 mg FAE , about 90 mg to about 110 238 FAE including each integer within the specified range . 5 mg FAE , about 90 mg to about 115 mg FAE , about 90 mg In one embodiment described herein , the pharmaceutical to about 120 mg FAE , about 90 mg to about 200 mg FAE , composition comprises about 180 mg FAE , about 182 mg about 90 mg to about 220 mg FAE , about 90 mg to about 230 FAE , about 184 mg FAE , about 186 mg FAE , about 188 mg mg FAE , about 95 mg to about 100 mg FAE , about 95 mg FAE , about 190 mg FAE , about 192 mg FAE , about 194 mg to about 110 mg FAE , about 95 mg to about 120 mg FAE , FAE , about 196 mg FAE , about 198 mg FAE , about 200 mg 10 about 95 mg to about 200 mg FAE , about 95 mg to about 380 FAE , about 202 mg FAE , about 204 mg FAE , about 206 mg mg FAE , about 95 mg to about 400 mg FAE , about 100 mg FAE , about 208 mg FAE , about 210 mg FAE , about 212 mg to about 105 mg FAE , about 100 mg to about 110 mg FAE , FAE , about 214 mg FAE , about 216 mg FAE , about 218 mg about 100 mg to about 115 mg FAE , about 100 mg to about FAE , about 220 mg FAE , about 222 mg FAE , about 224 mg)Ol 120 mg FAE , about 100 mg to about 205 mg FAE , about 100 FAE , about 226 mg FAE , about 228 mg FAE , about 230 mg 15 mg to about 210 mg FAE , about 100 mg to about 215 mg FAE , about 232 mg FAE , about 234 mg FAE, about 236 mg FAE , about 100 mg to about 220 mg FAE , about 100 mg to FAE , or about 238 mg FAE . about 230 mg FAE , about 100 mg to about 380 mg FAE , In one embodiment described herein , the pharmaceutical about 100 mg to about 400 mg FAE , about 170 mg to about composition comprises from about 360 mg FAE to about 220 mg FAE , about 180 mg to about 200 mg FAE , about 180 476 FAE including each integer within the specified range . 20 mg to about 220 mg FAE , about 180 mg to about 380 mg In one embodiment described herein , the pharmaceutical FAE , about 180 mg to about 400 mg FAE , about 190 mg to composition comprises about 360 mg FAE , about 362 mg about 200 mg FAE , about 190 mg to about 220 mg FAE , FAE , about 364 mg FAE , about 368 mg FAE , about 372 mg about 190 mg to about 380 mg FAE , about 190 mg to about FAE , about 376 mg FAE , about 380 mg FAE , about 384 mg 400 mg FAE , about 200 mg to about 210 mg FAE , about 200 FAE , about 388 mg FAE , about 392 mg FAE , about 396 mg 25 mg to about 212 mg FAE , about 200 mg to about 214 mg FAE , about 400 mg FAE , about 404 mg FAE , about 408 mg FAE , about 200 mg to about 216 mg FAE , about 200 mg to FAE , about 412 mg FAE , about 416 mg FAE , about 420 mg about 218 mg FAE , about 200 mg to about 220 mg FAE , FAE , about 424 mg FAE , about 428 mg FAE , about 432 mg about 200 mg to about 225 mg FAE , about 200 mg to about FAE , about 436 mg FAE , about 440 mg FAE , about 444 mg 230 mg FAE , about 200 mg to about 340 mg FAE , about 200 FAE , about 448 mg FAE , about 452 mg FAE , about 456 mg 30 mg to about 380 mg FAE , about 200 mg to about 400 mg FAE , about 460 mg FAE , about 464 mg FAE , about 468 mg FAE , about 200 mg to about 420 mg FAE , about 200 mg to FAE , about 472 mg FAE , or about 476 mg FAE . about 430 mg FAE , about 340 mg to about 430 mg FAE , In one embodiment described herein , the pharmaceutical about 340 mg to about 460 mg FAE , about 380 mg to about composition comprises from about 90 mg FAE to about 476 400 mg FAE , about 380 mg to about410 mg FAE , about 380 FAE including each integer within the specified range . In 35 mg to about 420 mg FAE , or about 380 mg to about 430 mg one embodiment described herein , the pharmaceutical com - FAE . position comprises about 90 mg FAE , about 91 mg FAE , In another embodiment, the effective amount of fumarate about 92 mg FAE , about 93 mg FAE , about 94 mg FAE , ester can comprise , but is not limited to , about 70 mg FAE about 95 mg FAE , about 96 mg FAE , about 97 mg FAE , to about 480 mg FAE ( e . g . , 70 - 480 mg FAE ) , including all about 98 mg FAE , about 99 mg FAE , about 100 mg FAE , 40 integers and fractions within the specified range . In one about 101 mg FAE , about 102 mg FAE , about 103 mg FAE , aspect, the daily effective amount of fumarate ester can about 104 mg FAE , about 105 mg FAE , about 106 mg FAE , comprise , but is not limited to , an effective amount of about about 107 mg FAE , about 108 mg FAE , about 109 mg FAE , 70 mg to about 90 mg FAE , about 75 mg to about 95 mg about 110 mg FAE , about 111 mg FAE , about 112 mg FAE , FAE , about 80 mg to about 100 mg FAE , about 85 mg to about 113 mg FAE , about 114 mg FAE , about 115 mg FAE , 45 about 105 mg FAE , about 90 mg to about 100 mg FAE , about 116 mg FAE , about 117 mg FAE , about 118 mg FAE , about 90 mg to about 105 mg FAE , about 90 mg to about 100 about 119 mg FAE , about 180 mg FAE , about 182 mg FAE , mg FAE , about 95 mg to about 100 mg FAE , about 95 mg about 184 mg FAE , about 186 mg FAE , about 188 mg FAE , to about 108 mg FAE , about 100 mg to about 110 mg FAE , about 190 mg FAE , about 192 mg FAE , about 194 mg FAE , about 100 mg to about 115 mg FAE , about 100 mg to about about 196 mg FAE , about 198 mg FAE , about 200 mg FAE , 50 120 mg FAE , about 105 mg to about 110 mg FAE , about 105 about 202 mg FAE , about 204 mg FAE , about 206 mg FAE , mg to about 115 mg FAE , about 105 mg to about 120 mg about 208 mg FAE , about 210 mg FAE , about 212 mg FAE , FAE , about 105 mg to about 125 mg FAE , about 110 mg to about 214 mg FAE , about 216 mg FAE , about 218 mg FAE , about 120 mg FAE , about 110 mg to about 125 mg FAE , about 220 mg FAE , about 222 mg FAE , about 224 mg FAE , about 115 mg FAE to about 120 mg FAE , about 115 mg FAE about 226 mg FAE , about 228 mg FAE , about 230 mg FAE , 55 to about 125 mg FAE , about 100 mg to about 200 mg FAE , about 232 mg FAE , about 234 mg FAE , about 236 mg FAE , about 105 mg to about 210 mg FAE , about 110 mg to about about 238 mg FAE , about 360 mg FAE , about 364 mg FAE , 220 mg FAE , about 115 mg FAE to about 230 mg FAE , about 368 mg FAE , about 372 mg FAE , about 376 mg FAE , about 120 mg to about 240 mg FAE , about 180 mg to about about 380 mg FAE , about 384 mg FAE , about 388 mg FAE , 200 mg FAE , about 180 mg to about 220 mg FAE , about 200 about 392 mg FAE , about 396 mg FAE , about 400 mg FAE , 60 mg to about 210 mg FAE , about 200 mg to about 220 mg about 404 mg FAE , about 408 mg FAE , about 412 mg FAE , FAE , about 210 mg to about 240 mg FAE , about 220 mg to about 416 mg FAE , about 420 mg FAE , about 424 mg FAE , about 250 mg FAE , about 380 mg to about 400 mg FAE , about 428 mg FAE , about 432 mg FAE , about 436 mg FAE , about 400 mg to about 420 mg FAE , about 400 mg to about about 440 mg FAE , about 444 mg FAE , about 448 mg FAE , 430 mg FAE , about 400 mg to about 440 mg FAE , about 400 about 452 mg FAE , about 456 mg FAE , about 460 mg FAE , 65 mg to about 450 mg FAE , about 400 mg to about 460 mg about 464 mg FAE , about 468 mg FAE , about 472 mg FAE , FAE , about 400 mg to about 480 mg FAE , about 410 mg to or about 476 mg FAE . about 420 mg FAE , about 410 mg to about 430 mg FAE , US 9 , 814 ,692 B2 63 64 about 410 mg to about 440 mg FAE , about 410 mg to about the specified range . In one embodiment, the drug load can 450 mg FAE , about 410 mg to about 460 mg FAE , about 410 comprise about 10 % to about 45 % by weight, including all mg to about 480 mg FAE , about 420 mg to about 430 mg integers and fractions within the specified range . In one FAE , about 420 mg to about 440 mg FAE , about 420 mg to embodiment, the drug load can comprise about 12 % to about about 450 mg FAE , about 420 mg to about 460 mg FAE , 5 16 % by weight, including all integers and fractions within about 420 mg to about 480 mg FAE , about 425 mg to about the specified range . In one embodiment, the drug load can 430 mg FAE , about 425 mg to about 440 mg FAE , about 425 comprise about 24 % to about 32 % by weight, including all mg to about 450 mg FAE , about 425 mg to about 460 mg integers and fractions within the specified range . In one FAE , about 425 mg to about 480 mg FAE , about 430 mg to embodiment, the drug load can comprise about 20 % to about about 440 mg FAE , about 430 mg to about 450 mg FAE , 10 22 % by weight, including all integers and fractions within about 430 mg to about 460 mg FAE , about 430 mg to about the specified range . In one embodiment, the drug load can 480 mg FAE , about 440 mg to about 450 mg FAE , about 440 comprise about 20 % to about 50 % by weight, including all mg to about 460 mg FAE , or about 440 mg to about 480 mg integers and fractions within the specified range . In one FAE , including all integers and fractions within the specified embodiment, the drug load can comprise about 40 % to about ranges . 15 43 % by weight, including all integers and fractions within In one embodiment, the daily effective amount of fumar the specified range . In one embodiment, the drug load can ate ester can comprise about 85 mg to about 118 mg FAE , comprise about 25 % to about 45 % by weight, including all about 90 mg to about 105 mg FAE , about 90 mg to about 110 integers and fractions within the specified range . In one mg FAE , about 90 mg to about 115 mg FAE , about 90 mg embodiment, the drug load can comprise about 29 % to about to about 120 mg FAE , about 90 mg to about 230 mg FAE , 20 43 % by weight, including all integers and fractions within about 100 mg to about 105 mg FAE , about 100 mg to about the specified range . In one embodiment, the drug load can 107 mg FAE , about 100 mg to about 108 mg FAE , about 100 comprise about 48 % to about 64 % by weight, including all mg to about 110 mg FAE , about 100 mg to about 115 mg integers and fractions within the specified range. In one FAE , about 100 mg to about 120 mg FAE , about 100 mg to embodiment, the drug load can comprise about 1 % , about about 205 mg FAE , about 100 mg to about 210 mg FAE , 25 2 % , about 2 . 5 % , about 5 % , about 10 % , about 15 % , about about 100 mg to about 215 mg FAE , about 100 mg to about 20 % , about 25 % , about 29 % about 30 % , about 35 % , about 220 mg FAE , about 100 mg to about 230 mg FAE , about 170 40 % , about 42 % , about 45 % , about 40 % , about 50 % , about mg to about 230 mg FAE , about 200 mg to about 210 mg 60 % , about 65 % , or even higher , by weight. In one embodi FAE , about 200 mg to about 212 mg FAE , about 200 mg to ment , the drug load can comprise about 11 . 3 % , 11 . 7 % , about 214 mg FAE , about 200 mg to about 215 mg FAE , 30 12 . 0 % , 12 . 1 % , 12 . 4 % , 12 . 6 % , 12 . 7 % , 12 . 9 % , 13 . 1 % , about 200 mg to about 216 mg FAE , about 200 mg to about 13 . 3 % , 13 . 6 % , 13 . 8 % , 14 . 1 % , 14 . 2 % , 14 . 3 % , 14 . 4 % , 218 mg FAE , about 200 mg to about 220 mg FAE, about 200 14 .6 % , 14 . 8 % , 14 . 9 % , 15 . 0 % , 15 . 2 % , 15 . 3 % , 15 . 4 % , mg to about 225 mg FAE , about 200 mg to about 230 mg 15 . 8 % , 15 . 9 % , 16 . 0 % , 16 . 5 % , 16 . 6 % , 16 .7 % , 17 . 1 % , FAE , about 200 mg to about 340 mg FAE , about 200 mg to 17 . 2 % , 17 . 3 % , 17 . 8 % , 17 . 9 % , 18 . 0 % , 22 . 7 % , 23 . 4 % , about 430 mg FAE , about 340 mg to about 430 mg FAE , or 35 24 .0 % , 24 . 3 % , 24 .8 % , 25 .2 % , 25 . 3 % , 25 . 7 % , 26 . 2 % , about 340 mg to about 460 mg FAE . 26 . 7 % , 27 . 1 % , 27 . 2 % , 27 . 6 % , 27 . 7 % , 28 . 1 % , 28 . 3 % , In one embodiment described herein , the pharmaceutical 28. 5 % , 28 . 6 % , 28 . 7 % , 28 . 8 % , 29 . 2 % , 29 . 5 % , 29 .6 % , compositions described herein are indicated for the treat 29 .7 % , 29. 8 % , 30 .0 % , 30 . 4 % , 30 .6 % , 30 .7 % , 30 .8 % , ment of patients with relapsing forms of multiple sclerosis . 30 . 9 % , 31. 7 % , 31 .9 % , 32 .0 % , 32 . 9 % , 33. 1 % , 33 . 2 % , Another embodiment described herein is a method for 40 33. 3 % , 34 . 2 % , 34 . 4 % , 34 . 6 % , 35 . 7 % , 35 . 8 % , 36 . 0 % , treating a patient with a relapsing form of multiple sclerosis 40 . 0 % , 42 . 8 % , 43 .0 % , 43 . 2 % , 53 .3 % , 56 . 0 % , 57. 6 % , comprising the administration of a dose of a fumarate ester 58 . 7 % , 61. 3 % , or 64 . 0 % FAE , each by weight. In one as described herein . In one aspect, the fumarate ester is embodiment, the drug load can comprise about 34 % FAE , by DMF, MMF, or a combination thereof. In another aspect, the weight . dose is between about 85 mg FAE and about 120 mg FAE , 45 In one embodiment described herein , pharmaceutical including each integer within the specified range . In another composition can comprise about 0 .4 mmol FAE to about 4 . 0 aspect, the total daily dose is between about 100 mg FAE mmol FAE , including all integers and fractions within the and about 230 mg FAE , including each integer within the specified range . In one embodiment, the pharmaceutical specified range . In another aspect, the total daily dose is composition comprises 0 . 4 mmol FAE , 0 . 5 mmol FAE , 0 .6 between about 170 mg FAE and about 230 mg FAE , 50 mmol FAE , 0 . 7 mmol FAE , 0 . 8 mmol FAE , 0 . 9 mmol FAE , including each integer within the specified range . In another 1 . 0 mmol FAE , 1 . 1 mmol FAE , 1. 2 mmol FAE , 1 . 3 mmol aspect, the total daily dose is between about 340 mg FAE FAE , 1. 4 mmol FAE , 1. 5 mmol FAE , 1. 6 mmol FAE , 1 .7 and about 460 mg FAE , including each integer within the mmol FAE , 1. 8 mmol FAE , 1. 9 mmol FAE , 2 .0 mmol FAE , specified range . In one embodiment the total daily dose is 2 . 1 mmol FAE , 2 . 2 mmol FAE , 2 . 3 mmol FAE , 2 . 4 mmol about 210 mg FAE , about 211 mg FAE , about 212 mg FAE , 55 FAE , 2 .5 mmol FAE , 2 .6 mmol FAE , 2 . 7 mmol FAE , 2 . 8 about 213 mg FAE , about 214 mg FAE , about 215 mg FAE , mmol FAE , 2 . 9 mmol FAE , 3 . 0 mmol FAE , 3 . 1 mmol FAE , about 216 mg FAE , about 217 mg FAE , about 218 mg FAE , 3 . 2 mmol FAE , 3 . 3 mmol FAE , 3 . 4 mmol FAE , 3 . 5 mmol about 219 mg FAE , or about 220 mg FAE . In one embodi FAE , 3 .6 mmol FAE , 3 .7 mmol FAE , 3. 8 mmol FAE , 3 .9 ment the total daily dose is about 420 mg FAE , about 422 mg mmol FAE , or 4 . 0 mmol FAE . In one embodiment, the FAE , about 424 mg FAE , about 426 mg FAE , about 428 mg 60 pharmaceutical composition comprises about 0 . 7 mmol FAE FAE , about 430 mg FAE , about 432 mg FAE , about 434 mg to about 1 .6 mmol FAE . In one aspect, the pharmaceutical FAE , about 436 mg FAE , about 438 mg FAE , or about 440 composition comprises about 0 . 7 mmol FAE . In another mg FAE . aspect , the pharmaceutical composition comprises about 0 . 8 In one embodiment described herein , the FAE may com - mmol FAE . In another aspect, the pharmaceutical compo prise a solution or suspension having an active pharmaceu - 65 sition comprises about 1 . 5 mmol FAE . tical ingredient load ( e .g . , drug load ) of about 1 % to about In another embodiment described herein , the effective 65 % by weight, including all integers and fractions within dose of fumarate ester for treating multiple sclerosis or US 9 , 814 ,692 B2 65 66 psoriasis is about 2 . 8 mmole FAE to about 3 . 1 mmol FAE . achieves a reduction of annualized relapse rate relative to In one aspect the effective dose of fumarate ester is about baseline without substantially experiencing one or more of 2 . 8 . In another aspect the effective dose of fumarate ester is flushing , abdominal pain , diarrhea , and nausea . In one aspect about 3 . 1 . the reduction of annualized relapse rate may be about 1 % , Another embodiment described herein is a pharmaceuti - 5 about 2 % , about 5 % , about 10 % , about 15 % , about 20 % , cal dosage form comprising any one of the pharmaceutical about 25 % , about 30 % , about 35 % , about 45 % , about 50 % , compositions described herein for administration to a sub or greater than about 50 % . ject having a general autoimmune or neurodegenerative For the treatment of multiple sclerosis ( e . g . , relapsing disorder, including but not limited to multiple sclerosis , forms of MS such as RRMS ) , the dosage form administered comprising a therapeutically effective amount of one or 10 to the subject or subject in need thereof comprises a phar more fumarate esters, wherein the administration is suffi maceutical composition comprising micronized solid par cient to achieve a reduction of about 0 . 224 annualized ticles of a fumarate ester as the only active ingredient or in relapse rate relative to baseline in the subject without combination with one or more NSAIDS ( e . g . , aspirin ) or substantially inducing one or more of flushing , abdominal leukotriene receptor antagonists (e . g . , montelukast or zaf pain , diarrhea , and nausea in the subject ; and wherein the 15 irlukast ) . In one aspect , the effective amount of fumarate administration does not require titration of the pharmaceu - ester is about 320 mg to about 460 mg FAE per day and the tical composition . subjects can receive the effective amount, e . g ., about 80 mg Another embodiment described herein is a method for to about 115 mg FAE quater in die ( PID ) , in the form of four treating , retarding the progression of, prophylaxis of, delay capsules a day , to be taken orally , including all integers and ing the onset of, ameliorating, or reducing the symptoms of 20 fractions within the specified ranges . In another aspect, the multiple sclerosis or psoriasis comprising the administration effective amount is about 85 mg to about 110 mg FAE quater of a therapeutically effective amount of one or more fumar- in die ( PID ) . In another aspect , the effective amount is about ate esters comprising any one of the pharmaceutical com 90 mg to about 100 mg FAE quater in die (CID ). In another positions described herein to a subject with multiple scle - aspect, the effective amount is about 90 mg to about 107 mg rosis , wherein the administration is sufficient to achieve a 25 FAE quater in die (QID ) . In another aspect, the effective reduction of about 0 . 224 annualized relapse rate relative to amount is about 100 mg to about 108 mg FAE quater in die baseline in the subject without substantially inducing one or (QID ) . In another aspect, the effective amount is about 105 more of flushing , abdominal pain , diarrhea , and nausea in mg to about 110 mg FAE quater in die ( PID ) . In one aspect , the subject. In one aspect, after administration of any one the the effective amount of fumarate ester is about 340 mg to pharmaceutical compositions described herein , the subject 30 about 460 mg FAE per day and the subjects can receive the experiences one or more of flushing , abdominal pain , diar- effective amount, e . g ., about 170 mg to about 230 mg FAE rhea , and nausea at a rate of less than about 10 % . In another bis in die (BID ) , in the form of two capsules a day, to be aspect, the endpoint may be less than about 2 % , about 5 % , taken orally , including all integers and fractions within the about 10 % , about 15 % , about 20 % , about 25 % , about 30 % , specified ranges . In another aspect, the effective amount is about 35 % , about 45 % , about 50 % , or greater than about 35 about 205 mg to about 230 mg FAE BID . In a further aspect , 50 % . the effective amount is about 210 mg to about 220 mg FAE Another embodiment described herein is a pharmaceuti - BID . In a further aspect, the effective amount is about 210 cal composition and a method for treating , retarding the mg to 216 mg FAE BID . In a further aspect , the effective progression of, delaying the onset of, prophylaxis of, ame amount is about 212 mg to 216 mg FAE BID . In another lioration of, or reducing the symptoms of a general autoim - 40 aspect, the effective amount of FAE is about 340 mg to about mune or neurodegenerative disorder, including but not lim - 460 mg FAE per day and the subjects can receive the ited to multiple sclerosis or psoriasis , themethod comprising effective amount, e . g ., about 340 to about 460 mg FAE the administration of a therapeutically effective amount of quaque die (QD ) , in the form of one capsule a day, to be one or more fumarate esters comprising any one of the taken orally , including all integers and fractions within the pharmaceutical compositions described herein to a subject in 45 specified ranges . need thereof, wherein the subject achieves a reduction of In another embodiment, for the treatment of multiple annualized relapse rate relative to baseline without substan - sclerosis the daily effective amount of FAE is from 80 mg tially experiencing one or more of flushing , abdominal pain , FAE to 85 mg FAE , 80 mg FAE to 90 mg FAE , 80 mg FAE diarrhea , and nausea . In another aspect , the endpointmay be to 95 mg FAE , 85 mg FAE to 100 mg FAE , 85 mg FAE to less than about 2 % , about 5 % , about 10 % , about 15 % , about 50 90 mg FAE , 85 mg FAE to 95 mg FAE , 90 mg FAE to 100 20 % , about 25 % , about 30 % , about 35 % , about 45 % , about mg FAE , 90 mg FAE to 105 mg FAE , 90 mg FAE to 95 mg 50 % , or greater than about 50 % , relative to baseline . FAE , 95 mg FAE to 100 mg FAE , 95 mg FAE to 105 mg Endpoints for treating multiple sclerosis using fumarate FAE , 95 mg FAE to 110 mg FAE , 100 mg FAE to 105 mg esters are described in the TECFIDERA? Prescribing Infor - FAE , 100 mg FAE to 110 mg FAE , 100 mg FAE to 115 mg mation (Biogen Idec Inc .) , and U . S . Patent Application 55 FAE , 105 mg FAE to 110 mg FAE , 105 mg FAE to 115 mg Publication No. US 2014 /0163100 , each of which is incor- FAE , 105 mg FAE to 120 mg FAE , 110 mg FAE to 115 mg porated by reference herein for such teachings. Other phar- FAE , 110 mg FAE to 120 mg FAE , 110 mg FAE to 125 mg maceutical compositions and methods for treating multiple FAE , 115 mg FAE to 120 mg FAE , 115 mg FAE to 125 mg sclerosis are described in U . S . Pat. Nos . 6 , 509, 376 ; 7 , 320 , FAE , 115 mg FAE to 130 mg FAE , 120 mg FAE to 125 mg 999 ; 7 ,619 , 001 ; 7 , 803 ,840 ; 8 ,399 ,514 ; 8 , 524 , 773 ; and 60 FAE , 120 mg FAE to 130 mg FAE , 120 mg FAE to 135 mg 8 ,759 , 393 , and International Patent Application Publication FAE , 125 mg FAE to 130 mg FAE , 125 mg FAE to 135 mg No. WO 2013 / 119677 , each of which is incorporated by FAE , 125 mg FAE to 140 mg FAE , 130 mg FAE to 135 mg reference herein for such teachings. FAE , 130 mg FAE to 140 mg FAE , 130 mg FAE to 145 mg Another embodiment described herein is a pharmaceuti - FAE , 135 mg FAE to 140 mg FAE , 135 mg FAE to 145 mg cal composition for administration to a subject with multiple 65 FAE , 135 mg FAE to 150 mg FAE , 140 mg FAE to 145 mg sclerosis or psoriasis comprising a therapeutically effective FAE , 140 mg FAE to 150 mg FAE , 140 mg FAE to 155 mg amount of one ormore fumarate esters , wherein the subject FAE , 145 mg FAE to 150 mg FAE , 145 mg FAE to 155 mg US 9 ,814 ,692 B2 67 68 FAE , 145 mg FAE to 160 mg FAE , 150 mg FAE to 155 mg FAE , 370 mg FAE to 380 mg FAE , 370 mg FAE to 385 mg FAE , 150 mg FAE to 160 mg FAE , 150 mg FAE to 165 mg FAE , 375 mg FAE to 380 mg FAE , 375 mg FAE to 385 mg FAE , 155 mg FAE to 160 mg FAE , 155 mg FAE to 165 mg FAE , 375 mg FAE to 390 mg FAE , 380 mg FAE to 385 mg FAE , 155 mg FAE to 170 mg FAE , 160 mg FAE to 165 mg FAE , 380 mg FAE to 390 mg FAE , 380 mg FAE to 395 mg FAE , 160 mg FAE to 170 mg FAE , 160 mg FAE to 175 mg 5 FAE , 385 mg FAE to 390 mg FAE , 385 mg FAE to 395 mg FAE , 165 mg FAE to 170 mg FAE , 165 mg FAE to 175 mg FAE , 385 mg FAE to 400 mg FAE , 390 mg FAE to 395 mg FAE , 165 mg FAE to 180 mg FAE , 170 mg FAE to 175 mg FAE , 390 mg FAE to 400 mg FAE , 390 mg FAE to 405 mg FAE , 170 mg FAE to 180 mg FAE , 170 mg FAE to 185 mg FAE , 395 mg FAE to 400 mg FAE , 395 mg FAE to 405 mg FAE , 175 mg FAE to 180 mg FAE , 175 mg FAE to 185 mg FAE , 395 mg FAE to 410 mg FAE , 400 mg FAE to 405 mg FAE , 175 mg FAE to 190 mg FAE , 180 mg FAE to 185 mg 10 FAE , 400 mg FAE to 410 mg FAE , 400 mg FAE to 415 mg FAE , 180 mg FAE to 190 mg FAE , 180 mg FAE to 195 mg FAE , 405 mg FAE to 410 mg FAE , 405 mg FAE to 415 mg FAE , 185 mg FAE to 190 mg FAE , 185 mg FAE to 195 mg FAE , 405 mg FAE to 420 mg FAE , 410 mg FAE to 415 mg FAE , 185 mg FAE to 200 mg FAE , 190 mg FAE to 195 mg FAE , 410 mg FAE to 420 mg FAE , 410 mg FAE to 425 mg FAE , 190 mg FAE to 200 mg333329999 FAE , 190 mg FAE to 205 mg FAE , 415 mg FAE to 420 mg FAE , 415 mg FAE to 425 mg FAE , 195 mg FAE to 200 mg FAE , 195 mg FAE to 205 mg 15 FAE , 415 mg FAE to 430 mg FAE , 420 mg FAE to 425 mg FAE , 195 mg FAE to 210 mg FAE , 200 mg FAE to 205 mg FAE , 420 mg FAE to 430 mg FAE , 420 mg FAE to 435 mg FAE, 200 mg FAE to 210 mg FAE , 200 mg FAE to 215 mg FAE , 425 mg FAE to 430 mg FAE , 425 mg FAE to 435 mg FAE , 205 mg FAE to 210 mg FAE , 205 mg FAE to 215 mg FAE , 425 mg FAE to 440 mg FAE , 430 mg FAE to 435 mg FAE , 205 mg FAE to 220 mg FAE , 210 mg FAE to 215 mg FAE , 430 mg FAE to 440 mg FAE , 430 mg FAE to 445 mg FAE , 210 mg FAE to 220 mg FAE , 210 mg FAE to 225 mg 20 FAE , 435 mg FAE to 440 mg FAE , 435 mg FAE to 445 mg FAE , 215 mg FAE to 220 mg FAE , 215 mg FAE to 225 mg FAE , 435 mg FAE to 450 mg FAE , 440 mg FAE to 445 mg FAE , 215 mg FAE to 230 mg FAE , 220 mg FAE to 225 mg FAE , 440 mg FAE to 450 mg FAE , 440 mg FAE to 455 mg FAE , 220 mg FAE to 230 mg FAE , 220 mg FAE to 235 mg FAE , 445 mg FAE to 450 mg FAE , 445 mg FAE to 455 mg FAE , 225 mg FAE to 230 mg FAE , 225 mg FAE to 235 mg FAE , 445 mg FAE to 460 mg FAE , 450 mg FAE to 455 mg FAE , 225 mg FAE to 240 mg FAE , 230 mg FAE to 235 mg 25 FAE , 450 mg FAE to 460 mg FAE , 450 mg FAE to 465 mg FAE , 230 mg FAE to 240 mg FAE , 230 mg FAE to 245 mg FAE , 455 mg FAE to 460 mg FAE , 455 mg FAE to 465 mg FAE , 235 mg FAE to 240 mg FAE , 235 mg FAE to 245 mg FAE , 455 mg FAE to 470 mg FAE , 460 mg FAE to 465 mg FAE , 235 mg FAE to 250 mg FAE , 240 mg FAE to 245 mg FAE , 460 mg FAE to 470 mg FAE , 460 mg FAE to 475 mg FAE , 240 mg FAE to 250 mg FAE , 240 mg FAE to 255 mg FAE , 465 mg FAE to 470 mg FAE , 465 mg FAE to 475 mg FAE , 245 mg FAE to 250 mg FAE9999 , 245 mg FAE to 255 mg 30 FAE , 465 mg FAE to 480 mg FAE , 470 mg FAE to 475 mg FAE , 245 mg FAE to 260 mg FAE , 250 mg FAE to 255 mg FAE , 470 mg FAE to 480 mg FAE , or 475 mg FAE to 480 FAE , 250 mg FAE to 260 mg FAE , 250 mg FAE to 265 mg mg FAE . The effective amount can be administered in one FAE , 255 mg FAE to 260 mg FAE , 255 mg FAE to 265 mg or more doses, once , twice , three , four , or more times per FAE, 255 mg FAE to 270 mg FAE , 260 mg FAE to 265 mg day . FAE , 260 ????????????????????????????????????????????????????mg FAE to 270 mg FAE , 260 mg FAE to 275 mg 35 For the treatment of autoimmune disorders, including FAE , 265 mg FAE to 270 mg FAE , 265 mg FAE to 275 mg multiple sclerosis and psoriasis , the dosage form adminis FAE, 265 mg FAE to 280 mg FAE , 270 mg FAE to 275 mg tered to the subject or subject in need thereof comprises a FAE , 270 mg FAE to 280 mg FAE , 270 mg FAE to 285 mg pharmaceutical composition comprising micronized solid FAE , 275 mg FAE to 280 mg FAE , 275 mg FAE to 285 mg particles of a fumarate ester as the only active ingredient. In FAE , 275 mg FAE to 290 mg FAE , 280 mg FAE to 285 mg 40 one embodiment, the effective amount of fumarate ester is FAE , 280 mg FAE to 290 mg FAE , 280 mg FAE to 295 mg about 340 mg to about 440 mg FAE per day and the subjects FAE, 285 mg FAE to 290 mg FAE , 285 mg FAE to 295 mg can receive the effective amount, e . g . , about 340 mg to about FAE , 285 mg FAE to 300 mg FAE , 290 mg FAE to 295 mg 440 mg FAE per day , in the form of two dosage forms FAE , 290 mg FAE to 300 mg FAE , 290 mg FAE to 305 mg comprising 85 mg to about 110 mg FAE , simultaneously FAE , 295 mg FAE to 300 mg FAE , 295 mg FAE to 305 mg 45 administered bis in die (BID ) , for a total of four capsules per FAE , 295 mg FAE to 310 mg FAE , 300 mg FAE to 305 mg day to be taken orally ( e . g . , two capsules administered ante FAE, 300 mg FAE to 310 mg FAE , 300 mg FAE to 315 mg meridiem and two capsules administered post meridiem ) . FAE , 305 mg FAE to 310 mg FAE , 305 mg FAE to 315 mg I n another embodiment, the effective amount of fumarate FAE , 305 mg FAE to 320 mg FAE , 310 mg FAE to 315 mg ester is about 380 mg to about 400 mg FAE per day and the FAE , 310 mg FAE to 320 mg FAE , 310 mg FAE to 325 mg 50 subjects can receive the effective amount, e . g ., about 380 mg FAE, 315 mg FAE to 320 mg FAE , 315 mg FAE to 325 mg to about 400 mg FAE per day, in the form of two dosage FAE , 315 mg FAE to 330 mg FAE , 320 mg FAE to 325 mg forms comprising about 95 mg to about 100 mg FAE , FAE , 320 mg FAE to 330 mg FAE , 320 mg FAE to 335 mg simultaneously administered bis in die (BID ), for a total of FAE , 325 mg FAE to 330 mg FAE , 325 mg FAE to 335 mg four capsules a day to be taken orally ( e . g . , two capsules FAE , 325 mg FAE to 340 mg FAE , 330 mg FAE to 335 mg 55 administered ante meridiem and two capsules administered FAE , 330 mg FAE to 340 mg FAE , 330 mg FAE to 345 mg post meridiem ) . In one aspect, the dosage form comprises FAE, 335 mg FAE to 340 mg FAE , 335 mg FAE to 345 mg about 95 mg FAE . In another aspect, the dosage form FAE , 335 mg FAE to 350 mg FAE , 340 mg FAE to 345 mg comprises 100 mg FAE . In one embodiment, dosing regimen FAE , 340 mg FAE to 350 mg FAE , 340 mg FAE to 355 mg comprises two 95 mg dosage forms administered BID for a FAE , 345 mg FAE to 350 mg FAE , 345 mg FAE to 355 mg 60 total of 380 mg FAE per day . In another embodiment, dosing FAE , 345 mg FAE to 360 mg FAE , 350 mg FAE to 355 mg regimen comprises two 100 mg dosage forms administered FAE , 350 mg FAE to 360 mg FAE , 350 mg FAE to 365 mg BID for a total of 400 mg FAE per day . FAE, 355 mg???????????????????????MMMMMMMMMMMMMMMMMMMMMMMMMMM FAE to 360 mg FAE , 355 mg FAE to 365 mg Without being bound by any theory , it is thought that FAE , 355 mg FAE to 370 mg FAE , 360 mg FAE to 365 mg simultaneously administering two small dosage forms, such FAE , 360 mg FAE to 370 mg FAE , 360 mg FAE to 375 mg 65 as two 95 mg FAE or 100 mg FAE soft capsule dosage forms FAE , 365 mg FAE to 370 mg FAE , 365 mg FAE to 375 mg ( e . g . , total fill weight of about 250 to about 300 mg in a 5 FAE , 365 mg FAE to 380 mg FAE , 370 mg FAE to 375 mg oval capsule) provides more rapid gastric emptying and US 9 ,814 ,692 B2 69 70 transit to the duodenum as compared to a single larger ranges. The dose is increased to the effective dose of about dosage form , such as a single 200 mg of FAE soft capsule 340 mg to about 440 mg FAE QD (e . g . , about 340 mg to dosage form ( e . g ., total fill weight of about 500 mg to about about 440 mg FAE per day ) , including all integers and 600 mg in a 12 oval capsule ). This may provide a more rapid fractions within the specified ranges. For those subjects who Tmor and also reduce Cmar because of the lower FAE dose . 5 experience GI or flushing side effects , taking FAE with food This may also reduce gastrointestinal side effects . can improve tolerability . In one aspect described herein , In another embodiment, the effective amount of fumarate FAE is administered after a meal . In another aspect ester is about 400 mg to about 420 mg FAE per day and the described herein , FAE is administered after a high - fatmeal subjects can receive the effective amount, e . g ., about 400 mg to reduce or ameliorate the one or more symptoms of to about 420 mg FAE per day, in the form of two dosage 10 flushing , abdominal pain , diarrhea , and nausea in the sub forms comprising about 180 mg to about 210 mg in the form ject. of two capsules per day , to be taken orally ( e .g . , one capsule In one embodiment, the pharmaceutical compositions administered ante meridiem and one capsules administered described herein can be administered without titration of the post meridiem ) . In one aspect, the dosage form comprises pharmaceutical composition . In one aspect, the pharmaceu 180 mg FAE . In another aspect , the dosage form comprises 15 tical compositions can be administered without titration and 190 mg FAE . In one aspect, the dosage form comprises without substantially inducing one or more side effects about 200 mg FAE . In another aspect, the dosage form including, but not limited to flushing, abdominal pain , comprises 205 mg FAE . In another aspect, the dosage form diarrhea , or nausea . comprises 210 mg FAE . In one embodiment, the pharmaceutical composition In another embodiment, the effective amount of fumarate 20 described herein does not elicit the flushing and gastroin ester is about 400 mg to about 440 mg FAE per day and the testinal side effects when the dose is about 85 mg to about subjects can receive the effective amount, e . g ., about 400 mg 110 mg FAE quater in die (CID ) or two doses simultane to about 440 mg FAE per day, in the form of two dosage ously bis in die (BID ) ( e. g ., 340 mg to about 440 mg FAE forms comprising about 200 mg to about 220 mg in the form per day ) , including all integers and fractions within the of two capsules a day , to be taken orally ( e . g . , one capsule 25 specified ranges . In another embodiment, the pharmaceuti administered ante meridiem and one capsules administered cal composition described herein does not elicit the flushing post meridiem ). In one aspect, the dosage form comprises and gastrointestinal side effects when the dose is about 170 about 200 mg FAE. In another aspect, the dosage form mg to about 220 mg FAE bis in die (BID ) ( e. g ., 340 mg to comprises 210 mg FAE . In another aspect , the dosage form about 440 mg FAE per day ) , including all integers and comprises 215 mg FAE . In another aspect, the dosage form 30 fractions within the specified ranges . In one embodiment, comprises 220 mg FAE . the pharmaceutical composition described herein does not For the treatment of autoimmune disorders , including elicit the flushing and gastrointestinal side effects when the multiple sclerosis and psoriasis, the dosage form adminis dose is about 340 mg to about 440 mg FAE quaque die ( QD ) tered to the subject or subject in need thereof comprises a ( e . g . , 340 mg to about 440 mg FAE per day ), including all pharmaceutical composition comprising micronized solid 35 integers and fractions within the specified ranges . particles of a fumarate ester as the only active ingredient or In one embodiment , the pharmaceutical composition in combination with one or more NSAIDS (e . g . , aspirin ) or described herein does not elicit flushing and gastrointestinal leukotriene receptor antagonists ( e . g . , montelukast or zaf- side effects when the effective amount is about 180 mg FAE irlukast) . In one aspect, the effective amount of fumarate quaque die (QD ) ( e . g ., 180 mg FAE per day ) . In another ester is about 340 mg to about 440 mg FAE per day and the 40 embodiment, the pharmaceutical composition described subjects can receive the effective amount, e . g . , about 85 mg herein does not elicit the flushing and gastrointestinal side to about 110 mg FAE quater in die ( CID ), in the form of four effects when the effective amount is about 170 mg to about capsules a day , to be taken orally , including all integers and 220 mg FAE quaque die (QD ) ( e . g . , 170 mg to about 220 mg fractions within the specified ranges. In one aspect, the FAE per day ) , including all integers and fractions within the effective amount of fumarate ester is about 340 mg to about 45 specified ranges . In another embodiment, the pharmaceuti 440 mg FAE per day and the subjects can receive the cal composition described herein does not elicit the flushing effective amount , e . g ., about 170 mg to about 220 mg FAE and gastrointestinal side effects when the effective amount is bis in die (BID ), in the form of two capsules a day, to be about 340 mg to about 440 mg FAE quaque die (QD ) ( e. g ., taken orally , including all integers and fractions within the 340 mg to about 440 mg FAE per day ) , including all integers specified ranges . In another aspect, the effective amount of 50 and fractions within the specified ranges . fumarate ester is about 340 mg to about 440 mg FAE per day In one embodiment described herein , without being and the subjects can receive the effective amount, e . g . , about bound to any theory , it is surprising and unexpected that the 340 mg to about 440 mg FAE quaque die ( QD ) , in the form pharmaceutical compositions described herein comprising of one capsule a day , to be taken orally , including all integers liquid dosage forms of FAE provide effective treatment of and fractions within the specified ranges. 55 multiple sclerosis at total daily dosages of about 380 mg Fumarate esters can cause flushing and gastrointestinal FAE to about 400 mg FAE when compared to a total daily (GI ) side effects in some subjects . While the side effects dosage of 480 mg dimethyl fumarate administered as TEC generally subside soon after subjects start on the treatment, FIDERA® . In one embodiment described herein , the FAE is in one aspect the starting dose is about 85 mg to about 110 DMF. In another embodiment described herein , the FAE is mg FAE BID orally for the first 7 days , including all integers 60 monomethyl fumarate . In another embodiment described and fractions within the specified range . The dose is herein , the FAE is DMF , MMF, other MMF prodrug , or a increased to the effective dose of about 170 mg to about 220 combination thereof. mg FAE BID ( e . g . , about 340 mg to about 440 mg FAE per I n another aspect, the administration of about 325 mg of day ) , including all integers and fractions within the specified non - enteric coated aspirin 30 -minutes prior to FAE dosing ranges . In another aspect, the starting dose is about 170 mg 65 can reduce the occurrence and severity of flushing . In one to about 220 mg FAE BID orally for the first 7 days, aspect , subjects who experience flushing with gastrointesti including all integers and fractions within the specified nal side effects may reduce the dose to about 100 mg to US 9 , 814 ,692 B2 71 72 about 120 mg FAE BID temporarily , including all integers microparticles of FAE in a liquid matrix . In one embodi and fractions within the specified range . Within a month , the ment, the matrix is a controlled release matrix . effective dose of about 170 mg to about 220 mg FAE BID In one embodiment, subjects having a general autoim should be resumed , including all integers and fractions mune or neurodegenerative disorder , including but not lim within the specified range . In another aspect, subjects who 5 ited to multiple sclerosis or psoriasis, are administered one experience flushing with gastrointestinal side effects may or more dosage forms comprising about 95 mg to about 100 reduce the dose to about 170 mg to about 220 mg FAE BID mg FAE , twice - daily for a total daily dose of about 190 mg temporarily , including all integers and fractions within the to about 200 mg, wherein the dosage forms comprise solid specified range. Within a month , the effective dose of about microparticles of FAE suspended in a liquid matrix . In one 10 embodiment, the matrix is a controlled release matrix . 340 mg to about 440 mg FAE QD should be resumed , In one embodiment, subjects having a general autoim including all integers and fractions within the specified mune or neurodegenerative disorder, including but not lim range . ited to multiple sclerosis or psoriasis , are simultaneously In one embodiment , a subject administered a FAE phar administered two dosage forms comprising about 95 mg to maceutical composition described herein may take one ofor 15 about 100 mg FAE , twice -daily for a total daily dose of more non - steroidal anti- inflammatory drugs (NSAID ) about 380 mg to about 400 mg, wherein the soft capsule before ( for example , about 10 minutes to an hour , e . g ., about comprises solid microparticles of FAE suspended in a liquid 30 minutes before ) taking a FAE pharmaceutical composi matrix . In one embodiment, the matrix is a controlled release tion described herein . In one embodiment, the subject matrix . administered a dosage form takes the one or more non - 20 In one embodiment, subjects having a general autoim steroidal anti- inflammatory drugs to reduce flushing. In one mune or neurodegenerative disorder , including but not lim embodiment, the one or more non -steroidal anti- inflamma ited to multiple sclerosis or psoriasis , are administered a tory drugs comprise aspirin , ibuprofen , naproxen , ketopro - dosage form containing about 200 mg FAE , twice daily for fen , celecoxib , or combinations thereof. The one or more a total daily dose of about 400 mg, wherein the dosage form non - steroidal anti - inflammatory drugs can be administered 25 comprises solid microparticles of FAE suspended in a in an amount of about 50 mg to about 500 mg before taking matrix . In one embodiment, the matrix is a controlled release the dosage form described herein . In one embodiment, a matrix . subject takes 325 mg aspirin about 30 - minutes before taking Pharmacokinetics of fumarate esters , particularly DMF, the dosage forms described herein . are described by Sheikh et al. , Clinical Therapeutics 35 ( 10 ) : In another embodiment , a subject administered a FAE 30 1582 - 1594 ( 2013 ) , which is incorporated by reference pharmaceutical composition described herein may take one herein for such teachings . After oral administration of dim or more leukotriene receptor antagonists . In another embodi- ethyl fumarate , the molecule undergoes rapid presystemic ment, a subject administered a FAE pharmaceutical compo - hydrolysis by esterases and is converted to the active sition described herein may take 10 to 20 mg of montelukast metabolite, monomethyl fumarate (MMF ). Dimethyl fumar ( Singulair® ) or zafirlukast (Accolate? ) . 35 ate is not quantifiable in plasma following oral administra In another embodiment described herein , subjects are tion . All pharmacokinetic analyses related to DMF are orally administered one or more non - steroidal anti - inflam - performed with plasma MMF concentrations. When matory drugs before taking the dosage form described herein monomethyl fumarate is orally administered , the MMF exhibit the same pharmacokinetic properties ( e . g ., Cmax and molecule concentration can be directly measured in plasma. AUC ) as subjects orally administered the dosage form 40 In one embodiment, the pharmaceutical composition described herein without administering one or more non - described herein is provided in a dosage form containing a steroidal anti - inflammatory drugs ( e . g . , aspirin , ibuprofen , total amount of about 85 mg to about 110 mg of a fumarate naproxen , ketoprofen , celecoxib , or combinations thereof) . ester, wherein subjects administered the dose exhibit a mean The NSAID can be administered about 30 -minutes before plasma monomethyl fumarate Cmor ranging from about 0 . 2 taking the dosage form described herein . 45 mg/ L to about 2 . 41 mg/ L , including all integers and fractions In one embodiment described herein , a subject is admin - within the specified ranges. In another aspect, the compo istered one or more dosage forms containing about 80 mg to sition is provided in a dosage form containing a total amount about 460 mg FAE , one or more times daily for a total daily of about 85 mg to about 110 mg of a fumarate ester , wherein dose of about 320 mg to about 460 mg, including all integers subjects administered the dose exhibit a mean plasma and fractions within the specified range . In one aspect , the 50 monomethyl fumarate Cmax ranging from about 0 . 4 mg/ L to pharmaceutical composition comprises an immediate about 2 .41 mg/ L , including all integers and fractions within release , delayed release , controlled release , or extended the specified ranges . In another aspect , the composition is release formulation of a fumarate ester. In one embodiment, provided in a dosage form containing a total amount of about the matrix is a controlled release matrix . In another embodi- 85 mg to about 110 mg of a fumarate ester, wherein subjects ment, the matrix is a delayed release matrix . In another 55 administered the dose exhibit a mean plasma monomethyl embodiment, the matrix is an extended release matrix . In fumarate Corranging from about 1 . 5 mg/ L to about 3 . 4 another aspect , the pharmaceutical composition comprises a mg/ L , including711AX all integers and fractions within the speci soft capsule . In another aspect , the pharmaceutical compo - fied ranges . In another aspect, the composition is provided in sition comprises a soft capsule comprising one or more a dosage form containing a total amount of about 85 mg to subcoatings , top coatings , enteric coatings , or combinations 60 about 110 mg of a fumarate ester, wherein subjects admin thereof. istered the dose exhibit a mean plasma monomethyl fumar In one embodiment, subjects having a general autoim - ate Cmar ranging from about 1 .03 mg/ L to about 2 . 41 mg/ L , mune or neurodegenerative disorder , including but not lim including all integers and fractions within the specified ited to multiple sclerosis or psoriasis, are administered one ranges . In another aspect , the composition is provided in a or more dosage forms comprising about 80 mg to about 110 65 dosage form containing a total amount of about 85 mg to mg FAE , twice - daily for a total daily dose of about 320 mg about 110 mg of a fumarate ester, wherein subjects admin to about 440 mg, wherein the dosage form comprises solid istered the dose exhibit a mean plasma monomethyl fumar US 9 , 814 ,692 B2 73 74 ate Cmax ranging from about 0 .4 mg/ L to about 0 . 75 mg/ L , provided in a dosage form containing a total amount of about including all integers and fractions within the specified 85 mg to about 110 mg of a fumarate ester , wherein subjects ranges . In another aspect, the composition is provided in a administered the dose form four times daily exhibit a mean dosage form containing a total amount of about 85 mg to plasma monomethyl fumarate AUCoverall ranging from about 110 mg of a fumarate ester , wherein subjects admin - 5 about 5 . 2 h ·mg / L to about 11 . 2 h ·mg / L , including all integers istered the dose exhibit a mean plasma monomethyl fumar - and fractions within the specified ranges . In another aspect , ate Cmax ranging from about 0 .76 mg/ L to about 1. 03 mg/ L , the composition is provided in a dosage form containing a including all integers and fractions within the specified total amount of about 85 mg to about 110 mg of a fumarate ranges . In another aspect , the composition is provided in a ester , wherein subjects administered the dose form four dosage form containing a total amount of about 85 mg to 10 times daily exhibit a mean plasma monomethyl fumarate about 110 mg of a fumarate ester , wherein subjects admin AUC versi at least about 1 . 0 h ·mg / L , at least 1 . 2 h ·mg / L , at istered the dose exhibit a mean plasma monomethyl fumar - least 1 . 4 h .mg / L , at least 1 . 6 h ·mg / L , at least 1 . 8 h ·mg / L , at ate Cmor ranging from about 1 . 04 mg/ L to about 1 . 75 mg/ L , least 2 . 0 h ·mg / L , at least 2 . 3 h•mg / L , at least about 2 . 6 including all integers and fractions within the specified h mg/ L , at least about 2 . 9 h ·mg / L , at least 3 . 2 h ·mg / L , at ranges . In another aspect, the composition is provided in a 15 least 3 . 5 h ·mg / L , at least 3 . 8 hómg/ L , at least 4 . 1 h ·mg / L , at dosage form containing a total amount of about 85 mg to least 4 . 4 h ·mg / L , at least 4 . 7 h ·mg / L , at least 5 . 0 h .mg / L , at about 110 mg of a fumarate ester, wherein subjects admin - least 5 . 3 h ·mg / L , at least 5 .6 h ·mg / L , at least 5 . 9 h ·mg / L , at istered the dose exhibit a mean plasma monomethyl fumar- least 6 . 2 h ·mg / L , at least 6 . 5 h mg/ L , at least 6 . 8 h ·mg / L , at ate Cmax ranging from about 1 .75 mg/ L to about 2 . 41 mg/ L , least 7 . 1 h ·mg / L , at least 7 . 4 h ·mg / L , at least 7 . 7 h ·mg / L , at including all integers and fractions within the specified 20 least 8 . 0 h ·mg / L , at least 8 . 3 h ·mg / L , at least 8 . 6 h ·mg / L , at ranges . In another aspect, the composition is provided in a least 8 . 9 h mg / L , at least 9 . 2 h ·mg / L , at least 9 . 5 h ·mg / L , at dosage form containing a total amount of about 85 mg to least 9 . 8 h ·mg / L , at least 10 . 1 h ·mg / L , at least 10 . 4 . h .mg / L , about 110 mg of a fumarate ester, wherein subjects admin - at least 10 . 7 himg/ L , at least 11. 0 h mg/ L , at least 11 . 3 istered the dose exhibit a mean plasma monomethyl fumar - h ·mg / L , at least 11 . 6 hómg/ L , at least 11. 9 h ·mg / L , at least ate Cmor of at least 0 . 4 mg / L , at least 0 . 5 mg / L , at least 0 . 6 25 12 . 2 h ·mg / L , at least 12 . 5 h ·mg / L , at least 12 . 8 h ·mg / L , at mg/ L , at least 0 . 7 mg/ L , at least 0 . 8 mg/ L , at least 0 . 9 mg/ L , least 13 . 1 hómg/ L , at least 13 . 3 h ·mg / L , at least 13 .6 h ·mg / L , at least 1 mg/ L , at least 1 . 1 mg/ L , at least 1 . 2 mg/ L , at least at least 13 . 9 hómg/ L , at least 14 . 2 h ·mg / L , at least 14 . 5 1 .3 mg/ L , at least 1 .4 mg/ L , at least 1 .5 mg /L , at least 1. 6 h ·mg / L , at least 14 .8 h ·mg / L , or at least 15 . 2 h ·mg / L . mg/ L , at least 1 . 7 mg/ L , at least 1 . 8 mg/ L , at least 1 . 9 mg/ L , In another aspect, the composition is provided in a dosage at least 2 mg/ L , at least 2 . 1 mg/ L , at least 2 . 2 mg/ L , at least 30 form containing a total amount of about 85 mg to about 110 2 . 3 mg/ L , at least 2 . 4 mg/ L , at least 2 . 5 mg/ L , at least 2 . 6 mg of a fumarate ester , wherein subjects administered the mg / L , at least 2 . 7 mg/ L , at least 2 . 8 mg/ L , at least 2 . 9 mg/ L , dose form exhibit a mean plasma monomethyl fumarate at least 3 mg/ L , at least 3 . 1 mg/ L , at least 3 . 2 mg/ L , at least AUCO - 121, ranging from about 0 . 5 h .mg / L to about 5 . 5 3 . 3 mg/ L , or at least 3 . 4 mg/ L . h ·mg / L , including all integers and fractions within the In another aspect , the composition is provided in a dosage 35 specified ranges . In another aspect , the composition is form containing a total amount of about 85 mg to about 110 provided in a dosage form containing a total amount of about mg of a fumarate ester , wherein subjects administered the 85 mg to about 110 mg of a fumarate ester, wherein subjects dose form four times daily exhibit a mean plasma monom - administered the dose form exhibit a mean plasma monom ethyl fumarate AUCoverall ranging from about 1 . 0 h .mg / L to ethyl fumarate AUC0- > 127 ranging from about 0 . 5 h ·mg / L to about 15 . 2 h ·mg / L , including all integers and fractions 40 about 2 . 5 h ·mg / L , including all integers and fractions within within the specified ranges . In another aspect , the compo - the specified ranges . In another aspect, the composition is sition is provided in a dosage form containing a total amount provided in a dosage form containing a total amount of about of about 85 mg to about 110 mg of a fumarate ester , wherein 85 mg to about 110 mg of a fumarate ester, wherein subjects subjects administered the dose form four times daily exhibit administered the dose form exhibit a mean plasma monom a mean plasma monomethyl fumarate AUCoverall ranging 45 ethyl fumarate AUCO - 12 , ranging from about 2 . 6 h ·mg / L to from about 2 . 01 hómg/ L to about 5 . 2 h ·mg / L , including all about 5 . 5 h .mg / L , including all integers and fractions within integers and fractions within the specified ranges . In another the specified ranges. In another aspect, the composition is aspect, the composition is provided in a dosage form con - provided in a dosage form containing a total amount of about taining a total amount of about 85 mg to about 110 mg of a 85 mg to about 110 mg of a fumarate ester, wherein subjects fumarate ester, wherein subjects administered the dose form 50 administered the dose form exhibit a mean plasma monom four times daily exhibit a mean plasma monomethyl fumar - ethyl fumarate AUCO - > 12h of at least about 0 . 5 h mg/ L , at ate AUCoverall ranging from about 1 . 0 h ·mg / L to about 5 . 2 least 1 . 0 h .mg / L , at least 1 . 2 h ·mg / L , at least 1. 4 h ·mg / L , at h•mg / L , including all integers and fractions within the least 1 . 6 h ·mg / L , at least 1 . 8 h ·mg / L , at least 2 . 0 h ·mg / L , at specified ranges . In another aspect, the composition is least 2 . 1 h ·mg / L , at least 2 . 2 h .mg / L , at least 2 . 3 hómg/ L , at provided in a dosage form containing a total amount of about 55 least 2 . 4 h ·mg / L , at least 2 . 5 hómg/ L , at least 2 . 6 h ·mg / L , at 85 mg to about 110 mg of a fumarate ester, wherein subjects least 2 . 7 h .mg / L , at least 2 . 8 h ·mg / L , at least 2 . 9 h .mg / L , at administered the dose form four times daily exhibit a mean least 3 h ·mg / L , at least 3 . 1 h ·mg / L , at least 3 . 2 h ·mg / L , at plasma monomethyl fumarate AUC vers ranging from least 3 . 3 h ·mg / L , at least 3 . 4 h .mg / L , at least 3 . 5 h .mg / L , at about 11. 3 h ·mg / L to about 15 .2 h ·mg / L , including all least 3 . 6 h ·mg / L , at least 3 . 7 h ·mg / L , at least 3 . 8 h .mg / L , at integers and fractions within the specified ranges. In another 60 least 3 . 9 h ·mg / L , at least 4 h ·mg / L , at least 4 . 1 h•mg/ L , at aspect , the composition is provided in a dosage form con - least 4 . 2 h ·mg / L , at least 4 . 3 h ·mg / L , at least 4 . 4 h .mg / L , at taining a total amount of about 85 mg to about 110 mg of a least 4 . 5 h ·mg / L , at least 4 . 6 h ·mg / L , at least 4 . 7 h ·mg / L , at fumarate ester, wherein subjects administered the dose form least 4 . 8 h ·mg / L , at least 4 .9 h ·mg / L , at least 5 hºmg /L , at four times daily exhibit a mean plasma monomethyl fumar - least 5 . 1 h ·mg / L , at least 5 . 2 h ·mg / L , at least 5 . 3 h ·mg / L , at ate AUCoverall ranging from about 3 . 2 h .mg / L to about 11 . 2 65 least 5 . 4 h .mg / L , or at least 5 . 5 h .mg / L . h .mg / L , including all integers and fractions within the In another aspect, the composition is provided in a dosage specified ranges . In another aspect, the composition is form containing a total amount of about 85 mg to about 110 US 9 ,814 ,692 B2 75 76 mg of a fumarate ester , wherein subjects administered the about 240 mg of a fumarate ester, wherein subjects admin dose form exhibit a mean plasma monomethyl fumarate istered the dose form exhibit a mean plasma monomethyl AUCO - s ranging from about 0 . 5 h ·mg / L to about 5 . 6 fumarate Tax of at least 1 . 6 hours , at least 1 . 8 hours , at least h ·mg / L , including all integers and fractions within the 2 hours , at least 2 . 2 hours , at least 2 . 4 hours, at least 2 . 6 specified ranges . In another aspect, the composition is 5 hours , at least 2 . 8 hours , at least 3 hours , at least 3 . 2 hours , provided in a dosage form containing a total amount of about at least 3 . 4 hours , at least 3 . 6 hours , at least 3 . 8 hours , at least 85 mg to about 110 mg of a fumarate ester , wherein subjects 4 hours, at least 4 . 2 hours , at least 4 . 4 hours , at least 4 .6 administered the dose form exhibit a mean plasma monom - hours , at least 4 . 8 hours , at least 5 hours , at least 5 . 2 hours , ethyl fumarate AUC , ranging from about 0 . 5 h ·mg / L to at least 5 .4 hours , at least 5 . 6 hours , at least 5 . 8 hours , at least about 2 . 6 h .mg / L , including all integers and fractions within 10 6 hours , at least 6 . 2 hours , at least 6 . 4 hours , at least 6 . 6 the specified ranges . In another aspect, the composition is hours , at least 6 . 8 hours , at least 7 hours , at least 7 . 2 hours , provided in a dosage form containing a total amount of about at least 7 . 4 hours , at least 7 . 6 hours, at least 7 . 8 hours, at least 85 mg to about 110 mg of a fumarate ester , wherein subjects 8 hours , at least 8 . 2 hours , or at least 8 . 4 hours . administered the dose form exhibit a mean plasma monom - In one embodiment described herein , a subject is admin ethyl fumarate AUCOs ranging from about 2 . 6 h .mg / L to 15 istered a capsule containing about 170 mg to about 220 mg about 5 . 5 h ·mg / L , including all integers and fractions within FAE , twice daily for a total daily dose of about 340 mg to the specified ranges . In another aspect, the composition is about 440 mg, including all integers and fractions within the provided in a dosage form containing a total amount of about specified range . In one aspect, the pharmaceutical compo 85 mg to about 110 mg of a fumarate ester , wherein subjects sition comprises an immediate release , delayed release , administered the dose form exhibit a mean plasma monom - 20 controlled release , or extended release formulation of a ethyl fumarate AUCO - s of at least about 0 . 5 h ·mg / L , at least fumarate ester. In another aspect, the pharmaceutical com 1 . 0 h ·mg / L , at least 1 . 2 h .mg / L , at least 1 . 4 h ·mg / L , at least position comprises a soft capsule . 1 . 6 h .mg / L , at least 1 . 8 h ·mg / L , at least 2 h ·mg / L , at least 2 . 1 In another aspect, the composition is provided in a dosage h ·mg / L , at least 2 . 2 h ·mg / L , at least 2 . 3 h ·mg / L , at least 2 . 4 form containing a total amount of about 170 mg to about 220 h ·mg / L , at least 2 .5 h ·mg / L , at least 2 . 6 h .mg / L , at least 2 . 7 25 mg of a fumarate ester , wherein subjects administered the h ·mg / L , at least 2 . 8 h ·mg / L , at least 2 . 9 h ·mg / L , at least 3 dose form exhibit a mean plasma monomethyl fumarate h ·mg / L , at least 3 . 1 h ·mg / L , at least 3 . 2 h .mg / L , at least 3 . 3 Cmax ranging from about 0 . 4 mg/ L to about 2 .41 mg/ L , h ·mg / L , at least 3 . 4 h ·mg / L , at least 3 . 5 h ·mg / L , at least 3 . 6 includingma all integers and fractions within the specified h .mg / L , at least 3 . 7 hómg/ L , at least 3 . 8 hómg/ L , at least 3 . 9 ranges . In another aspect, the composition is provided in a h ·mg / L , at least 4 h ·mg / L , at least 4 . 1 h .mg / L , at least 4 . 2 30 dosage form containing a total amount of about 170 mg to h ·mg / L , at least 4 . 3 h ·mg / L , at least 4 . 4 h ·mg / L , at least 4 . 5 about 220 mg of a fumarate ester , wherein subjects admin h ·mg / L , at least 4 . 6 h .mg / L , at least 4 . 7 h ·mg / L , at least 4 . 8 istered the dose form exhibit a mean plasma monomethyl h•mg / L , at least 4 . 9 h ·mg / L , at least 5 h ·mg / L , at least 5 . 1 fumarate Cmor ranging from about 1 . 0 mg/ L to about 3 . 4 h ·mg / L , at least 5 . 2 h .mg / L , at least 5 . 3 h ·mg / L , at least 5 . 4 mg/ L , including all integers and fractions within the speci h ·mg / L , or at least 5 . 5 h ·mg / L . 35 fied ranges . In another aspect, the composition is provided in In another aspect , the composition is provided in a dosage a dosage form containing a total amount of about 170 mg to form containing a total amount of about 85 mg to about 110 about 220 mg of a fumarate ester , wherein subjects admin mg of a fumarate ester , wherein subjects administered the istered the dose form exhibit a mean plasma monomethyl dose form exhibit a mean plasma monomethyl fumarate fumarate Cmax ranging from about 1 . 03 mg/ L to about 2 . 41

Tmaxmar ranging from about 1 . 5 hours to about 8 . 5 hours , 40 mg/ L , including all integers and fractions within the speci including all integers and fractions within the specified fied ranges . In another aspect, the composition is provided in ranges . In another aspect, the composition is provided in a a dosage form containing a total amount of about 170 mg to dosage form containing a total amount of about 85 mg to about 220 mg of a fumarate ester, wherein subjects admin about 110 mg of a fumarate ester, wherein subjects admin - istered the dose form exhibit a mean plasma monomethyl istered the dose form exhibit a mean plasma monomethyl 45 fumarate Cmor ranging from about 0 . 4 mg/ L to about 0 . 75 fumarate Tmax ranging from about 1 . 6 hours to about 2 .5 mg/ L , including all integers and fractions within the speci hours , including all integers and fractions within the speci f ied ranges . In another aspect, the composition is provided in fied ranges . In another aspect, the composition is provided in a dosage form containing a total amount of about 170 mg to a dosage form containing a total amount of about 85 mg to about 220 mg of a fumarate ester, wherein subjects admin about 110 mg of a fumarate ester, wherein subjects admin - 50 istered the dose form exhibit a mean plasma monomethyl istered the dose form exhibit a mean plasma monomethyl fumarate Cmax ranging from about 0 .76 mg/ L to about 1 . 03 fumarate Tmax ranging from about 2 .6 hours to about 5 mg/ L , including all integers and fractions within the speci hours , including all integers and fractions within the speci - fied ranges. In another aspect , the composition is provided in fied ranges . In another aspect , the composition is provided in a dosage form containing a total amount of about 170 mg to a dosage form containing a total amount of about 85 mg to 55 about 220 mg of a fumarate ester , wherein subjects admin about 110 mg of a fumarate ester , wherein subjects admin - istered the dose form exhibit a mean plasma monomethyl istered the dose form exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1 .04 mg/ L to about 1 . 75 fumarate Tmor ranging from about 5 . 1 hours to about 7 . 5 mg/ L , including all integers and fractions within the speci hours, including all integers and fractions within the speci f ied ranges . In another aspect, the composition is provided in fied ranges . In another aspect, the composition is provided in 60 a dosage form containing a total amount of about 170 mg to a dosage form containing a total amount of about 85 mg to about 220 mg of a fumarate ester, wherein subjects admin about 110 mg of a fumarate ester, wherein subjects admin - istered the dose form exhibit a mean plasma monomethyl istered the dose form exhibit a mean plasma monomethyl fumarate Cmax ranging from about 1 .75 mg/ L to about 2 .41 fumarate Tmax ranging from about 7 . 6 hours to about 8 .5 mg/ L , including all integers and fractions within the speci hours , including all integers and fractions within the speci- 65 fied ranges . In another aspect, the composition is provided in fied ranges. In another aspect , the composition is provided in a dosage form containing a total amount of about 170 mg to a dosage form containing a total amount of about 240 mg to about 220 mg of a fumarate ester, wherein subjects admin US 9 ,814 ,692 B2 78 istered the dose form exhibit a mean plasma monomethyl In another aspect, the composition is provided in a dosage fumarate Cmar of at least 0 .4 mg/ L , at least 0 .5 mg/ L , at least form containing a total amount of about 170 mg to about 220 0 .6 mg/ L , at least 0 .7 mg/ L , at least 0 . 8 mg/ L , at least 0 . 9 mg of a fumarate ester , wherein subjects administered the mg/ L , at least 1 mg/ L , at least 1 . 1 mg/ L , at least 1 . 2 mg/ L , dose form exhibit a mean plasma monomethyl fumarate at least 1. 3 mg/ L , at least 1. 4 mg/ L , at least 1 .5 mg/ L , at least 5 AUCo -> 12h ranging from about 1. 0 h ·mg /L to about 5 . 5 1 . 6 mg/ L , at least 1 . 7 mg/ L , at least 1 . 8 mg/ L , at least 1 . 9 h ·mg / L , including all integers and fractions within the mg/ L , at least 2 mg/ L , at least 2 . 1 mg/ L , at least 2. 2 mg/ L , specified ranges. In another aspect, the composition is at least 2 . 3 mg /L , at least 2 .4 mg/ L , at least 2 . 5 mg/ L , at least provided in a dosage form containing a total amount of about 2 .6 mg/ L , at least 2 .7 mg/ L , at least 2 .8 mg /L , at least 2 .9 170 mg to about 220 mg of a fumarate ester , wherein mg/ L , at least 3 mg/ L . at least 3 . 1 mg/ L . at least 3 . 2 mg/ L . 10 subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCO - 12h ranging from about 1 . 0 at least 3 . 3 mg/ L , or at least 3 . 4 mg/ L . h ·mg / L to about 2 . 5 h ·mg / L , including all integers and In another aspect , the composition is provided in a dosage fractions within the specified ranges . In another aspect, the form containing a total amount of about 170 mg to about 220 composition is provided in a dosage form containing a total mg of a fumarate ester , wherein subjects administeredinistered thethe 15 amount of about 170 mg to about 220 mg of a fumarate ester , dose form twice -daily exhibit a mean plasma monomethyl wherein subjects administered the dose form exhibit a mean fumarate AUCoverall ranging from about 1 . 0 h ·mg / L to about plasma monomethyl fumarate AUC - 12 ranging from 15 . 2 h ·mg / L , including all integers and fractions within the about 2 .6 h ·mg / L to about 5 . 5 h ·mg / L , including all integers specified ranges. In another aspect, the composition is and fractions within the specified ranges . In another aspect, provided in a dosage form containing a total amount of about 20 the composition is provided in a dosage form containing a 170 mg to about 220 mg of a fumarate ester , wherein total amount of about 170 mg to about 220 mg of a fumarate subjects administered the dose form twice - daily exhibit a ester , wherein subjects administered the dose form exhibit a mean plasma monomethyl fumarate AUCoverall ranging mean plasma monomethyl fumarate AUC . -- > 12h of at least from about 2 .01 hômg/ L to about 5 . 2 h ·mg / L , including all about 1 . 0 h ·mg / L , at least 1 . 2 h ·mg / L , at least 1 . 4 h .mg / L , at integers and fractions within the specified ranges . In another 25 least 1 . 6 h .mg / L , at least 1 . 8 h ·mg / L , at least 2 . 0 h ·mg / L , at aspect , the composition is provided in a dosage form con - least 2 . 1 h ·mg / L , at least 2 . 2 h ·mg / L , at least 2 . 3 h .mg / L , at taining a total amount of about 170 mg to about 220 mg of least 2 . 4 h .mg / L , at least 2 . 5 h ·mg / L , at least 2 .6 h ·mg / L , at a fumarate ester , wherein subjects administered the dose least 2 . 7 h ·mg / L , at least 2 . 8 h ·mg / L , at least 2 . 9 h .mg / L , at form twice - daily exhibit a mean plasma monomethyl fumar - least 3 hómg/ L , at least 3 . 1 h .mg / L , at least 3 . 2 h .mg / L , at ate AUCoverall ranging from about 1 . 0 h ·mg / L to about 5 . 2 30 least 3 . 3 h ·mg / L , at least 3 .4 h .mg / L , at least 3 . 5 h ·mg / L , at h ·mg / L , including all integers and fractions within the least 3 . 6 h ·mg / L , at least 3 . 7 h ·mg / L , at least 3 . 8 h .mg / L , at specified ranges. In another aspect, the composition is least 3 . 9 h ·mg / L , at least 4 h .mg / L , at least 4 . 1 h .mg / L , at provided in a dosage form containing a total amount of about least 4 . 2 h ·mg / L , at least 4 . 3 hómg/ L , at least 4 . 4 h•mg / L , at 170 mg to about 220 mg of a fumarate ester, wherein least 4 . 5 h ·mg / L , at least 4 .6 h .mg / L , at least 4 . 7 h ·mg / L , at subjects administered the dose form twice - daily exhibit a 35 least 4 . 8 h ·mg / L , at least 4 . 9 h•mg/ L , at least 5 hómg/ L , at mean plasma monomethyl fumarate AUCoverall ranging least 5 . 1 h ·mg / L , at least 5 . 2 h ·mg / L , at least 5 . 3 hómg / L , at from about 11. 3 h ·mg /L to about 15 . 2 h .mg / L , including all least 5 . 4 h ·mg / L , or at least 5 .5 h .mg / L integers and fractions within the specified ranges . In another In another aspect, the composition is provided in a dosage aspect , the composition is provided in a dosage form con - form containing a total amount of about 170 mg to about 220 taining a total amount of about 170 mg to about 220 mg of 40 mg of a fumarate ester, wherein subjects administered the a fumarate ester , wherein subjects administered the dose dose form exhibit a mean plasma monomethyl fumarate form twice - daily exhibit a mean plasmamonomethyl fumar - AUCO - s ranging from about 1 . 0 h .mg / L to about 5 .6 ate AUCoverall ranging from about 4 . 8 h ·mg / L to about 11. 2 h ·mg / L , including all integers and fractions within the h ·mg / L , including all integers and fractions within the specified ranges . In another aspect, the composition is specified ranges . In another aspect, the composition is 45 provided in a dosage form containing a total amount of about provided in a dosage form containing a total amount of about 170 mg to about 220 mg of a fumarate ester, wherein 170 mg to about 220 mg of a fumarate ester, wherein subjects administered the dose form exhibit a mean plasma subjects administered the dose form twice -daily exhibit a monomethyl fumarate AUC . - - . ranging from about 1 . 0 mean plasma monomethyl fumarate AUCuern , at least about himg/ L to about 2 . 5 h ·mg / L , including all integers and 1 .0 h .mg / L , at least 1. 2 h ·mg / L , at least 1overall .4 h ·mg / L , at least 50 fractions within the specified ranges . In another aspect, the 1 . 6 h ·mg / L , at least 1 . 8 h ·mg / L , at least 2 . 0 h ·mg / L , at least composition is provided in a dosage form containing a total 2 .3 h ·mg / L , at least about 2 . 6 hómg/ L , at least about 2 . 9 amount of about 170 mg to about 220 mg of a fumarate ester , h ·mg / L , at least 3 . 2 h ·mg / L , at least 3 . 5 h ·mg / L , at least 3 . 8 wherein subjects administered the dose form exhibit a mean h ·mg / L , at least 4 . 1 h ·mg /L , at least 4 . 4 h ·mg / L , at least 4 . 7 plasma monomethyl fumarate AUCO - , ranging from about h ·mg / L , at least 5 .0 h ·mg / L , at least 5 . 3 h .mg / L , at least 5 . 6 55 2 . 6 h ·mg / L to about 5 . 5 h .mg / L , including all integers and h ·mg / L , at least 5 . 9 h ·mg / L , at least 6 . 2 h ·mg / L , at least 6 . 5 fractions within the specified ranges . In another aspect, the h ·mg / L , at least 6 . 8 h ·mg / L , at least 7 . 1 h ·mg / L , at least 7 . 4 composition is provided in a dosage form containing a total h ·mg / L , at least 7 . 7 h ·mg / L , at least 8 . 0 h ·mg / L , at least 8 . 3 amount of about 170 mg to about 220 mg of a fumarate ester , h ·mg / L , at least 8 . 6 h ·mg / L , at least 8 . 9 h ·mg / L , at least 9 . 2 wherein subjects administered the dose form exhibit a mean h ·mg / L , at least 9 . 5 h .mg / L , at least 9 . 8 h ·mg / L , at least 10 . 1 60 plasma monomethyl fumarate AUCO - s of at least about 1 . 0 h ·mg / L , at least 10 . 4 . h ·mg / L , at least 10 . 7 h ·mg / L , at least h ·mg / L , at least 1 . 2 h ·mg / L , at least 1 . 4 h ·mg / L , at least 1 . 6 11 . 0 h ·mg / L , at least 11 . 3 h ·mg / L , at least 11 . 6 h ·mg / L , at h ·mg / L , at least 1 . 8 h ·mg / L , at least 2 h ·mg / L , at least 2 . 1 least 11. 9 h mg· / L , at least 12 . 2 h ·mg / L , at least 12 . 5 h ·mg / L , h ·mg / L , at least 2 . 2 hómg/ L , at least 2 . 3 h .mg / L , at least 2 . 4 at least 12 . 8 h ·mg / L , at least 13 . 1 h ·mg / L , at least 13 .3 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 13 .6 h ·mg / L , at least 13 . 9 h .mg / L , at least 65 h .mg / L , at least 2 . 8 h .mg / L , at least 2 . 9 h ·mg / L , at least 3 14 . 2 h ·mg / L , at least 14 . 5 h ·mg / L , at least 14 . 8 h ·mg / L , or h ·mg / L , at least 3 . 1 h mg/ L , at least 3 . 2 h .mg / L , at least 3 . 3 at least 15 . 2 h ·mg / L . h ·mg / L , at least 3. 4 h .mg /L , at least 3 . 5 h .mg / L , at least 3 .6 US 9 ,814 ,692 B2 79 80 h ·mg / L , at least 3 .7 h ·mg / L , at least 3 .8 h ·mg / L , at least 3 . 9 aspect, the composition is provided in a dosage form con h ·mg / L , at least 4 h ·mg / L , at least 4 . 1 h ·mg / L , at least 4 . 2 taining a total amount of about 340 mg to about 440 mg of h ·mg / L , at least 4 . 3 h ·mg / L , at least 4 . 4 h ·mg / L , at least 4 . 5 a fumarate ester , wherein subjects administered the dose h ·mg / L , at least 4 . 6 h ·mg / L , at least 4 . 7 h ·mg / L , at least 4 . 8 form once daily exhibit a mean plasma monomethyl fumar h ·mg / L , at least 4 . 9 h•mg / L , at least 5 h ·mg / L , at least 5 . 1 5 ate Cmor ranging from about 1 . 5 mg/ L to about 5 . 2 mg/ L , h ·mg / L , at least 5 . 2 hómg/ L , at least 5 . 3 h .mg / L , at least 5 . 4 including all integers and fractions within the specified h ·mg / L , at least 5 . 5 h ·mg / L , or at least 5 . 6 h ·mg / L . ranges. In another aspect , the composition is provided in a In another aspect, the composition is provided in a dosage dosage form containing a total amount of about 340 mg to form containing a total amount of about 170 mg to about 220 about 440 mg of a fumarate ester, wherein subjects admin mg of a fumarate ester , wherein subjects administered the 10 istered the dose form once daily exhibit a mean plasma dose form exhibit a mean plasma monomethyl fumarate monomethyl fumarate Cmax ranging from about 0 .4 mg/ L to Tmax ranging from about 1. 5 hours to about 8 .5 hours , about 0 .75 mg/ L , including all integers and fractions within including all integers and fractions within the specified the specified ranges . In another aspect, the composition is ranges . In another aspect , the composition is provided in a provided in a dosage form containing a total amount of about dosage form containing a total amount of about 170 mg to 15 340 mg to about 440 mg of a fumarate ester , wherein about 220 mg of a fumarate ester, wherein subjects admin subjects administered the dose form once daily exhibit a istered the dose form exhibit a mean plasma monomethyl mean plasma monomethyl fumarate Cmax71 ranging from fumarate Tmax ranging from about 1. 6 hours to about 2 .5 about 0 .76 mg /L to about 1. 03 mg/ L , including all integers hours, including all integers and fractions within the speci- and fractions within the specified ranges . In another aspect , fied ranges . In another aspect , the composition is provided in 20 the composition is provided in a dosage form containing a a dosage form containing a total amount of about 170 mg to total amount of about 340 mg to about 440 mg of a fumarate about 220 mg of a fumarate ester, wherein subjects admin ester, wherein subjects administered the dose form once istered the dose form exhibit a mean plasma monomethyl daily exhibit a mean plasma monomethyl fumarate Cmax fumarate Tmax ranging from about 2 .6 hours to about 5 ranging from about 1 .04 mg/ L to about 1 . 75 mg/ L , including hours , including all integers and fractions within the speci - 25 all integers and fractions within the specified ranges . In fied ranges. In another aspect , the composition is provided in another aspect, the composition is provided in a dosage form a dosage form containing a total amount of about 170 mg to containing a total amount of about 340 mg to about 440 mg about 220 mg of a fumarate ester , wherein subjects admin - of a fumarate ester, wherein subjects administered the dose istered the dose form exhibit a mean plasma monomethyl form once daily exhibit a mean plasma monomethyl fumar fumarate Tor ranging from about 5 . 1 hours to about 7 . 5 30 ate Cmor ranging from about 1 . 75 mg/ L to about 2 .41 mg/ L , hours, including all integers and fractions within the speci- including all integers and fractions within the specified fied ranges . In another aspect , the composition is provided in ranges . In another aspect , the composition is provided in a a dosage form containing a total amount of about 170 mg to dosage form containing a total amount of about 340 mg to about 220 mg of a fumarate ester, wherein subjects admin about 440 mg of a fumarate ester, wherein subjects admin istered the dose form exhibit a mean plasma monomethyl 35 istered the dose form once daily exhibit a mean plasma fumarate Tmor ranging from about 7 . 6 hours to about 8 . 5 monomethyl fumarate Cmor ranging from about 2 .42 mg / L to hours, including all integers and fractions within the speci- about 3 . 5 mg/ L , including all integers and fractions within fied ranges . In one aspect, the composition is provided in a the specified ranges . In another aspect, the composition is dosage form containing a total amount of about 170 mg to provided in a dosage form containing a total amount of about about 220 mg of a fumarate ester, wherein subjects admin - 40 340 mg to about 440 mg of a fumarate ester , wherein istered the dose form exhibit a mean plasma monomethyl subjects administered the dose form once daily exhibit a fumarate Tmar of at least 1 . 6 hours , at least 1 . 8 hours , at least mean plasma monomethyl fumarate Cmor ranging from 2 hours , at least 2 . 2 hours, at least 2 . 4 hours, at least 2 . 6 about 3 .6 mg/ L to about 5 . 2 mg/ L , including all integers and hours , at least 2 . 8 hours, at least 3 hours , at least 3 . 2 hours , fractions within the specified ranges . In another aspect, the at least 3 . 4 hours, at least 3 . 6 hours , at least 3 . 8 hours , at least 45 composition is provided in a dosage form containing a total 4 hours , at least 4 . 2 hours, at least 4 . 4 hours , at least 4 . 6 amount of about 340 mg to about 440 mg of a fumarate ester , hours , at least 4 . 8 hours , at least 5 hours , at least 5 . 2 hours, wherein subjects administered the dose form once daily at least 5 . 4 hours , at least 5 . 6 hours, at least 5 . 8 hours , at least exhibit a mean plasma monomethyl fumarate Cmar of at least 6 hours , at least 6 . 2 hours, at least 6 . 4 hours , at least 6 . 6 about 1 . 0 mg / L , at least 1 . 1 mg/ L , at least 1 . 2 mg/ L , at least hours , at least 6 . 8 hours , at least 7 hours , at least 7 . 2 hours , 50 1 . 3 mg/ L , at least 1 . 4 mg/ L , at least 1 . 5 mg/ L , at least 1 . 6 at least 7 . 4 hours, at least 7 .6 hours , at least 7 . 8 hours , at least mg/ L , at least 1 . 7 mg/ L , at least 1 . 8 mg/ L , at least 1 . 9 mg/ L , 8 hours , at least 8 . 2 hours , or at least 8 . 4 hours . at least 2 . 0 mg/ L , at least 2 . 1 mg/ L , at least 2 . 2 mg/ L , at least In one embodiment described herein , a subject is admin - 2 . 3 mg/ L , at least 2 . 4 mg / L , at least 2 . 5 mg/ L , at least 2 . 6 istered a capsule containing about 340 mg to about 440 mg mg/ L , at least 2 . 7 mg/ L , at least 2 . 8 mg/ L , at least 2 . 9 mg/ L , FAE , once daily for a total daily dose of about 340 mg to 55 at least 3 . 0 mg /L , at least 3 . 1 mg/ L , at least 3 . 2 mg / L , at least about 440 mg, including all integers and fractions within the 3 . 3 mg/ L , at least 3 . 4 mg/ L , at least 3 . 5 mg/ L , at least 3 .6 specified ranges. In one aspect, the pharmaceutical compo - mg/ L , at least 3 .7 mg/ L , at least 3 . 8 mg/ L , at least 3. 9 mg/ L , sition comprises an immediate release , delayed release , at least 4 . 0 mg/ L , at least 4 . 1 mg/ L , at least 4 . 2 mg/ L , at least controlled release , or extended release formulation of a 4 . 3 mg/ L , at least 4 . 4 mg/ L , at least 4 . 5 mg/ L , at least 4 .6 fumarate ester . In another aspect, the pharmaceutical com - 60 mg/ L , at least 4 . 7 mg/ L , at least 4 . 8 mg/ L , at least 4 . 9 mg/ L , position comprises a soft capsule . In another aspect, the at least 5 . 0 mg/ L , or at least 5 . 1 mg/ L composition is provided in a dosage form containing a total In another aspect, the composition is provided in a dosage amount of about 340 mg to about 440mg of a fumarate ester, form containing a total amount of about 340 mg to about 440 wherein subjects administered the dose form once daily m g of a fumarate ester, wherein subjects administered the exhibit a mean plasma monomethyl fumarate Cmax ranging 65 dose form once daily exhibit a mean plasma monomethyl from about 0 . 4 mg/ L to about 5 . 2 mg /L , including all fumarate AUC0 - 12h ranging from about 1 . 0 h ·mg / L to about integers and fractions within the specified ranges. In another 15 .5 h ·mg /L , including all integers and fractions within the US 9 ,814 ,692 B2 81 82 specified ranges. In another aspect, the composition is and fractions within the specified ranges . In another aspect , provided in a dosage form containing a total amountof about the composition is provided in a dosage form containing a 340 mg to about 440 mg of a fumarate ester , wherein total amount of about 340 mg to about 440 mg of a fumarate subjects administered the dose form once daily exhibit a ester, wherein subjects administered the dose form once mean plasma monomethyl fumarate AUCO - 12h ranging 5 daily exhibit a mean plasma monomethyl fumarate AUCOD - > 00 from about 1 . 0 h .mg / L to about 2 . 5 h .mg / L , including all ranging from about 2 . 6 hómg/ L to about 5 . 5 hómg/ L , includ integers and fractions within the specified ranges . In another ing all integers and fractions within the specified ranges . In aspect , the composition is provided in a dosage form con another aspect, the composition is provided in a dosage form taining a total amount of about 340 mg to about 440 mg of containing a total amount of about 340 mg to about 440 mg a fumarate ester, wherein subjects administered the dose 10 of a fumarate ester, wherein subjects administered the dose form once daily exhibit a mean plasma monomethyl fumar - form once daily exhibit a mean plasma monomethyl fumar ate AUC . -- 12h ranging from about 2 .6 h ·mg / L to about 5 . 5 ate AUC . -- . ranging from about 5 .6 h ·mg / L to about 7 .5 h ·mg / L , including all integers and fractions within the h mg/ L , including all integers and fractions within the specified ranges. In another aspect, the composition is specified ranges. In another aspect, the composition is provided in a dosage form containing a total amount of about 15 provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester, wherein 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCO - 124 ranging mean plasma monomethyl fumarate AUCO - > ranging from from about 5 .6 h ·mg / L to about 7 .5 hómg/ L , including all about 7 . 6 h ·mg / L to about 11 . 5 h ·mg / L , including all integers integers and fractions within the specified ranges . In another 20 and fractions within the specified ranges . In another aspect , aspect , the composition is provided in a dosage form con - the composition is provided in a dosage form containing a taining a total amount of about 340 mg to about 440 mg of total amount of about 340 mg to about 440 mg of a fumarate a fumarate ester, wherein subjects administered the dose ester , wherein subjects administered the dose form once form once daily exhibit a mean plasma monomethyl fumar - daily exhibit a mean plasma monomethyl fumarate AUCO - > ate AUC0 - 12 , ranging from about 7 . 6 hómg / L to about 10 . 5 25 ranging from about 10 . 5 h ·mg / L to about 15 . 5 h .mg / L , h ·mg /L , including all integers and fractions within the including all integers and fractions within the specified specified ranges . In another aspect , the composition is ranges. In another aspect , the composition is provided in a provided in a dosage form containing a total amount of about dosage form containing a total amount of about 340 mg to 340 mg to about 440 mg of a fumarate ester, wherein about 440 mg of a fumarate ester , wherein subjects admin subjects administered the dose form once daily exhibit a 30 istered the dose form once daily exhibit a mean plasma mean plasma monomethyl fumarate AUC0 - 12h ranging monomethyl fumarate AUCO - s of at least about 1 . 0 h ·mg / L , from about 10 . 5 h .mg /L to about 15 . 5 h ·mg / L , including all at least 1 . 2 h .mg / L , at least 1 . 4 h .mg / L , at least 1 .6 h .mg / L , integers and fractions within the specified ranges . In another at least 1 . 8 h .mg / L , at least 2 . 0 h .mg / L , at least 2 . 3 h :mg / L , aspect , the composition is provided in a dosage form con - at least 2 . 6 h ·mg / L , at least 2 . 9 h ·mg / L , at least 3 . 2 h ·mg / L , taining a total amount of about 340 mg to about 440 mg of 35 at least 3 . 5 h :mg / L , at least 3 . 8 h•mg/ L , at least 4 . 1 h .mg / L , a fumarate ester, wherein subjects administered the dose at least 4 . 4 h .mg / L , at least 4 . 7 h ·mg / L , at least 5 h ·mg / L , at form once daily exhibit a mean plasma monomethyl fumar - least 5 . 3 hómg/ L , at least 5 . 6 hómg / L , at least 5 . 9 h ·mg / L , at ate AUC . -> 12h of at least about 1 . 0 h ·mg / L , at least 1 . 2 least 6 . 2 h ·mg / L , at least 6 . 5 h ·mg / L , at least 6 . 8 h ·mg / L , at h ·mg / L , at least 1 . 4 h .mg / L , at least 1 . 6 hómg/ L , at least 1 . 8 least 7 . 1 h .mg / L , at least 7 . 4 h .mg / L , at least 7 . 7 h .mg / L , at h ·mg / L , at least 2 . 0 h ·mg / L , at least 2 . 3 h ·mg / L , at least 2 . 6 40 least 8 . 0 h ·mg / L , at least 8 . 3 hómg/ L , at least 8 . 6 h ·mg / L , at h ·mg / L , at least 2 . 9 hómg/ L , at least 3 . 2 h .mg / L , at least 3 . 5 least 8 . 9 hómg/ L , at least 9 . 2 h .mg / L , at least 9 . 5 h .mg / L , at h ·mg / L , at least 3 . 8 h ·mg / L , at least 4 . 1 h ·mg / L , at least 4 . 4 least 9 . 8 h ·mg / L , at least 10 . 1 h ·mg / L , at least 10 . 4 h .mg / L , h ·mg / L , at least 4 . 7 h ·mg / L , at least 5 h ·mg / L , at least 5 . 3 at least 10 . 7 h ·mg / L , at least 11. 0 h .mg / L , at least 11 . 3 h ·mg / L , at least 5 . 6 h ·mg / L , at least 5 . 9 h ·mg / L , at least 6 . 2 hómg/ L , at least 11 . 6 h ·mg / L , at least 11 . 9 h ·mg / L , at least h ·mg / L , at least 6 .5 h ·mg / L , at least 6 . 8 h .mg / L , at least 7 . 1 45 12 . 2 h ·mg / L , at least 12 . 5 h ·mg / L , at least 12 . 8 h ·mg / L , at h ·mg / L , at least 7 . 4 h .mg / L , at least 7 . 7 h .mg / L , at least 8 . 0 least 13 . 1 h .mg / L , at least 13 . 4 h .mg / L , at least 13 . 7 h ·mg / L , h ·mg / L , at least 8 . 3 h ·mg / L , at least 8 . 6 h ·mg / L , at least 8 . 9 at least 14 h ·mg / L , at least 14 . 3 h .mg / L , at least 14 .6 h ·mg / L , h .mg / L , at least 9 . 2 h .mg / L , at least 9 . 5 h ·mg / L , at least 9 . 8 at least 14 . 9 h ·mg / L , at least 15 . 2 h ·mg / L , or at least 15 . 5 h ·mg / L , at least 10 . 1 h .mg / L , at least 10 . 4 h ·mg / L , at least h ·mg / L . 10 . 7 h ·mg / L , at least 11 . 0 h ·mg / L , at least 11 . 3 h ·mg / L , at 50 In another aspect , the composition is provided in a dosage least 11 . 6 h .mg / L , at least 11 . 9 h .mg / L , at least 12 . 2 hómg/ L , form containing a total amount of about 340 mg to about 440 at least 12 . 5 h ·mg / L , at least 12 . 8 h ·mg / L , at least 13 . 1 mg of a fumarate ester, wherein subjects administered the h ·mg / L , at least 13 . 4 h .mg / L , at least 13 . 7 h ·mg / L , at least 14 dose form once daily exhibit a mean plasma monomethyl h ·mg / L , at least 14 . 3 h ·mg / L , at least 14 . 6 h .mg / L , at least fumarate Tmox ranging from about 1 .5 hours to about 10 . 5 14 .9 h ·mg / L , at least 15 . 2 h .mg / L , or at least 15 .5 h ·mg / L . 55 hours including all integers and fractions within the speci In another aspect, the composition is provided in a dosage fied ranges . In another aspect, the composition is provided in form containing a total amount of about 340 mg to about 440 a dosage form containing a total amount of about 340 mg to mg of a fumarate ester , wherein subjects administered the about 440 mg of a fumarate ester , wherein subjects admin dose form once daily exhibit a mean plasma monomethyl istered the dose form once daily exhibit a mean plasma fumarate AUCO - s ranging from about 1 . 0 h ·mg / L to about 60 monomethyl fumarate Tax ranging from about 1 .6 hours to 15 . 5 h ·mg / L , including all integers and fractions within the about 2 . 5 hours , including all integers and fractions within specified ranges . In another aspect , the composition is the specified ranges. In another aspect, the composition is provided in a dosage form containing a total amount of about provided in a dosage form containing a total amount of about 340 mg to about 440 mg of a fumarate ester , wherein 340 mg to about 440 mg of a fumarate ester, wherein subjects administered the dose form once daily exhibit a 65 subjects administered the dose form once daily exhibit a mean plasma monomethyl fumarate AUCO( - s> 00 ranging from mean plasma monomethyl fumarate Tmax ranging from about 1 . 5 h .mg / L to about 2 . 5 h ·mg / L , including all integers about 2 . 6 hours to about 5 hours , includingmax all integers and US 9 ,814 ,692 B2 83 84 fractions within the specified ranges. In another aspect , the about 330 min , about 50 % after about 360 min , is about 50 % composition is provided in a dosage form containing a total after about 390 min , about 50 % after about 420 min , about amount of about 340 mg to about 440mg of a fumarate ester, 50 % after about 480 min , about 50 % after about 540 min , wherein subjects administered the dose form once daily about 50 % after about 600 min , about 50 % after about 660 exhibit a mean plasmamonomethyl fumarate Tmax ranging 5 min , about 50 % after about 720 min , about 50 % after about from about 5 . 1 hours to about 7 . 5 hours , including all 780 min , about 50 % after about 840 min , about 50 % after integers and fractions within the specified ranges . In another about 900 min , about 50 % after about 960 min , or about aspect, the composition is provided in a dosage form con 50 % after 1080 min . In another aspect , the in vitro disso taining a total amount of about 340 mg to about 440 mg of a fumarate ester , wherein subjects administered the dose 105lution rate at pH 6 . 8 is about 50 % after about 0 .5 hour, about form once daily exhibit a mean plasma monomethyl fumar 50 % after about 1 hour, about 50 % after about 2 hours, about ate Tmax ranging from about 7 .6 hours to about 8 . 5 hours , 50 % after about 3 hours , about 50 % after about 4 hours , including all integers and fractions within the specified about 50 % after about 5 hours , about 50 % after about 6 ranges. In another aspect, the composition is provided in a hours , about 50 % after about 7 hours , about 50 % after about dosage form containing a total amount of about 340 mg to 15 on8 hours , about 50 % after about 9 hours , about 50 % after about 440 mg of a fumarate ester, wherein subjects admin about 10 hours, about 50 % after about 11 hours , about 50 % istered the dose form once daily exhibit a mean plasma after about 12 hours , about 30 % after about 13 hours, about monomethyl fumarateT ranging from about 8 .6 hours to 50 % after about 14 hours , about 50 % after about 15 hours , about 10 .6 hours , including all integers and fractions within about 50 % after about 16 hours , about 50 % after about 17 the specified ranges. In another aspect , the composition is 20 hours , or about 50 % after about 18 hours . In one aspect, the provided in a dosage form containing a total amountof about in vitro dissolution rate at pH 6 . 8 is about 50 % after about 340 mg to about 440 mg of a fumarate ester, wherein 10 minutes . In another aspect , the in vitro dissolution rate at subjects administered the dose form once daily exhibit a pH 6 . 8 is about 50 % after about 20 minutes . In another mean plasma monomethyl fumarate TmorMAX of at least 1 .6 aspect, the in vitro dissolution rate at pH 6 . 8 is about 50 % hours, at least 1 . 8 hours , at least 2 hours , at least 2 . 2 hours, 25 after about 45 minutes . In another aspect , the in vitro at least 2 . 4 hours , at least 2 . 6 hours , at least 2 . 8 hours , at least dissolution rate at pH 6 . 8 is about 50 % after about 60 3 hours , at least 3 . 2 hours, at least 3 . 4 hours, at least 3 . 6 minutes. In one aspect , the in vitro dissolution rate at pH 6 . 8 hours, at least 3 .8 hours , at least 4 hours, at least 4 . 2 hours, is about 50 % after about 120 minutes. In another aspect, the at least 4 . 4 hours , at least 4 . 6 hours , at least 4 . 8 hours , at least in vitro dissolution rate at pH 6 . 8 is about 50 % after about 5 hours , at least 5 . 2 hours , at least 5 . 4 hours , at least 5 . 6 30 180 minutes . In another aspect, the in vitro dissolution rate hours , at least 5 . 8 hours , at least 6 hours , at least 6 . 2 hours, at pH 6 . 8 is about 50 % after about 240 minutes . In one at least 6 . 4 hours, at least 6 . 6 hours , at least 6 . 8 hours, at least aspect , the in vitro dissolution rate at pH 6 . 8 is about 50 % 7 hours , at least 7 . 2 hours , at least 7 . 4 hours , at least 7 . 6 after about 480 minutes . hours , at least 7 . 8 hours , at least 8 hours , at least 8 . 2 hours , Another embodiment described herein is a method for at least 8 . 4 hours, at least 8 . 6 hours , at least 8 . 8 hours , at least 35 manufacturing an oral pharmaceutical composition compris 9 .0 hours, at least 9 .2 hours, at least 9. 4 hours , at least 9. 6 ing the steps of: hours, at least 9 . 8 hours, at least 10 hours, at least 10 . 2 hours, ( a ) introducing mono - and diglycerides into a 200 L at least 10 . 4 hours, or at least 10 . 6 hours. mixing vessel , adding polyvinylpyrrolidone , and mix Another embodiment described herein is a pharmaceuti ing at 400 - 200 rpm at 60 - 5° C . for not less than 30 min cal composition for treating , prophylaxis , or amelioration of 40 until the solution is clear; general autoimmune or neurodegenerative disorders, com ( b ) adding polyoxyl 40 hydrogenated castor oil and mix prising a fumarate ester , wherein the composition exhibits an ing the solution at 400 + 200 rpm at 60 + 5° C . for not less in vitro dissolution rate ( % dissolution per minute ) at pH 6 .8 , than 30 min until the solution is clear; as described herein in any one of Drawings 2 - 14 , 16 , or ( c ) adding lactic acid and mixing at 400 200 rpm at 60 + 5° 20 -23 . 45 C . for not less than 30 min until uniformly blended ; Another embodiment described herein is a pharmaceuti - ( d ) cooling the solution in 200 L tank to 25 + 5° C . while cal composition for treating , prophylaxis , or amelioration of mixing at 400 + 200 rpm ( a placebo fill can be removed general autoimmune or neurodegenerative disorders , includ at this step ); ing but not limited to multiple sclerosis or psoriasis , com ( e ) vacuum transferring the solution to a 500 L vacuum prising a fumarate ester , wherein the composition exhibits an 50 deaerator at 20 + 5° C . and mixing under vacuum for no in vitro dissolution rate comprising about 10 % to about 80 % less than 5 min ; dissolution after about 5 minutes to about 480 minutes at pH ( f ) introducing solid particles of the fumarate ester API 6 . 8 , including all integers and fractions within the specified (PSD : 40 - 150 um ) into the deaerator vessel and homog ranges of dissolution and time. In another aspect, the in vitro enizing the suspension for no less than 15 min ; dissolution rate at pH 6 . 8 is about 50 % after about 20 55 ( g ) vacuum transferring the suspension to a 200 L medi minutes to about 1080 minutes , including all integers and cine tank and deaerating no less than 30 min at 20 : 59 fractions within the specified ranges of dissolution and time . C . ; and In one aspect, the in vitro dissolution rate at pH 6 . 8 is about (h ) homogenizing to form a final suspension at 10 - 50 rpm . 50 % after about 5 min , is about 50 % after about 10 min , When the pharmaceutical composition is encapsulated in about 50 % after about 20 min , about 50 % after about 30 60 a soft capsule , the following steps are included : min , about 50 % after about 40 min , about 50 % after about ( i ) preparing a gel mass composition comprising a film 50 min , about 50 % after about 60 min , about 50 % after forming, water -soluble polymer , an appropriate plasti about 70 min , about 50 % after about 80 min , about 50 % cizer, and solvent; after about 90 min , about 50 % after about 120 min , about (j ) casting the gel mass into films or ribbons using 50 % after about 150 min , about 50 % after about 180 min , 65 heat- controlled drums or surfaces ; about 50 % after about 210 min , about 50 % after about 240 ( k ) transferring the homogenized suspension ( h ) to an min , about 50 % after about 300 min , is about 50 % after encapsulation line; US 9 , 814 ,692 B2 85 86 (1 ) encapsulating the homogenized fill solution within the ubiquitin ligase Rbx1 . Thus, under normal conditions , the gel mass films or ribbons using rotary dye encapsula substrate (Nrf2 ) is polyubiquitinated and targeted for deg tion ; radation . In response to oxidative stress , Nrf2 is released ( m ) drying and finishing capsules ; from the Keap1/ Nrf2 complex , preventing its degradation ( n ) optionally , pre - coating capsules with a sub - coating 5 resulting in the concommitant translocation of NRF2 to the and drying ; nucleus and activation of ARE -mediated gene transcription . ( 0 ) optionally , coating capsules with a coating and drying ; Based on this understanding , any of the non - limiting meth (p ) optionally , coating capsules with a top coating and ods for determining the activation of Nrf2 may be used that drying ; and are further described herein . See U . S . Pat . No . 8 , 399 ,514 , ( q ) post processing and packaging . 10 An analagous process can be used to produce pharma which is incorporated by reference herein for its teachings ceutical compositions comprising soybean oil where steps thereof. ( a ) - ( c ) above are replaced with ( r ) and ( s ) : Nrf2 activation may be determined by assessing the in ( r ) introducing soybean oil into a 200 L mixing vessel and vitro activation levels of Nrf2 and / or Nrf2 mRNA or protein mixing at 400 + 200 rpm at 60 + 5° C . for not less than 30 15 expression levels . The sequence of the promoter region of min until the solution is clear; the Nrf2 gene ( - 1065 to - 35 ) is known . In vitro Nrf2 ( s ) optionally , adding lactic acid and mixing at 400 + 200 activation may be measured using a cell model system rpm at 60 + 5° C . for not less than 30 min until uniformly transfected or transduced with an expression construct con blended ; taining the Nrf2 promoter element described above and an and then resuming with step ( d ). If lactic acid is omitted 20 artificial reporter gene ( e . g ., luciferase or a fluorescent from the formulation , then step ( s ) is omitted and the reporter gene (GFP , RFP , YFP etc ., ) . See , e . g ., Chan et al. , process has step (r ) followed by step (d ) . Proc . Natl . Aacd . Sci . USA 93 : 13943 - 13948 ( 1996 ) and When pharmaceutical composition is encapsulated in a Kwak et al. , Mol. Cell. Biol. 22 ( 9 ) : 2883 - 2892 ( 2002) , each hard capsule , the following steps are included instead of of which is incorporated by reference herein for their teach ( i) - ( q ) for soft capsules: 25 ings thereof . Nrf2 activation may be assessed by measuring (i ) preparing a gel mass composition comprising a film reporter gene expression in treated vs. non - treated cells forming, water- soluble polymer , an appropriate plasti using standard imaging or fluorescence quantification tech cizer, and solvent; niques. Alternatively , PCR ( e. g ., qRT- PCR ) or Northern ( i) using the gel mass to form hard capsules via dip - blotting may be used to determine expression levels of Nrf2 molding and spinning , drying, stripping , and trimming 30 mRNA, or Western blotting to determine Nrf2 protein levels . the capsules , See , e . g. , Kwak et al. , Mol . Cell. Biol. 22 (9 ) :2883 - 2892 ( k ) transferring the homogenized suspension ( h ) to an ( 2002 ) and Kwak et al. , Mol. Med . 7 : 135 - 145 ( 2001 ), each encapsulation line ; ofwhich is incorporated by reference herein for their teach ( 1) filling the capsules with the homogenized suspension ; ings thereof. Antibodies against Nrf2 are can be produced by ( m ) capping and finishing the capsules ; 35 methods known in the art and are commercially available ( n ) optionally , precoating capsules with a sub - coating from , for example , Stressgen® , Enzo Life Sciences . and drying ; In addition , Nrf2 activation may be assessed by deter ( o ) optionally , coating capsules with a coating and drying ; mining the subcellular localization and / or nuclear translo ( p ) optionally , coating capsules with a top coating and cation of Nrf2 in treated vs. non - treated cells . Such assays drying ; and 40 include cell staining , or analysis of cytoplasmic versus ( q ) post processing and packaging . nuclear cell extracts. For example , an Nrf2 - green fluores Another embodiment described herein is a method for cence protein GFP( ) fusion protein construct can be intro treating a neurological disease , neurodegenerative disease , duced into cells and visualized as described in , e .g ., Kraft et autoimmune disease , or an iatrogenic disease or disorder al. , J . Neurosci. 24 : 1101 - 1112 ( 2004 ) and in Satoh et al. , comprising orally administering one or more doses of one or 45 Proc. Natl . Aacd . Sci. USA 103 ( 3 ): 768 - 773 (2006 ). more fumarate esters described herein to a patient in need Nrf2 activation may be determined through indirect mea thereof, wherein the administration activates or modulates surement of the expression levels and /or activity of one or one or more cellular signaling pathways . In one aspect , the more genes under the control of Nrf2 in treated vs. non cellular signaling pathway comprises the nuclear erythroid - treated cells . For example, the expression levels of NADPH derived 2 - like 2 (Nrf2 ) dependent antioxidant response 50 dehydrogenase quinone 1 (NQO1 ) may be determined element ( ARE ) pathway . Without being bound by any using , for example , qRT- PCR , Northern blotting , or Western theory , it is believed that at least one aspect of the pharma - blotting , see , e . g ., Wierinckx et al. , J . Neuroimmunology cological activity of the fumarate esters described herein 166 : 132 - 143 (2005 ) . Methods for measuring enzymatic exert an anti- inflammatory and neuroprotective effect in activity of NQO1, using menadione as a substrate , are patients with , for example , multiple sclerosis or psoriasis , by 55 described in Dinkova -Kostova et al. , Proc. Natl. Aacd . Sci. activating the Nrf2 cellular signaling pathway. Although not USA 98 :3404 -09 ( 2001) . completely understood , the Nrf2 pathway is involved in the The cell type being contacted with the one or more cellular response to oxidative stress , which has been linked fumarate esters described herein may comprise a neuron or to neuronal degeneration in multiple sclerosis and in other a neuronal cell line , a colon carcinoma cell line ( e . g . , neurodegenerative or autoimmune diseases ( e . g . , HIV ) , see , 60 DLD1 ) , a neuroblastoma cell line ( e . g ., SkNSH or IMR32 ) , e . g ., Gao et al. , Clin . Pharmacol . 6 : 19 - 34 ( 2014 ) , which is or a primary immune cell ( e . g . , a monocyte or T - lymphocyte incorporated by reference herein for its teachings thereof. or B - lymphocyte ). The cell may be a cell in culture ( in vitro ) It is currently thought that under basal conditions, Nrf2 is or be inside of a mammal ( in vivo ). Alternatively , endog sequestered in the cytoplasm to the actin -bound Kelch -like enous Nrf2 activation may be determined by measuring the ECH - associated protein 1 (Keapl ) . Keapl associates with 65 levels of Nrf2 or a Nrf2 regulated gene ( e . g ., NQ01) in a the Cullin3 ubiquitin ligase adaptor protein , which positions primary cell or cell population ( e . g. , a monocyte , T - lympho Keap1 and its substrate in proximity (e . g. , NRF2 ) to the E3 cyte , or neuronal cell ) taken from a human patient having US 9 , 814 ,692 B2 87 88 neurological disease , neurodegenerative disease, or autoim - experiments in a USP Apparatus II ( e . g . , paddle method at mune disease ( e . g . , multiple sclerosis or psoriasis ) . 100 rpm ) . For these experiments , the capsules were intro It will be apparent to one of ordinary skill in the relevant duced in to simulated gastric fluid , 0 . 1 NHC1, pH 1 . 2 , for 2 art that suitable modifications and adaptations to the com - hours . After 2 hours, the capsules were transferred to simu positions, formulations , methods, processes , and applica - 5lated intestinal fluid , phosphate buffer , pH 6 . 8. The results tions described herein can be made without departing from are shown in FIG . 2 . The results show that the capsules the scope of any embodiments or aspects thereof. The retain their enteric properties for at least 2 hours in simulated compositions and methods provided are exemplary and are gastric fluid at pH 1 .2 . Both types of capsules released DMF not intended to limit the scope of any of the specified shortly ( ~ 10 minutes ) after being transferred to simulated embodiments . All of the various embodiments , aspects , and 10 options disclosed herein can be combined in any and all intestinal fluid , pH 6 . 8 . The enteric soft capsules comprising variations or iterations . The scope of the compositions, matrices comprising PEG 400 released DMF more rapidly formulations, methods, and processes described herein than those comprising Capmul® MCM ( ABITEC Corp . ; include all actual or potential combinations of embodiments, medium chain mono - and diglycerides ). aspects, options, examples and preferences herein 15 described . The exemplary compositions and formulations Example 2 described herein may omit any component , substitute any component disclosed herein , or include any component disclosed elsewhere herein . The ratios of the mass of any Stability of the Enteric Soft Capsules Over Time component of any of the compositions or formulations 20 The temporal stability of the dimethyl fumarate enteric disclosed herein to the mass of any other component in the soft capsule fill formulation shown in Table 11 was assessed . formulation or to the total mass of the other components in A sample of DMF enteric soft capsules was subjected to the formulation are hereby disclosed as if they were accelerated aging by a 1 month of exposure to 40° C . and expressly disclosed . Should the meaning of any terms in any 75 % relative humidity conditions and then evaluated in of the patents or publications incorporated by reference 25 two - stage dissolution experiment. A second sample of DMF conflict with the meaning of the terms used in this disclo - enteric soft capsules was subject to two - stage dissolution sure, the meanings of the terms or phrases in this disclosure shortly after manufacturing . Both sets of enteric capsules are controlling. Furthermore , the foregoing discussion dis remained intact in the acidic conditions for at least 2 hours . closes and describes merely exemplary embodiments. All FIG . 3 . The freshly manufactured capsules released DMF patents and publications cited herein are incorporated by 30 slightly faster than the age -accelerated capsules when the pH reference herein for the specific teachings thereof. was shifted to 6 . 8 (phosphate buffer) . EXAMPLES TABLE 11 Example 1 35 DMF Fill Composition Ingredient mg/ capsule % weight DMF Enteric Soft Capsule Fills Dimethyl fumarate 240 32 . 0 Based on results of dimethyl fumarate (DMF ) solubility (Mean PSD : 80 um ) testing in various lipid or lipophilic vehicles ( data not Capmul ® MCM 367 .5 49. 0 shown ) , two formulations were selected for further studies 40 Povidone K 30 52 . 5 7 . 0 and encapsulated in enteric soft gelatin capsules : one having Tween ? 80 75 10 . 0 polyethylene glycol and one with medium chain mono - and Lactic acid 15 2 . 0 diglycerides . Organic acids such as caprylic acid , lactic acid , or oleic acid , were incorporated into the matrix fill to prevent TOTAL 750 mg 100 % the hydrolysis of dimethyl fumarate and to retain enteric 45 properties of the shell . Application batches of enteric soft capsules were prepared by rotary die encapsulation using the Example 3 fill compositions shown in Table 10 . TABLE 10 DMF Release in Enteric Soft Capsules A developmental batch of enteric soft capsules compris DMF Fill Compositions ing a Capmul® MCM matrix containing particles of dim nul ® MCM Matrix PEG Matrix ethyl fumarate ( Table 11) was subject to two - stage dissolu ( A413 - A ) (A413 - B ) tion at pH 1 . 2 in simulated gastric fluid for 2 hours, then the 55 buffer was changed to phosphate buffer, pH 6 . 8 , containing Ingredient mg/ capsule % wt mg/ capsule % wt 2 % Cremophor RH 40 . FIG . 4 . The enteric capsules Dimethyl Fumarate 240 32 . 0 240240 32 . 0 remained intact in the acidic condition , and then began (Mean PSD : 80 um ) releasing DMF within 20 minutes of the pH -shift to simu Capmul ® MCM 367 . 5 49 . 0 lated intestinal fluid . PEG 400 — — 382 . 5 51. 0 Povidone K30 52. 5 7 . 0 37 . 5 5 . 0 Tween ® 80 75 10 . 0 75 10 . 0 Example 4 Lactic acid 15 2 . 0 15 2 . 0 TOTAL 750 100 % 750 100 % Surfactants Affect DMF Release Rate 65 Enteric soft capsules were prepared with matrices com The enteric soft capsules comprising the matrix formula - prising 10 % Tween® 80 (Uniqema , ICI Americas Inc ; tions shown in Table 9 were subject to two - stage dissolution polyoxyethylene ( 80 ) sorbitan monooleate ; e . g ., polysorbate US 9 ,814 ,692 B2 89 90 80 ) or 10 % Cremophor RH 40 (BASF SE ; polyoxyl 40 Example 6 hydrogenated castor oil ) ( Table 12 ) and then tested in dissolution experiments at pH 6 . 8 . FIG . 5 . The enteric soft capsules with fills containing Cremophor® released DMF DMF Enteric Soft Capsules are Amenable to Controlled or much more rapidly than those containing Tween® 80 . Extended Release 5 The release profile of DMF is modified by varying the TABLE 12 enteric soft capsule shell composition or by altering the fill composition or particle size of the active ingredient. Three DMF Fill Compositions different release profiles were observed under two -stage TweenTween ® 80 CrenCremophor nophor ?® RH 40 10 dissolution experiments. All enteric soft capsules were resis Matrix Matrix tant to acid for at least 2 hours , and begin releasing DMF Ingredient mg/ capsule % wt mg/ capsule upon transition to pH 6 . 8 . FIG . 7 . A release profile was % wt observed in an enteric soft capsule comprising a matrix of Dimethyl Fumarate 240 32 . 0 240 32 . 0 Capmul® MCM and Cremophor® RH 40 ( Table 15 ; (Mean PSD : 80 um ) Capmul ® MCM 367 . 5 49 . 0 367 . 5 49 . 0 15 Release Profile 1 ) . A different release profile was observed Povidone K 30 52 . 5 7 . 0 0 5252 .5 5 7 . 0 with an enteric soft capsule shell comprising a Capmul® Tween ? 80 175 10 . 00 MCM and Tween 80 matrix ( Table 11 ; Release Profile 2 ) . Cremophor ® RH 40 75 10 . 0 2 . 0 7515 2 . 0 Another release profile was observed with an enteric soft Lactic acid 15 2.0 capsule shell comprising a matrix of soybean oil, Tween TOTAL 750 100 % 750 100 % 20 80 , and solid particles of DMF having a mean particle distribution size of 148 um ( Table 16 ; Release Profile 3 ) . Example 5 TABLE 15 Polyvinylpyrrolidone Concentration Affects DMF Release 25 Rate DMF Fill Composition (P31 ) 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 experi Ingredient mg/ capsule % weight ments at pH 6 . 8 . FIG . 6 . The enteric soft capsules with 30 matrices containing 5 % Povidone K30 released DMF more Dimethyl fumarate 240 32 . 0 rapidly at pH 6 .8 than those with fills containing 3 % (Mean PSD : 80 um ) Povidone K30 . Capmul ® MCM 367 . 5 49 . 0 TABLE 13 Cremophor ® RH 40 75 10 . 0 Povidone K 30 52 . 5 7 . 0 DMF Fill Compositions Lactic acid 15 2 . 0 3 % PVP 5 % PVP Ingredient mg/ capsule % wt mg/ capsule % wt TOTAL 750 mg 100 % Dimethyl Fumarate 240 32 . 0 240 32 . 0 (Mean PSD : 80 um ) Capmul ® MCM 397 . 5 5353 382382 . 5 51 Cremophor ® RH 40 75 10 . 0 75 10 . 0 TABLE 16 Povidone K 30 22. 5 3 . 0 37 .5 5 . 0 Lactic acid 15 22 . 0 1515 2 .0 45 DMF Fill Composition ( P6 ) TOTAL 750 100 % 750 100 % Viscosity : 43191 Cp 122000 Cp Ingredient mg/ capsule % weight Based on the foregoing formulation studies , the Capmul® 50 Dimethyl fumarate 240 43. 6 MCM -based formulation was selected for further analysis . A (Mean PSD 148 um ) batch was manufactured using the formulation below ( Table Soybean oil 285 . 25 51. 9 14 ) . Aerosil 200 75 9910 . 0 Tween ® 80 11 2 . 0 TABLE 14 55 Caprylic acid 2 . 0 DMF Fill Composition TOTAL 550 mg 100 % Ingredient mg/ capsule % weight Dimethyl Fumarate 240 (Mean PSD : 80 um ) 60 Example 7 Capmul ® MCM 375 Cremophor ® RH 40 75 Povidone K 30 52 . 5 DMF Particle Size Affects Release Rate Lactic acid 15 Invoere Enteric soft capsules comprising matrices with DMF TOTAL 750 mg 100 % 65 particles of differing mean particle size distributions as shown in Table 17 were subject to dissolution at pH 6 . 8 . FIG . 8 . US 9 ,814 ,692 B2 9191 TABLE 17 Matrices with Varying DMF Particle Sizes FormulationFormulation A (P7 ) B (P8 ) C (P9 ) Ingredient mg capsule % weight mg/ capsule % weight mg/ capsule % weight DMF Mean PSD : 240 43 . 6 - 168 um 43. 6 DMF Mean PSD : I 240 43 . 6 | 148 um DMF Mean PSD : ?240 43 . 6 90 um PEG 400 244 44 . 4 244 44 . 4 244 44 . 4 Povidone K30 244 244 44. 4 244 Tween ? 80 55 10 55 10 55 Caprylic acid Lactic acid TOTAL 550 100 550 100 5 50 100 Formulation D (P25 ) E (P15 ) F (P23 ) Ingredient mg capsule % weight mg capsule % weight mg/ capsule % weight DMF Mean PSD : 240 34 . 3 76 um 34. 3 - DMF Mean PSD : 240 28 . 2 2 240 28 . 2 26 um PEG 400 355 50 . 7 508 59 . 8 482482 5656 .. 8 Povidone K30 21 Tween ? 80 85 Caprylic acid como Lactic acid Elan§ TOTAL 700 100 850 100 850 100

Example 8 d90s90 um were prepared and analyzed in two stage (pH 1. 2 Enteric soft capsules comprising various matrices com and pH 6 .8 ) or single stage (pH 6 . 8 ) dissolution experiments prising DMF particles having particle size distribution of (data not shown) . ( Tables 18 -20 ) . TABLE 18 Various DMF Fill Compositions FormulationFormulation A (P32 ) B ( P33 ) C (P34 ) Ingredient mg/ capsule % weight mg/ capsule % weight mg/ capsule % weight DMF 240 32 . 0 240 3232 . 0 0 240 32 . 0 PSD : d90 590 um Capmul ® MCM 360 48 . 0 322 . 5 43 . 0 352 . 5 47. 0 Cremophor ® RH 40 112 . 5 5 1515 . . 0 150150 20 . 0 112 . 55 15 . 0 Lactic acid 3737 . 55 55 .. 0 37 . 55 55 .. 0 37 . 5 5 . 0 TOTAL 750 100 750 100 750 100 D (P35 ) E (P37 ) F (P38 ) Ingredient mg/ capsule % weight mg /capsule % weight mg /capsule % weight DMF 240 32. 0 240 32. 0 240 32 . 0 PSD : d90 590 um 240 32. 0 240 32. 0 240 32. 0 Capmul ® MCM 315 42 . 0 360 48 . 0 360 48 . 0 Cremophor ? RH 40 150 20 . 0 75 10 . 0 75 10 . 0 Lactic acid 37 . 5 5 . 0 37 . 5 5 . 0 37 . 5 5 5. 0 Povidone K 30 7 .5 1 . 0 US 9 ,814 ,692 B2 93 94 TABLE 18 - continued Various DMF Fill Compositions PEG 400 37 . 5 5 . 0 Polypropylene glycol 37 . 5 5 .0 TOTAL 750 100 750 100 750 100 G (P39 ) H (P41 ) I (P43 ) Ingredient mg/ capsule % weight mg capsule % weight mg/ capsule % weight DMF 240 28. 2 240 28 .. 2 240 28 . 2 PSD : d90 s90 um Capmul ® MCM 482 . 5 56 . 8 397. 5 46 . 8 397 . 5 46 . 8 Cremophor ? RH 40 85 10 . 0 85 10 . 0 Lactic acid 42 . 5 5 . 0 4242 .. 5 55 . 0 42. 5 5 5 . 0 Labrasol ® 85 10 .0 170 20 . 0 TOTAL 850 100 850 100 850 100

TABLE 19 Various DMF Fill Compositions Formulation A (P44 ) | B ( P45 ) C ( P46 ) Ingredient mg/ capsule % weight mg/ capsule % weight mg/ capsule % weight DMF 240 28 . 2 240 28. 2 240 28 . 2 PSD : d90 590 um Capmul ® MCM 372 43. 8 355 41 . 8 329 . 5 38. 8 Cremophor ® RH 40 85 10 . 0 8585 10 . 0 8585 10 . 0 Lactic acid 42. 5 5 ..0 0 42 . 5 5 55 . 0 42 .. 5 5 . 0 Labrasol ® 85 1010 . 0 85 10 . 0 85 10 .. 0 Povidone K 30 25 . 55 3 . 0 25 . 5 3 . 0 Mannitol 42 . 5 5 . 0 42 . 55 5 . 0 TOTAL 850 100 850 100 850 100 D ( P47 ) E (P48 ) F (P49 ) Ingredient mg capsule % weight mg capsule % weight mg/ capsule % weight DMF 240 28. 2 240 28 . 2 240 28 . 2 PSD : d90 590 um Capmul ® MCM 384 . 75 45 . 3 284 . 195 33 . 43 312 . 5 36 . 76 Cremophor ® RH 40 85 10 . 0 85 10 . 0 85 10 . 0 Lactic acid 42 .5 5 . 0 42 . 5 5 .. 0 42 . 5 *5 . 0 Povidone K 30 1212 . 75 75 1. . 5 —- - Labrasol ® — 85 10 . 00 85 10 . 0 PEG 3350 85 10 . 0 113. 305 13. 33 85 10 . 00 TOTAL 850 100 850 100 850 100 G (P50 ) H (P51 ) I (P52 ) Ingredient mg/ capsule % weight mg/ capsule % weight mg1/ capsule % weight DMF 240 28 . 2 240 28 . 2 240 28 . 2 PSD : d90 590 um Capmul ® MCM 333. 75 39 . 26 287 33 . 76 333 . 75 39 . 26 Cremophor ® RH 40 85 10 . 0 85 10 .00 85 10 .00 Lactic acid 42 . 5 5 .0 42 . 5 5 . 0 42 . 5 5 . 0 Labrasol ® 85 10 . 0 85 10 . 0 85 10 . 00 PEG 3350 63. 75 7 . 50 Povidone K 17 25 . 5 3 . 00 Mannitol 8585 10 . 00 Crospovidone - CL 63. 75 7 . 50 TOTAL 850 100 850 100 850 100 US 9 ,814 ,692 B2 95 96 TABLE 20 Various DMF Fill Compositions Formulation A (P53 ) B ( P54 ) C (P55 ) Ingredient mg/capsule % weight mg capsule % weight mg/ capsule % weight DMF 240 28 . 24 240 28 . 24 240 28 .24 PSD : d90 590 um Capmul ® MCM 397 . 5 46 . 76 397 . 5 46 . 76 390 . 7 45 . 96 Cremophor ® RH 40 85 10 .00 00 85 10 . 00 85 10 .00 Lactic acid 42 . 5 5 .00 42 . 5 5 . 00 42 . 5 5 .00 PEG 3350 85 10 . 00 PEG 400 - 42. 5 5 . 00 Lutrol ® F 68 - 85 10 .00 - Sodium lauryl sulfate 49 . 3 5 . 80 TOTAL 850 100 850 100 850 100 D (P56 ) E (P57 ) F (P58 ) Ingredient mg/ capsule % weight mg/ capsule % weight mg/ capsule % weight DMF 240 28 . 24 240 28 . 24 240 28 . 24 PSD : d90 590 um Capmul ® MCM 355 41. 76 363 . 5 42 . 76 355 41 .76 Cremophor ® RH 40 10 . 00 85 10 .00 85 10 . 00 Lactic acid 42 . 5 5 .00 42 . 5 5 . 00 42 . 5 5 .00 PEG 400 85 10 .00 85 10 . 00 85 10 . 00 Crospovidone CL 42 . 5 5 .00 - Crospovidone CL - F —- 34 4 . . 0000 – Crospovidone CL - M 42 . 5 5 . 00 TOTAL 850 100 850 100 850 100 G (P59 ) H (P60 ) Ingredient mg/ capsule % weight mg/ capsule % weight mg/ capsule % weight DMF 240 28 . 24 240 28 . 24 240 28 . 24 PSD : d90 s90 um Capmul ® MCM 312 . 5 36 . 76 355 41. 76 329 . 5 38 . 76 Cremophor ® RH 40 85 10 . 00 85 10 . 00 85 10 . 00 Lactic acid 42 . 5 5 . 00 42 . 5 5 . 00 42 . 5 5 . 00 Labrasol ® 85 10 . 00 85 10 . 00 85 10 . 00 Pearlitol ® Flash 85 10 .00 - — 42 . 5 5 . 00 Croscarmellose 42 . 5 5 . 00 25 . 5 3 . 00 Sodium TOTAL 850850 100 850 100100 850 100100 45 Example 9 TABLE 21 -continued Capsule Shell Thickness Affects Release Rate DMF Fill Compositions Application batches of enteric soft capsules with shell PEG 400 42 . 5 5 . 0 thicknesses of 0 .028 inches or 0 . 033 inches were prepared 50 Crospovidone- CL 1717 2 . 0 comprising DMF particles having particle size distributions TOTAL 850 100 % 850 100 % of d90s90 um in variousmatrices ( Table 2 ' ) and analyzed in C (APP022414 - A ) D ( APP022414 - B ) two stage (pH 1. 2 and pH 6 . 8 ) dissolution experiments (FIG . ( 0 .028 inch ribbon ) ( 0 .028 inch ribbon ) 9 ) . 55 Ingredient mg/ capsule mg capsule TABLE 21 % wt % wt Dimethyl Fumarate 240 28 .24 240 28. 24 DMF Fill Compositions PSD : d90 s 90 um A ( APP021214 ) B ( APP020714 ) Capmul ® MCM 312 . 5 36 . 76 312 . 5 36 . 76 ( 0 .028 inch ribbon ) ( 0 .033 inch ribbon ) Cremophor ® RH 40 85 10 . 0 85 10 . 0 – 60 Povidone K30 42 . 5 5 . 0 42 . 5 5 . 0 Ingredient mg capsule % wt mg capsule % wt PEG 600 127. 5 15 . 0 — Crospovidone- CL 42 . 5 5 . 0 Dimethyl Fumarate 240 28 . 2 240 28 . 2 Labrasol ® 85 1010 .. 0 PSD : d90 s 90 um Pearlitol ® Flash 85 10 . 0 Capmul ® MCM 440 51 . 8 465 . 5 54 .8 Cremophor ® RH 40 85 10 . 0 85 10 . 0 65 TOTAL 850 100 % 850 100 % Povidone K30 42. 5 5 .0 42 . 5 5 . 0 US 9 ,814 ,692 B2 97 98 Example 10 TABLE 24 A GMP batch of enteric soft capsules (0 .038 - inch shell DMF Fill Composition thickness) comprising DMF particles having a particle size distribution of PSD : d90590 um was prepared with the 5 Ingredient mg/ capsule % weight matrix composition shown in Table 22 and analyzed in two Dimethyl fumarate 120 28 . 2 stage (pH 1 .2 and pH 6 .8 ) dissolution experiments (FIG . 14 ) PSD : d90 < 90 um and compared to application batches ( Table 19 ). Capmul ® MCM 228 . 5 53. 8 Cremophor ® RH 40 42. 5 10 . 0 Povidone K 30 12 . 75 3 . 0 TABLE 22 Lactic acid 21 . 25 5 . 0 GMP DMF Fill Composition TOTAL 425 mg 100 % Ingredient mg/ capsule % weight Dimethyl fumarate 240 32. 0 PSD : d90 s 90 um 15 Example 13 Capmul ® MCM 375 50 . 0 Cremophor ® RH 40 75 10 . 0 Povidone K 30 22 . 5 3 . 0 A batch of enteric soft capsules ( 0 .038 - inch shell thick Lactic acid 37 . 5 5 . 0 ness ) comprising monomethyl fumarate (MMF ) particles having particle size distribution of PSD : d90s90 um was TOTAL 750 mg 100 % 20 prepared with the matrix composition shown in Table 25 . This example provides MMF ( 240 mg ). Example 11 TABLE 25 Povidone K30 and PEG 600 Affect DMF Release Rate 25 MMF Fill Composition DMF matrices were prepared with and without Povidone K30 or PEG 600 ( Table 23 ) and analyzed in single stage (pH Ingredient mg/ capsule % weight 6 . 8 ) dissolution experiments ( FIG . 11 ) . Monomethyl fumarate 240 28 . 2 PSD : d90 s 90 um 30 Capmul ® MCM 457 53 . 8 TABLE 23 Cremophor ® RH 40 85 10 . 0 Povidone K 30 25 . 5 3 . 0 DMF Fill Compositions Lactic acid 42 . 5 5 . 0 B ( P63) A ( P62 ) TOTAL 850 mg 100 % mg mg 35 Ingredient capsule % weight capsule % weight Dimethyl fumarate 240 28 . 2 240 28 . 24 Example 14 PSD : d90 s 90 um Capmul ® MCM 482 . 5 56 . 8 384 . 75 45 . 26 Cremophor ® RH 40 05 10 . 0 85 10 . 00 40 A batch of enteric soft capsules ( 0 . 038- inch shell thick Povidone K 30 - 12 .. 75 1 . 50 ness ) comprising monomethyl fumarate (MMF ) particles PEG 600 85 10 . 00 having particle size distribution of PSD : d90s90 um was Lactic acid 42 . 5 5 . 0 42. 5 5 . 0 prepared with the matrix composition shown in Table 26 . TOTAL 850 mg 100 % 850 mg 100 % This example provides MMF (480 mg) . 45 C ( P64) D (P65 ) TABLE 26 mg/ mg Ingredient capsule % weight capsule % weight MMF Fill Composition Dimethyl fumarate 240 28 . 24 240 28 . 24 Ingredient mg capsule % weight 50 PSD : d90 s 90 um Monomethyl fumarate 480 Capmul ® MCM 457 53. 76 372 43 . 76 48 - 56 . 4 Cremophor ® RH 40 85 10 .00 85 10 .00 PSD : d90 s 90 um 25 . 5 3 . 00 Capmul ® MCM 216 - 470 25 . 5 -47 Povidone K 30 25 . 5 3 . 00 Cremophor ® RH 40 7 . 3 - 120 0 . 85 - 12 PEG 600 - 85 10 . 00 42 . 5 5 . 00 42. 5 5 . 00 Povidone K 30 7 . 3 -50 0 . 85 - 5 Lactic acid 21 . 7 - 50 2 . 55 - 5 55 Lactic acid TOTAL 850 mg 100 % 850 mg 100 % TOTAL 850 mg -1000 mg 100 %

Example 12 60 Example 15 A batch of enteric soft capsules (0 .038 - inch shell thick ness ) comprising DMF particles having particle size distri Enteric soft capsules comprising particles of dimethyl bution of PSD : 090590 um was prepared with the matrix fumarate , monomethyl fumarate , or a combination thereof composition shown in Table 24 and analyzed in two stage having particle size distribution of PSD : d90s90 um can be (pH 1 .2 and pH 6 .8 ) dissolution experiments (FIG . 12 ). This 65 prepared with an 850 mgmatrix in the compositions shown example provides a lower dose of DMF ( 120 mg) compared in Table 27 . This example provides DMF or MMF in a QD with that shown in Table 11 (240 mg) . formulation ( ~ 480 mg ) . US 9, 814 ,692 B2 99 100 TABLE 27 DMF or MMF 850 mg Fill Compositions Percent Weight ( % Ingredient EX1 EX2 EX3 EX4 EX5 EX6 Dimethyl fumarate or Monomethyl 56 . 4 56 . 4 56 .4 56 . 4 56 . 4 56 . 4 fumarate PSD : d90 590 um Capmul ® MCM 30 . 6 39 . 95 28 . 9 28 . 9 25 .5 32 . 7 Cremophor ® RH 40 8 . 5 0 . 85 8 . 5 8 . 5 10 . 2 6 . 1 Povidone K 30 0 . 85 0 . 85 2 . 55 2 . 55 4 . 25 1. 8 Lactic acid 4 . 25 2 .55 4 . 25 4 . 25 4 .25 3 . 0 TOTAL 100 100 100 100 100 100

Example 16 TABLE 29 Enteric soft capsules comprising particles of dimethyl GMP DMF Fill Composition fumarate , monomethyl fumarate , or a combination thereof 20 Ingredient mg/ capsule % weight having particle size distribution of PSD : d90s90 um can be prepared with a 1000 mg matrix in the compositions shown Dimethyl fumarate 240 32. 0 in Table 28 . This example provides DMF or MMF in a QD PSD : d90 s 90 um Capmul ® MCM 375 50 . 0 formulation (~ 480 mg) . Cremophor ? RH 40 75 10 . 0 25 Povidone K 30 22 . 5 3 . 0 TABLE 28 Lactic acid 37 . 5 5 . 0 DMF or MMF 1000 mg Fill Compositions TOTAL 750 mg 100 % Percent Weight ( % ) - 3030 Ingredient EX1 EX2 EX3 EX4 EX5 EX6 TABLE 30 Dimethyl fumarate or 48 48 48 48 48 48 Monomethyl GMP DMF Stability fumarate PSD : d90 s90 um Capmul ® MCM 44 36 47 34 34 389 . 35 Initial 25° C . , 60 % Relative Humidity Cremophor ® RH 40 2 10 1 10 10 7 . 2 Povidone K 30 3 2 . 2 To 1M 2 M 3M 6 M Lactic acid 5 3 5 5 3 .6 Assay 101. 2 % 101. 0 % 102. 4 % 101. 25 98 . 8 % TOTAL 100 100 100 100 100 100 Degradation 40 Products Monomethyl 0 . 14 % 0 . 13 % 0 . 14 % 0 . 16 % 0 . 18 % Fumarate Example 17 RRT 0 . 74 ND ND 0 .07 % 0 . 09 % 0 . 18 % RRT 1 . 61 0 .05 % ND ND ND ND RRT 2 . 18 ND ND ND < 0 . 05 % 0 .09 % Stability of the Enteric Soft Capsules Over Time 45 Total 0 .19 % 0. 13 % 0 .21 % 0 .25 % 0. 45 % The temporal stability of the dimethyl fumarate enteric Degradation soft capsule pharmaceutical composition shown in Table 29 Products was assessed under three ICH conditions. A sample of DMF enteric soft capsules was subject to chemical analysis and 50 30° C . , 65 % Relative Humidity 40° C ., 75 % Rel. Humid . two- stage dissolution shortly after manufacturing ( T . ) . 1M 2M 3M 1M 2 M Samples of DMF enteric soft capsules were subjected to Assay 100 . 1 % 99 . 4 % 99 . 5 % 99 . 3 % 113. 1 % * Room Temperature Conditions (25º C . and 60 % relative Degradation humidity ) for 1 month , 2 , months, 3 months, and 6 months . Products Other samples of DMF enteric soft capsules were subjected 55 Monomethyl 0 . 14 % 0 . 17 % 0 .22 % 0 .22 % 0 . 26 % to Intermediate Conditions ( 30° C . and 65 % relative humid Fumarate ity ) for 1 month , 2 months , and 3 months . Additional RRT 0 . 74 0 . 14 % 0 . 22 % 0 . 28 % 0 . 3 % 0 . 46 % samples of DMF enteric soft capsules were subjected to RRT 1 .61 0 . 06 % 0 . 11 % 0 .14 % 0 . 15 % 0 . 35 % Accelerated Conditions ( 40° C . and 75 % relative humidity ) RRT 2 . 18 0 . 34 % 0 . 5 % 0 .64 % 0 .67 % 1 .07 % Total 0 . 14 % 0 . 17 % 0 .22 % 0 . 22 % 0 . 26 % for 1 month and 2 months. After the designated incubation 60 Degradation period , the capsules were chemically analyzed and evaluated Products in two - stage dissolution experiments at pH 1 . 2 and 6 . 8 as * Data were collected on fill extracted from leaking capsules . described herein if conditions permitted ( i. e ., non -leaking Note : capsules ) . Two - stage dissolution results for DMS enteric Leaking capsules were observed at the 2 - and 3 - month time points for the accelerated 65 condition (40° C . , 75 % RH ) . This was expected for the enteric soft gelatin capsules. The intermediate condition ( 30° C . , 65 % RH ) and long - term condition ( 25º C . , 60 % RH ) will Temperature Conditions ( 25º C . and 60 % RH ) are shown in be assessed at the 12 -month and 24 -month time points to assess chemical stability . FIG . 13 . US 9, 814 ,692 B2 101 102 Example 18 TABLE 31- continued Fill compositions with increasing amounts of one or more Fumarate Ester 750 mg Fill Compositions fumarate esters ( e . g ., dimethyl fumarate , monomethyl Povidone K 30 3 ??3 3 3 3 fumarate , or a combination thereof ranging from about 0 .5 5 Lactic acid aw uw uw5 uw5 uw5 mmol to about 4 .0 mmol) having a particle size distribution of PSD : d90s100 um in a 750 mg fill are shown in Table 31 . TOTAL 100 100 100 100 100 100 Millimole values for DMF or MMF specify the millimoles Ingredient EX13 EX14 EX15 EX16 EX17 EX18 of the respective species at the specified mass (mg ) . These fill compositions may be encapsulated by a soft capsule shell mg// capsule composition as described herein . In one embodiment, the Fumarate Ester 160 170 180 190 194 200 one or more fumarate esters comprise about 0 . 5 mmol to PSD : d90 s . 100 um 1:52 about 3 .7 mmol FAE. In one embodiment , the fumarate ester mmol DMF 1 . 11 1 . 18 1 . 25 1 .32 1. 35 1. 39 (FAE ) comprises DMF. In another embodiment, the fumar mmol MMF 1 . 23 1 . 31 1 . 38 1 .46 1 . 49 1 .54 ate ester comprises MMF. In another embodiment, the Capmul ® MCM 455 445 435 425 421 415 Cremophor ® 75 75 75 75 75 75 fumarate ester comprises MMF, DMF, or a combination RH 40 thereof. Povidone K 30 22 . 5 22 . 5 22 . 5 22. 5 22. 5 22 . 5 Lactic acid 37 . 5 37 . 5 37 . 5 37 . 5 37 . 5 37 . 5 TABLE 31 20 TOTAL 750 naaz*2750 750 750 750 750 Ratio FAE to Fill 0 .27 0 . 29 0 .32 0 . 34 0 .35 0 . 36 Fumarate Ester 750 mg Fill Compositions Percent Weight ( % ) Ingredient EX1 EX2 EX3 EX4 EX5 EX6 Fumarate Ester 21. 3 22. 7 24 25 .3 25. 9 26. 7 mg/ capsule PSD : d90 s 25 100 um a8 Fumarate Ester 80 85 90 95 97 100100 Capmul ® MCM 60 .7 59. 3 58 56 .7 92a3-156 . 1 55. 3 PSD : d90 s Cremophor ® 10 10 10 10 10 10 100 um RH 40 mmol DMF 0 . 56 0 .59 0 0 ..62 0 .. 66 00 . 67 0 . 69 PovidonePovidone K 30 3 3 3 3 3 3 mmol MMF 0 .61 0 .65 0 . 69 0 .73 0 . 75 0 . 77 Lactic acid uw uw uw uw uw5 5 Capmul ® MCM 535 530 525 520 518 515 30 Cremophor ® 75 75 75 75 75 75 TOTAL 100 100 100 100 100 100 RH 40 Povidone K 30 22 . 5 22 . 5 22 . 5 22 . 5 22 . 5 22 . 5 Ingredient EX19 EX20 EX21 EX22 EX23 EX24 LacticPovidone acid K 30 2237 . 5 3722. . 5 3722 . 5 3722. . 5 3722 . 5 2237 . 5 Ingredient mg/ capsule capsule TOTAL 750 750 750 750 750 750 35 Ratio FAE to Fill 0 .12 0 . 13 0 .14 0 .15 0 . 15 0. 15 Fumarate Ester 210 214 216 220 230 240 Percent Weigh PSD : d90 s 100 um :* Fumarate Ester 10. 7 11. 3 12 12. 7 12. 9 13. 3 lineaddellistalataliandimmol DMF 1 . 46 1 . 48 1 . 50 1 . 53 1. 60 1 .67 PSD : d90 s mmol MMF 1 .61 1 .64 1 .66 1 .69 1 . 77 1 . 84 100 um Capmul ® MCM 405 **:401 399 395 385 375 ca 1 ® MCM 71. 3 70 . 7 70 69 . 3 69 . 1 68. 7 Cremophor ® 75 75 75 75 75 75 Cremophor ® 10 10 10 10ao 10 1010 RH 40 RH 40 Povidone K 30 22. 5 22. . 5 2222 . 5 22 . 5 22 . 55 2222. 5 Povidone K 30 ???? Lactic acid 37 . 5 37. 5 37. 5 37. 5 37 .5 37. 5 LacticPovidone acid K 30 53 35 53 3 3 3 uw uw uw TOTAL 750 750 750 750 750 750 TOTAL 100 100 100 100 100 100 45 Ratio FAE to Fill 0 .39 0 . 40 0 . 40 0 .42 0 . 44 0. 47 Percent Weight ( % ) Ingredient EX EX8 EXO EX10 EX11 EX12 Fumarate Ester 28 28. 5 28 .8 29. 3 30 . 7 32 mgmg/ capsule capsule PSD : d90 s Fumarate Ester 105 107 108 110 115 120 50 100Capmul um ® MCM 54 53. 5 53. 2 52 .7 51. 3 50 PSD : d90 s . Cremophor ® 10 10 10 10 10 10 100 um RH 40 mmol DMF 0 .73 0 . 74 0 .75 0 .76 0 . 80 0 . 83 Povidone K 30 mmol MMF 0 . 81 0 . 82 0 . 83 0 . 85 0 . 88 0 . 92 Lactic acid Capmul ® MCM 510 508 507ON 505 500 495 uw uw uw uw uw uw Cremophor ® 75 75 75 75 75 75 55 TOTAL 100 100 100 100 100 100 RH 40 Povidone K 30 3722 . 5 3722. . 5 3722 . 5 3722. . 5 2237 .. 5 3722 . 5 Ingredient EX25 EX26 EX27 EX2822me laEX29 EX30 Lactic acid *Pelatihan mg/ capsulecapsule TOTAL 750 750 750 750 750 750 Ratio FAE to Fill 0 . 16 0 . 17 0 . 17 0 . 17 0 . 18 0 . 19 Percent Weight ( % ) 60 Fumarate Ester 320 340 360 380 388 400 PSD : d90 s Fumarate Ester 14 14 . 3 14. 4 14 .7 15 .3 16 100 um PSD : d90 s . mmol DMF 2 . 22 2 . 36 2 . 50 2 .64 2 .69 2 .78 100 um mmol MMF 2 . 46 2 .61 2 . 77 2 .92 2 . 98 3 . 07 Capmul ® MCM 68 67. 7 676 . 67 . 3 66 . 7 66 Capmul ® MCM 295 275 255 235 227 215 Cremophor ® 10 10 10 10 10 10 65 Cremophor ® 75 75 75 75 75 75 RH 40 28 segona RH 40 US 9, 814 ,692 B2 103 104 TABLE 31 -continued TABLE 32 Fumarate Ester 750 mg Fill Compositions Fumarate Ester Fill Compositions Povidone K 30 22 . 5 22 . 5 22 . 5 22 . 5 22 . 5 22 . 5 Percent Lactic acid 37 . 5 37. 5 37 . 5 37 . 5 37. 5 37 . 5 Weight ( % ) mg/ capsule TOTAL 750 750 750 750 750 750 Ingredient EX1- EX4 EX1 EX2 EX3 EX4 Ratio FAE to Fill 0. 74 0 .83 0. 92 1. 03 1. 07 1. 14 Fumarate Ester PSD : 28. 5 80 85 160 170 Percent Weight (% ) d90 < 100 um mmol DMF N / A 0 . 56 0 . 59 1 . 11 1 . 18 Fumarate Ester 42. 7 453 . 48 50. 7 51. 7 53. 3 0 .61 2921 mmol MMF N / A 0 .65 1 . 23 1 .31 PSD : d90 s JK11assäenelu 150 Capmul ® MCM 53. 5 159 300 318 100 um Cremophor ® RH 40 10 28 29 . 8 56 59. 5 Capmul ® MCM 39. 3 36 . 7 34 31. 3 30. 3 28 . 7 Povidone K 30 w 8 . 4 8 . 9 16 . 8 17 . 9 Cremophor ® 10 10 10 10 10 10 Lactic acid 5 14 14 . 9 28 29. 8 RH 40 6uw 15 PovidonePovidone K 3030 3 3 3 w3 w3 TOTAL 100 280 298 560 595 Lactic acid 5 uw 5 uw5 5 a5 18:9*19219931 uw Percent TOTAL 100 100 100 100 100 100 Weight ( % ) mg/ capsule Ingredient EX31 EX32 EX33 EX34 EX35 EX36 20 Ingredient EX5- EX8 EX5 EX6 EX7 EX8 mg capsule Fumarate Ester PSD : 28. 5 90 95 180 190 mg/ capsule d90 s 100 um mmol DMF N / A 0 . 62 0 .66 1. 25 1. 32 Fumarate Ester 420 428 432 440 460 480 mmol MMF N / A 0 .69 0 .73 1 . 38 1 .46 PSD : d90 s . 25 Capmul ® MCM 53. 5 169 178 337 356 100 um Cremophor ® RH 40 10 31 . 5 33 . 3 63 66 . 5 mmol DMF 2 .91 2 . 97 3 .00 3 .05 3 .19 3 . 33 Povidone K 30 3 9 . 5 10 18. 9 20 mmol MMF 3 . 23 3 .29 3 . 32 3 . 38 3 .54 3 .69 Lactic acid 15 .8 16 . 6 31. 5 33. 3 Capmul ® MCM 195 187 183 175 155 135 Cremophor ® 75 75 75 75 75 75 TOTAL 100 315 333 630 665 RH 40 30 Povidone K 30 22 .5 22. 5 22 .5 22. 5 22. 5 22. 5 Percent Lactic acid 37 .5 37. 5 37 .5 37 .5 37 .5 37 .5 Weight ( % ) mg/ capsule 750 Ingredient asideneilasaznale TOTAL 750 750 750 750 750 EXO -EX12 EX9 EX10 EX11 EX12 Ratio FAE to Fill 0 .74 0 .83 0 . 92 1 .03 1 .07 1 . 14 35 Percent Weight ( % ) Fumarate Ester PSD : 28 .5 100 107 200 214 d90 s 100 um mmol DMF N / A 0 .69 0 . 74 1 . 39 1 .48 Fumarate Ester 56 57 .1 57. 6 58 .7 61. 3 64 mmol MMF N / A 0 . 77 0 .82 1 .54 1 .64 PSD : d90 s Capmul ® MCM 53 .5 187 201 375 401 100 um Cremophor ® RH 40 10 35 37. 5 70. 1 75 Capmul ® MCM 26 24. 9 24 .4 23. 3 20. 7 18 40 Povidone K 30 10 . 5 11 . 3 21 22 . 5 Cremophor® 10 10 10 10 10 10 Lactic acid 17. 5 18 . 8 35 . 1 37. 5 RH 40 uw5 uw6 uwo Povidone K 30 3 3 3 TOTAL 100 350 375 701 750 Lactic acid uw uw uw uw5 uw5 uw5 Percent TOTAL 100 100 100 100 100 100 45 Weight ( % ) mg/ 1512 :capsule199223293 Ingredient EX13 -EX16 992a1:855433 EX17 EX18 EX19 EX20 Fumarate Ester PSD : 28. 5 105 110 210 220 Example 19 50 d90 < 100 um mmol DMF N / A 0 . 73 0 . 76 1 . 46 1 .53 mmol MMF N / A 0 . 81 0 .85 1 . 61 1 .69 Fill compositions having one or more fumarate esters Capmul ® MCM 53 . 5 197 206 393 412 ( e . g ., dimethyl fumarate , monomethyl fumarate , or a com Cremophor RH 40 36 . 8 38 .5 73 . 5 77 . 0 Povidone K 30 11. 0 11. 6 22 . 1 23 . 1 bination thereof ranging from about 0 .5 mmol to about 3 . 5 18. 4 19 . 3 36 . 8 38 . 5 mmol) having a particle size distribution of PSD : d90s100 55 Lactic acid uwo um with a constant weight ratio of fumarate ester to fill ( e . g . , TOTAL 1:5522-|e1311asia100 368 385 735 770 about 0 .40 ) are shown in Table 32 . Millimole values for Percent DMF or MMF specify the millimoles of the respective Weight mg/ capsule species at the specified mass (mg ) . These fill compositions Ingredient EX13 -EX16 EX17 EX18 EX19 EX20 may be encapsulated by a soft capsule shell composition as Fumarate Ester PSD : 28 . 5 115 120 230 240 described herein . In one embodiment, the fumarate ester d90 s 100 um mmol DMF N / A 0 .80 0 . 83 1. 60 1. 67 comprises DMF. In another embodiment , the fumarate ester mmol MMF N / A 0 . 88 0. 92 1. 77 1. 84 comprises MMF. In another embodiment, the fumarate ester Capmul ® MCM 53 . 5 215 225 431 449 comprises MMF, DMF, or a combination thereof. US 9, 814 ,692 B2 105 106 TABLE 32 - continued TABLE 34 Fumarate Ester Fill Compositions Two - stage Dissolution Analysis Parameters USP Apparatus II Agitation Rate 100 RPM Cremophor ® RH 40 40 . 3 42. 0 80 . 5 84 . 0 5 Temperature 37 . 0 + 0 .5º C . 12 . 1 12 . 6 24 . 2 25 . 2 Media / Volume 0 . 1N HCI, pH 1 . 2 , 500 mL Povidone K 30 Phosphate buffer, pH 6 . 8 , 500 mL Lactic acid Tuwa 20 . 1 21. 0 40 . 3 42. 0 Sample Profile : Samples obtained at 60 min and 120 min in 0 . 1N HCI Samples obtained at 10 , 20 , 30 , 45 , 60 , 120 min in TOTAL 100 403 420 805 840 phosphate buffer pH 6 . 8 10 Percent Weight ( % ) mg/ capsule Example 21 Ingredient EX13 -EX16 EX13 EX14 EX15 EX16 Method for Measurement of Fumarate Ester Particles Size 15 Distribution Fumarate Ester PSD : 28 . 5 350 375 400 428 Fumarate ester particles (dimethyl fumarate or mono d90 s 100 um methyl fumarate ) in the form of a dry powder were measured mmol DMF N / A 2 .42 2 . 6 2 . 78 2 . 97 using a Malvern Mastersizer 2000 instrument equipped with mmol MMF N / A 2 .68 2 . 883 .07 3 .29 vacuum unit and air pressure following manufacturer Capmul ® MCM 53 . 5 655 702 750 802202 20 instructions ; see, e . g . The Mastersizer 2000 Operators Guide ; MAN0247 - 2 - 0 , Malvern Instruments Ltd . ( 1999 ) , Cremophor RH® 40 10 123 131 140 150 which is incorporated by reference herein for such teachings. Povidone K 30 3 36 .8 39 .4 42. 1 45 Approximately 1 . 0 gram of the test sample was introduced Lactic acid 5 61. 3 65. 6 70 . 1 75 into the dry powder feeder and measured under the param eters shown in Table 35 , and the volume size distribution and TOTAL 100 1225 1313 1402 1500 the volumemean diameter were determined . In one aspect , described herein , 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. Example 20 30 TABLE 35 A batch of enteric soft capsules (0 .038 -inch shell thick Particle Size Distribution Measurement Parameters ness ) comprising monomethyl fumarate particles having Analysis Model General Purpose particle size distribution of PSD : d90s90 um were prepared Sensitivity Normal with the matrix composition shown in Table 33 . 35 Particle RI 1 . 468 Vibration feed rate 60 % Dispersive air pressure 1 . 3 bars TABLE 33 Absorption 0 . 1 Measurement time 6 seconds Monomethyl Fumarate Fill Composition Measurement snaps 6 ,000 40 Background time 6 seconds Fill Ingredients Percent Weight (% ) Mass / capsule (mg ) Background snaps 6 ,000 Monomethyl fumarate , 28 . 50 214 No. of measurements 1 per cycle PSD : d90 s 90 um Obscuration 0 . 5 % to 6 . 0 % Capmul ® MCM 53. 50 401 Cremophor ® RH 40 10 .00 75 Povidone K 30 3 .00 23 45 Lactic Acid 5 .00 Example 22 Total Fill Weight 100 % 750 Clinical Study of Test Pharmaceutical Compositions Com Total Capsule Weight 1116 prising Fumarate Esters Patient Population Non - smoking male or females ( n = 24 ) within the age 50 range of 18 to 65 years, having a Body Mass Index ( BMI) Samples from a batch of enteric soft capsules comprising greater than or equal to 18 . 5 kg/ m² and less than or equal to the composition shown in Table 33 were subject to two- stage 29. 9 kg /m² and having given their written informed consent dissolution experiments in a USP Apparatus II with the were at the Period - I check - in of the study. The patient parameters shown in Table 34. For these experiments , the demographics and number of patients dosed is provided in capsule was introduced in to simulated gastric fluid , 0 . 1 N » Table 36 . They did not have any significant diseases or clinically significant abnormal findings during screening , HC1, pH 1. 2 , for 2 hours . After 2 hours , the capsule was medical history , physical and clinical examinations , labora transferred to simulated intestinal fluid , phosphate buffer , tory evaluation , 12 -lead ECG recording and vital sign mea pH 6 .8 . Samples were removed from the apparatus at the surement. Female volunteers had a negative pregnancy test . indicated time points and the analyte was detectedled using 60 VolunVolunteers who meet all the inclusion and exclusion criteria high performance liquid chromatography (HPLC ) with a UV wewere enrolled into the study . detector. The results are shown in FIG . 14 . The results show All the subjects willing to participate in the study were that the capsules retain their enteric properties for at least 2 screened no more than 28 days before the first drug admin hours in simulated gastric fluid at pH 1 . 2 . The capsules istration in order to assess their eligibility by satisfying all of began releasing monomethyl fumarate within ~ 10 minutes 65 the inclusion and exclusion criteria . During screening , the after being transferred to simulated intestinal fluid , pH 6 . 8 , medical history of the subjects was elicited and they under and achieved 100 % dissolution after 120 minutes at pH 6 . 8 . went a general clinical examination , measurement of blood US 9 ,814 ,692 B2 107 108 pressure, heart rate , body temperature, respiratory rate , Dosing water was measured and poured into individual 12 - Lead ECG , clinical laboratory evaluations, immunologi- containers before dosing . The containers were then covered cal tests for HIV (Human Immunodeficiency Virus ) , HBsAg and allowed to remain at ambient temperature until used . ( Hepatitis B Surface Antigen ) and HCV (Hepatitis C Virus ), The drug was provided to the subjects in unit -dose contain Alcohol screen , Nicotine screen and Screen for drugs of 5 ers . A visual inspection of each subject ' s mouth and hands abuse . Urine pregnancy test was performed for all female was performed immediately after dosing to ensure drug subjects . Subjects were selected for inclusion in the study no ingestion . more than 28 days before the first drug administration . During the first 4 -hours post- dose , subjects were encour aged to stay awake , seated in an upright position , and TABLE 36 10 allowed to rise under supervision only for brief periods of time, in order to comply with study - related activities and to Study Population Inclusion Numbers and Parameter Information use the washroom . Subjects were permitted to lie down for No. Planned for Inclusion 24 treatment of any adverse event. Enrolled and Checked - in 34 (Subject Nos . 1001 - 1024 and 10 standby subjects ) 1615 No water ingestion was permitted from 1 . 0 - hour pre - dose Dosed Period - I 24 to 1. 0 -hour post -dose , with the exception of the 240 mL of Period - II (7 days later) 23 dosing water. Dismissed 01 Analyzed No food was allowed for at least 4 hours ' post -dose . Considered for statistical analysis 23 Standardized meals with beverages were provided to the - 20 subjects at the following times: between 4 . 5 - and 5 . 5 -hours Parameters Dosed Subjects (24 ) Completed Study (23 ) post - dose; between 9 . 5 - and 10 . 5 -hours post - dose; and at Age ( years ) 42 . 2 + 12 . 81 42 . 2 + 13 . 10 13. 5 -hours post- dose . Height (cm ) 171 . 14 + 8 .668 171. 32 8 . 817 All meals and beverages were free of alcohol, grapefruit Weight (kg ) 75 .05 – 10 . 135 75 .35 10 . 258 products , xanthine , and caffeine and were identical between BMI (kg / m² ) 25 . 55 + 2 . 280 25 .60 = 2 . 320 25 the study periods . Safety was assessed from the screening period to the end Study Methodology of the study. It was assessed through clinical examinations, The performed study was a randomized , pilot, two -way vital signs assessment, 12 -lead electrocardiogram (ECG ) , crossover, open - label, single -dose , fasting study , with a clinical laboratory parameters ( e. g ., biochemistry, hematol screening period of 28 -days prior to the first dose adminis - 30 ogy , immunology, and urine analysis ), pregnancy test for tration . In each study period , 19 blood samples, including female subjects ) , subjective symptomatology , and monitor ing of adverse events . one pre -dose blood sample ,were collected from each subject A total of 19 pharmacokinetic blood samples (6 mL each ) except for the subject who did not complete the study to were drawn in each period according to the following analyze the pharmacokinetic profile of the Test pharmaceu -| 35os schedule : 0 (pre - dose ) , and at intervals of 0 . 33 , 0 .67 , 1 , 1 . 25 , tical composition as well as the Reference pharmaceutical 1 . 5 , 1 . 75 , 2 , 2 . 25 , 2 . 5 , 2 . 75 , 3 , 3 . 33 , 3 .68 , 4 , 4 .5 , 5 , 6 , and product. 8 -hours post - dose . Based on the eliminationon halfhalf -life life of dimethyl fumarate ,, a The plasmao samples of subjects were analyzed using a washout period of 7 -days was kept in between the succes - validated LC -MS / MS method for monomethyl fumarate . sive dosing days . Multiple blood samples were collected to 40 Calibration curve using an 8 -point calibration curve stan assess the bioequivalence between the Test and the Refer dards, with concentrations ranging from 21. 35 ng/ mL to ence product. For this study with a crossover design , each 4967 .75 ng/ mL were used to determine the concentrations of subject except for one dismissed subject received both the monomethyl fumarate in the samples of various subjects . products ( Test Product - T and Reference Product- R ) during Pharmacokinetic Parameter Calculations the study . Hence , every subject acted as his own control and 45 The pharmacokinetic parameters were calculated from the no separate group of subjects was required to act as the drug concentration versus time point by non - compartmental control group . Subjects were dosed according to the treat - model using WinNonlin Professional Software Version 5 . 3 ment sequence provided in Table 37 . The duration of the (Pharsight Corporation ) for monomethyl fumarate . Statisti clinical part of the study was about 9 days (one day prior to cal comparison of the pharmacokinetic parameters of the the drug administration in Period - I until the last study 50 two products ( Test, Reference ) was performed using PROC procedure in Period - II ) . MIXED of SAS® Version 9 . 3 (SAS Institute Inc . ) . The maximum measured plasma concentration (Cmax ) and TABLE 37 the time of observing the peak concentration ( Tmor ) was taken directly from the plasma concentration versus time Treatment Sequence 55 profile of the individual subjects . Area under plasma concentration versus time curve Period - I Period - II (AUC . -> z ) in h .ng /mL from time zero to the last measurable Sequence 1 Treatment- R (Reference ) Treatment- T ( Test) concentration as calculated by the linear trapezoidal rule . Sequence 2 Treatment- T ( Test ) Treatment- R (Reference ) Area under the plasma concentration versus time curve 60 (AUC ) in hing /mL from time zero to infinity ; where After an overnight fast of at least 10 hours , a single oral AUC0 -- - = AUCO - x + CdN ; C , is the lastmeasurable concen dose ( 240 mg) of a Test controlled release pharmaceutical tration and à , is the terminal rate constant. The AUC0 - > 0000 composition comprising a fumarate ester or a Reference was the sum of measurable and extrapolated parts . dimethyl fumarate composition was administered to the First order rate constants associated with the terminal subjects in sitting posture with 240 mL of drinking water at 65 ( log - linear ) portion of the curve were estimated via linear ambient temperature . The administration was as per the regression of time versus log concentration . This parameter randomization schedule and under open - label conditions . was calculated by linear least squares regression analysis US 9 ,814 ,692 B2 109 110 using last three or more non - zero plasma concentration Example 22 values . The units of 1 , were hours- ? ( 1 /h ). Fumarate Ester Oil Composition The terminal half -life was calculated using the formula : Additional fill formulations were developed comprising 0 .6937 . The unit of t1 /2 was hour ( h ) . 5 oils . Oils such as soybean oil, mineral oil , and vegetable oil The residual area in percentage was determined by the were incorporated into the fill and tested . Based on the formula : results , batches of soft capsules were prepared by rotary die encapsulation using the fill compositions shown in Table 40 . [ (AUCO - -0 - AUCO - >2 ) AUCO_ _00 ]* 100. The pharmacokinetic parameters of monomethyl fumar - 10 TABLE 40 ate for Test Product- T and Reference Product - R are sum Exemplary Oil Fill Composition marized in Table 38 . The mean plasma concentration versus time curve over eight hours is shown in FIG . 15 . Ingredient mg/ capsule % weight 15 Fumarate Ester (PSD : d90 s 100 um ) 100 - 250 20 - 50 Oil ( e . g . , mineral or vegetable oils ) 375 -225 45 - 75 00 - 2525 0 - 5 TABLE 38 Lactic Acid TOTAL 500 mg 100 % Pharmacokinetic Parameters of Monomethyl Fumarate ; Test Product - T and Reference Product - R _ 20 Mean + SD Example 23 Pharmacokinetic (Un - transformed data ) Parameters Test Product - T Reference Product- R Soft capsules comprising particles of dimethyl fumarate , monomethyl fumarate , or a combination thereof having Tmax (h ) 2 . 5 ( 1 - 5 ) 2 . 5 ( 1 - 5 ) Cmax (ng /mL ) 1321. 3 + 618 . 9 1174 . 7 + 433 . 9 particle size distribution of PSD : d90s100 um can be AUCo hùng / mL . 1818 . 415 + 532 . 5886 1907 .405 + 525 .7948 prepared with 750 mg or 500 mg matrix fills as shown in AUCO- 00 1919 .247 = 533 . 8147 * 2119 .693 + 688 . 1376 Tables 42 and 43 . rz ( 1 / h ) 1 . 323 + 0 . 3573* 1 . 103 = 0 . 3930 t1/ 2 ( h ) 0 . 563 + 0 . 1586 * 0 .864 + 0 . 8508 TABLE 42 Residual Area in 1 . 799 + 1 .0276 * 6 .481 1 14 . 0612 30 Percentage Exemplary Fill Composition

1 * n = 20 Ingredient mg/capsule % weight n = 22 Fumarate Ester (PSD : d90 s 100 um ) 150 - 375 20 - 50 Mono - and di - glycerides 150 - 375 20 - 50 Statistical Methods 35 Polyvinyl pyrrolidone 5 . 6 - 37. 5 0 .75 - 5 Polyoxyl 40 Hydrogenated castor oil 5 . 6 - 90 0 . 75 - 12 Descriptive statistics were calculated and reported for all Lactic Acid 0 - 37 . 5 0 . 0 - 5 pharmacokinetic parameters of monomethyl fumarate . TOTAL 750 mg 100 % ANOVA , power , and ratio analysis for in - transformed phar macokinetic parameters Cmax , AUCO - > , and AUCo -- were 40 calculated and reported for monomethyl fumarate . The 90 % TABLE 43 confidence interval for the ratio of the geometric least Exemplary Fill Composition squares means were calculated for the in - transformed phar macokinetic parameters , Cmax , AUC . -> , and AUC . -- . for 45 Ingredient mg/ capsule % weight monomethyl fumarate . All statistical analyses for monom Fumarate Ester (PSD : d90 s 100 um ) 100 - 250 20 - 50 Mono - and di - glycerides 100 - 250 20 - 50 ethyl fumarate were performed using PROC MIXED of Polyvinyl pyrrolidone 3 . 8 - 25 0 . 75 - 5 SAS® Version 9 . 3 ( SAS Institute Inc. , USA ) . Polyoxyl 40 Hydrogenated castor oil 3 . 8 -60 0 .75 - 12 The relative bioavailability analysis ( e . g . , geometric least 50 Lactic Acid 0 - 25 0 . 0 - 5 squares means, ratios, 90 % confidence interval, intra subject TOTAL 500 mg 100 % CV, and power) of Test Product- T versus Reference Prod uct - R for monomethyl fumarate is summarized in Table 39 . TABLE 39 Relative Bioavailability Results for Monomethyl Fumarate ( n = 23) Geometric Least Squares Means 90 % Test Reference Ratio Confidence Intra Power Parameters Product- T Product - R ( T / R ) % Interval Subject CV ( % ) ( % )

Vmax 1189 . 160 1102. 137 107. 9 92. 04 - 126 .49 32 . 1 75 . 3 AUC0- > T 1747 .744 1847. 786 94 . 6 87 .59 - 102 . 14 15 . 2 99 . 8 AUCO - 1875 .657 * 2034 . 147 92 . 2 85 . 17 - 99. 82 14 . 3 99 . 7 * n = 20 în = 22 US 9, 814 ,692 B2 111 112 Example 24 TABLE 45 - continued Soft capsules comprising particles of dimethyl fumarate , Exemplary Fill Composition monomethyl fumarate , or a combination thereof having Ingredient mg/ capsule % weight particle size distributions of PSD : d90s100 um were pre Polyoxyl 40 Hydrogenated castor oil 50 10 . 0 pared with 750 mg or 500 mg matrix fills as shown in Tables Lactic Acid 25 5 . 0 44 - 46 . TOTAL 500 mg 100 %

TABLE 44 10 Exemplary Fill Composition TABLE 46 Ingredient mg/ capsule % weight Exemplary Fill Composition Fumarate Ester (PSD : d90 s 100 um ) 214 28. 5 Mono - and di - glycerides 400 53 . 5 15 Ingredient mg/ capsule % weight Polyvinyl pyrrolidone 23 3 . 0 Polyoxyl 40 Hydrogenated castor oil 75 10 . 0 Fumarate Ester (PSD : d90 s 100 um ) 214 42 . 8 Lactic Acid 5 . 0 Oil 261 52 . 2 Lactic Acid 25 5 . 0 TOTAL 750 mg 100 % - 20 TOTAL 500 mg 100 %

TABLE 45 Example 25 Exemplary Fill Composition Soft capsules comprising particles of a fumarate ester 25 having particle size distributions of PSD : d90s100 um were Ingredient mg/ capsule % weight prepared with 750 mg or 500 mg matrix fills as shown in Fumarate Ester ( PSD : d90 s 100 um ) 214 28. 5 Tables 47 - 49 . Note that lactic acid is optional; when lactic Mono - and di - glycerides 196 53 . 5 acid is omitted , the amount of mono and diglycerides Polyvinyl pyrrolidone 15 3 . 0 ( Tables 47 -48 ) or soybean oil ( Table 49 ) is increased accord ingly . TABLE 47 Exemplary Fill Composition (750 mg ) 11 oblong capsule Component mg % wt mg % wt mg % wt mg % wt Fumarate Ester ( PSD : 100 13 . 3 107 14 . 3 107. 5 14 . 3 108 14 . 4 d90 s100 um ) Mono - and di - glycerides 514 68 .5 507 67 . 6 506 . 5 67 .5 506 67 .5 Polyvinyl pyrrolidone 23 3 . 1 23 3. 1 23 3 .1 23 3 . 1 Polyoxyl 40 75 10 ,.0 0 7575 1010 . 0 75 1010 . 0 75 10 .. 0 hydrogenated castor oil Lactic acid (optional ) 38 5 . 1 38 5 . 1 38 5 . 1 38 5 . 1 TOTAL 750 100 % 750 100 % 750 100 % 750 100 % Vehicle 650 87 643 86 642. 5 86 642 86 Lipid 612 82 605 81 604. 5 81 604 81 ??? 100 13 107 14 107. 5 14 108 14 Ratio API: Lipid 6 .12 6 . 12 5 .65 5 . 65 5 .62 5 .62 5 .59 5 .59 Ratio API: Vehicle 6 .50 6 .50 6 .01 6 .01 5 .98 5 . 98 5 .94 5 . 94 Fumarate Ester (PSD : 200 26 .7 214 28 .5 215 28 .7 216 28 .8 d90 s100 um ) Mono - and di - glycerides 414 55 .2 400 53 . 3 399 53 .2 398 53. 1 Polyvinyl pyrrolidone 23 3 . 1 23 3 . 1 23 3 . 1 w 3 . 1 Polyoxyl 40 75 10 . 0 75 1010 .. 0 0 75u 10 . 0 0 75u 1010 . 0 hydrogenated castor oil Lactic acid (optional ) 38 5 . 1 38 5 . 1 38 5 . 1 38 5 . 1

TOTAL 750 100 % 750 100 % 750 100 % 750 100 % Vehicle 550 73 536 71 535 71 534 71 Lipid 512 68 498 6666 497 6666 496496 66 ??? 200 27 214 29 215 29 216 29 Ratio API: Lipid 2 .56 2 . 56 2 . 33 2 .33 2 . 31 2 .31 2 . 30 2 . 30 Ratio API: Vehicle 2 .75 2 .75 2 .50 2 .50 2 .49 2 .49 2 .47 2 .47 US 9, 814 ,692 B2 113 114 TABLE 48 Exemplary Fill Composition (500 mg) 12 oval capsule Component mg % wt mg % wt mg % wt mg % wt Fumarate Ester (PSD : 100 20 .0 107 21. 4 107. 5 21 .5 108 21. 6 d90 s100 um ) Mono - and di - glycerides 310 62 . 0 303 60 .6 302 .5 60 .5 302 60 . 4 Polyvinyl pyrrolidone 15 3 . 0 15 3 . 0 15 3 . 0 15 3 . 0 Polyoxyl 40 50 10 . 0 50 10 . 0 50 10. 0 50 10 . 0 hydrogenated castor oil Lactic acid (optional ) 25 5. 0 25 5. 0 25 5. 0 255 .0 TOTAL 500 100 % 500 100 % 500 100 % 500 100 % Vehicle 400 80 393 79 392 . 5 79 392 78 Lipid 375 75 368 74 367. 5 74 367 73 ??? 100 20 1 07 21 107. 5 22 108 22 Ratio API: Lipid 3 .75 3 .75 3 .44 3 .44 3 .42 3 .42 3 .40 3 . 40 Ratio API: Vehicle 4 . 00 4 . 00 3 .67 3 .67 3 .65 3 .65 3 .63 3 .63 Fumarate Ester ( PSD : 200 40 . 0 214 42. 8 215 43 . 0 216 43 . 2 d90 s100 um ) Mono - and diglycerides 210 42 . 0 196 39. 2 195 3 9 . 0 194 38 . 8 Polyvinyl pyrrolidone 15 3. 0 15 3 . 0 15 3 .0 15 32219993. 0 Polyoxyl 40 50 10 . 0 50 10 . 0 0 50 1010 . 0 50 1010 .. 0 hydrogenated castor oil Lactic acid (optional ) 25 5 .0 25 5. 0 25 5. 0 25 5 . 0 TOTAL 500 100 % 500 100 % 500 100 % 500 100 % Vehicle 300 60 286 57 285 57 284 57 Lipid 275 55 261 52 260 52 259 52 ??? 200 40 214 43 215 43 216 43 Ratio API: Lipid 1 . 38 1 . 38 1 . 22 1 . 221 . 21 1 .21 1 . 20 1 . 20 Ratio API: Vehicle 1. 50 1. 50 1 .34 1 .34 1 .33 1. 33 1 .31 1 .31

TABLE 49 Exemplary Fill Composition (500 mg) 12 oval capsule | Component mg % wt mg % wt mg % wt mg % wt Fumarate Ester (PSD : 100 20 .0 107 21. 4 107. 5 21 . 5 108 21. 6 d90 s100 um ) Soybean oil 375 75 . 0 368 73 . 6 367. 5 73. 5 367 73 . 4 Lactic acid (optional ) 25 5 . 0 25 5 . 0 25 05 . 12525 5 . 0 | TOTAL 500 100 % 500 100 % 500 100 % 500 100 % Vehicle 400 80 393 79 392. 5 79 392 79 Lipid 375 75 368 74 367 . 5 74 367 73 ??? 100 20 107 21 107 . 5 22 108 22 Ratio API: Lipid 3 .75 3 .75 3 .44 3 . 44 3 . 42 3 .42 3 .40 3 . 40 Ratio API : Vehicle 4 .00 4 .00 3 .67 3 .67 3 .65 3 .65 3 .63 3 .63 Fumarate Ester ( PSD : 200 40 .0 214 42. 8 215 43. 0 216 43 . 2 d90 s100 um ) Soybean oil 275 55 . 0 261 5 2 . 2 260 52 . 0 259 51 . 8 Lactic acid (optional ) 25 5 . 0 25 5 . 0 25 5 . 0 25 5 . 0 TOTAL 500 100 % 500 100 % 500 100 % 500 100 % Vehicle 300 60 286 57 285 57 284 57 Lipid 275 55 261 52 260 52259 52 API 200 40 214 43 215 43 216 43 Ratio API:Lipid 1 .38 1 . 38 1 .22 1 . 22 1 . 21 1 .21 1 . 20 1 . 20 Ratio API: Vehicle 1 . 50 1 .50 1 . 34 1 . 34 1 . 33 1 . 33 1 .31 1 .31

Example 26 create an osmotic gradient between the fill and the acidic media . Water influx across the gradient into the shell further DMF and MMF Enteric Soft Capsule Comparison dissolves MMF and facilitates diffusion of it out of the Comparisons among enteric soft capsules comprising 60 capsule . dimethyl fumarate ( DMF ) or monomethyl fumarate (MMF ) show that about 15 % of the MMF is released from the Example 27 enteric soft capsule in acidic media (pH 1 . 2 ) in contrast to DMF ( FIG . 16 ) . Without being bound to any theory , this Vehicle and Enteric Capsule Shell Analyses difference is believed to be due to MMF' s increased solu - 65 Experiments were conducted to evaluate the effect of the bility in the matrix fill and in water . Solid particles of MMF matrix fill on a fumarate ester ' s release from enteric soft are thought to partially dissolve in the capsule matrix fill and capsules in acidic media . FIGS . 17 - 19 show the release of a US 9 ,814 ,692 B2 115 116 fumarate ester from different matrix fills in enteric soft transition to pH 6 . 8 . FIG . 21 illustrates the average of three capsules over 180 minutes in pH 1 . 2 media . FIG . 17 shows two - stage dissolutions of fumarate ester capsules in a coated a fill comprising soybean oil ; FIG . 18 shows a fill compris soft gel capsules , high - Bloom soft capsules , or enteric soft ing mixture of soybean and vegetable oil ; and FIG . 19 shows capsules . The enterically coated enteric soft capsules a fill comprising a mixture of mono - and di - glycerides ( e . g ., 5 released about 50 % of the fumarate ester after about 40 - 50 Capmul® MCM ) . About 23 % of the fumarate ester released minutes after transition to pH 6 . 8 . FIG . 22 compares the data from the soybean oil fill after 180 min . About 15 % of the shown in FIG . 21 with the release of DMF from an enteric fumarate ester released from the soybean and vegetable oil soft capsule (as shown in FIG . 16 ). FIG . 23 compares the fill after 180 min . About 25 % of the fumarate ester released effect of a pre - coating (aqueous hydroxypropyl methylcel from the soybean oil fill after 180 min . 10 lulose ) applied prior to the application of the enteric coating of typical soft capsules or enteric soft capsules comprising Example 28 a matrix fill of a fumarate ester. The enterically coated soft capsules released about 50 % of the fumarate ester after Capsule Analysis about 30 - 40 minutes after transition to pH 6 . 8 . The enteri In order to prevent the release of fumarate ester fills from 15 cally coated enteric soft capsule released about 50 % of the capsules , the effect of coatings was evaluated . Soft capsules fumarate ester after about 40 - 50 minutes after transition to and enteric soft capsules were manufactured containing pH 6 . 8 . fumarate ester fill matrices ( e . g . , Tables 44 - 46 ) . These capsules were then coated with an enteric coating ( e . g . , Example 29 aqueous methacrylic acid copolymer ( Eudragit® L100 -55 ) 20 and triethyl citrate ) and evaluated in two - stage dissolution Soft capsules comprising particles of fumarate esters experiments . Typical soft gel capsules ( e .g . , Table 5 ) , high - (e . g ., monomethyl fumarate , dimethyl fumarate , or a com Bloom soft capsules (e .g ., Table 6 ), or enteric soft capsules bination thereof) having particle size distributions of PSD : ( e. g ., Table 8 ) were coated and evaluated . FIG . 20 illustrates d90s100 um were prepared with 600 mg , 700 mg, or 800 mg the average of three two -stage dissolutions of fumarate ester 25 matrix fills as shown in Tables 50 - 55 . Note that lactic acid capsules in a coated soft gel capsules or a high - Bloom soft is optional ; when lactic acid is omitted , the amount of mono capsules . The enterically coated soft capsules released about and diglycerides ( Tables 50 , 52 , 54 ) or soybean oil ( Tables 50 % of the fumarate ester after about 30 - 40 minutes after 51 , 53 , 55 ) is increased accordingly . TABLE 50 Exemplary Fill Composition (600 mg) Component mg % wt mg % wt mg % wt mg % wt Fumarate Ester (PSD : 100 16. 7 107 17 .8 107. 5 17. 9 108 18. 0 d90 s100 um ) Mono - and di - glycerides 392 65 . 3 385 64. 2 384 .5 64 . 1 384 64 .0 Polyvinyl pyrrolidone 1818 3 . 0 18 3. 0 18 3 .0 18 3 . 0 Polyoxyl 40 60 10 . 0 60 10 . 0 60 10 . 0 60 10 . 0 hydrogenated castor oil Lactic acid (optional ) 30 5 .0 305 .0 30 5. 0 30 5. 0 TOTAL 600 100 % 600 100 % 600 100 % 600 100 % Vehicle 500 83 493 82 492 . 5 82 492 82 Lipid 470 78 463 77 462. .5 777 462 77 ??? 100 17 107 18 107. 5 18 108 18 Ratio API :Lipid 4 . 70 4 . 70 4 . 33 4 .33 4 .30 4 . 30 4 . 28 4 . 28 Ratio API: Vehicle 5 .00 5. 00 4 .61 4. 61 4. 58 4. 58 4. 56 4 .56 Fumarate Ester (PSD : 200 33. 3 214 35. 7 215 35 .8 216 36. 0 d90 s100 um ) Mono- and diglycerides 292 48. 7 278 46. 3 277 46 .2 276 46 .0 Polyvinyl pyrrolidone 18 3 .0 18 3 . 0 18 3 .0 18 3 .0 Polyoxyl 40 60 10 .0 60 10. 0 60 10 .0 60 10 . 0 hydrogenated castor oil Lactic acid (optional ) 30 5 .0 30 5 .0 30 5 .0 30 5 .0 TOTAL 600 100 % 600 100 % 600 100 % 600 100 % Vehicle 400 67 386 64 385 64 384 64 Lipid 370 62 356 5959 3553a 59 354 59 ??? 200 33 214 36 215u 36 216 36 Ratio API: Lipid 1. 85 1. 85 1. 66 1. 66 1. 65 1. 65 1. 64 1. 64 Ratio API: Vehicle 2. 00 2 .00 1 . 80 1. 80 1. 79 1. 79 1. 78 1. 78 US 9, 814 ,692 B2 117 118 TABLE 51 Exemplary Fill Composition (600 mg) Component mg % wt mg % wt mg % wt mg % wt Fumarate Ester (PSD : 100 16 . 7 107 17. 8 107. 5 17 . 9 108 18 . 0 d90 s100 um ) Soybean oil 470 78. 3 463 77 .2 462. 5 77 . 1 462 77. 0 Lactic acid (optional ) 30 5 . 0 30 5 .0 30 5 . 0 30 5 . 0 TOTAL 600 100 % 600 100 % 600 100 % 600 100 % Vehicle 500 83 493 82 492 . 5 82 492 82 Lipid 470 78 463 77 462. 5 77 462 77 ??? 100 17 107 18 107. 5 18 108 18 Ratio API: Lipid 4 .70 4 .70 4 .33 4 . 33 4 . 30 4 . 30 4 . 28 4 . 28 Ratio API: Vehicle 5 . 00 5 .00 4 .61 4 .61 4 .58 4 . 58 4 . 56 4 . 56 Fumarate Ester (PSD : 200 33. 3 214 35 .7 215 35 . 8 216 36. 0 d90 < 100 um ) Soybean oil 370 61. 7 356 59 . 3 355 59 . 2 354 59 . 0 Lactic acid (optional ) 30 5 . 0 30 5 . 0 30 5 . 0 30 5 . 0 TOTAL 600 100 % 600 100 % 600 100 % 600 100 % Vehicle 400 67 386 64 385 64 384 64 Lipid 370 62 356 59 355 59354 59 ??? 200 33 214 36 215 36 216 36 Ratio API: Lipid 1 . 85 1 .85 1 . 66 1 . 66 1 . 65 1 .65 1 . 64 1 .64 Ratio API: Vehicle 2 .00 2 .00 1 .80 1. 80 1 . 79 1 .79 1 . 78 1 . 78

TABLE 52 Exemplary Fill Composition (700 mg) Component mg % wt mg % wt mg % wt mg % wt Fumarate Ester (PSD : 100 1 4 . 3 107 15 . 3 107. 5 15 . 4 108 15 .4 d90 s100 um ) Mono - and di - glycerides 474 67 . 7 467 66 . 7 466 . 5 66 . 6 466 66 . 6 Polyvinyl pyrrolidone 21 3 . 0 21 3 . 0 21 3. 0 21 3 . 0 Polyoxyl 40 70 10 .0 70 100 . 70 10. 0 70 10 .0 hydrogenated castor oil Lactic acid (optional ) 35 5 .0 35 5. 0 35 5 .0 35 5. 0 TOTAL 700 100 % 700 100 % 700 100 % 700 100 % Vehicle 600 86 593 85 592. 5 85 592 85 Lipid 565 81 558 80 557. 5 80 557 80 ??? 100 14 107 15 107, 5 15 108 15 Ratio API: Lipid 5 .65 5 . 65 5 . 21 5 .21 5 . 195 .195 . 16 5 . 16 Ratio API: Vehicle 6 . 00 6 .00 5 . 54 5 .54 5 .51 5 .51 5 .48 5 . 48 Fumarate Ester ( PSD : 200 28 .6 214 30 .6 215 30 .7 216 30. 9 d90 s100 um ) Mono - and diglycerides 374 53 . 4 360 5 1. 4 359 51. 3 358 51. 1 Polyvinyl pyrrolidone 21 3 .0 21 3 . 0 21 3 .0 21 3 .0 Polyoxyl 40 70 10 . 0 70 10 .0 70 10 . 0 70 10 . 0 hydrogenated castor oil Lactic acid (optional ) 35 5. 0 35 5. 0 35 5. 0 35 5. 0 TOTAL 700 100 % 700 100 % 700 100 % 700 100 % Vehicle 500 71 48669 485 69 484 69 Lipid 465 66 451 64 450 64 44964 API 200 29 214 31 215 31 216 31 Ratio API: Lipid 2. 33 2. 33 2. 11 2. 11 2. 09 2. 09 2. 08 2 .08 Ratio API: Vehicle 2. 50 2. 50 2. 27 2. 27 2. 26 2. 26 2. 24 2. 24 US 9 ,814 ,692 B2 119 120 TABLE 53 Exemplary Fill Composition (700 mg) Component mg % wt mg % wt mg % wtmg % wt Fumarate Ester (PSD : 100 14 . 3 107 15 . 3 107. 5 15 . 4 108 15 . 4 d90 < 100 um ) Soybean oil 565 80. 7 558 79. 7 557. 5 79 .6 557 79. 6 Lactic acid (optional ) 35 5 .0 35 5 .0 35 5 .0 35 33 . 0 TOTAL 700 100 % 700 100 % 100 100 % 700 100 % Vehicle 600 86 593 85 592. 5 85 592 113 Lipid 565 81 558 80 557. 5 80 557 80 ??? 100 14 107 15 107 . 5 15 108 15 Ratio API: Lipid 5 . 65 5 .65 5 .21 5 .21 5 . 19 5 . 19 5 . 16 5 . 16 Ratio API: Vehicle 6 .00 6 .00 5 .54 5 . 54 5 .51 5 .51 5 . 48 7 . 30 Fumarate Ester (PSD : 200 28. 6 214 30 . 6 215 30 .7 216 30. 9 d90 s100 um ) Soybean oil 465 66 .4 451 64. 4 450 64 . 3 449 64 . 1 Lactic acid (optional ) 35 5 . 0 35 5 . 0 35 5 . 0 35 5 . 0 TOTAL 700 100 % 700 100 % 700 100 % 700 100 % Vehicle 500 71 486 69 485 69 484 69 Lipid 465 66 451 64 450 64 449 6 4 ??? 200 29 214 31 215 31 216 31 Ratio API: Lipid 2. 33 2. 33 2 . 11 2. 11 2. 09 2. 09 2. 08 2. 08 Ratio API: Vehicle 2 . 50 2 .50 2 .27 2 . 27 2 . 26 2 . 26 2 .24 2 . 24

TABLE 54 Exemplary Fill Composition (800 mg) Component mg % wt mg % wt mg % wt mg % wt Fumarate Ester (PSD : 100 12 . 5 107 15 . 3 107. 5 13 . 4 108 13 . 5 d90 s100 um ) Mono - and diglycerides 556 69 .5 549 68. 6 548. 5 68 .6 548 68 . 5 Polyvinyl pyrrolidone 24 3 . 0 24 3 . 0 24 3 . 0 24 3 . 0 Polyoxyl 40 80 10 . 0 80 10 . 0 80 10. 0 80 10 . 0 hydrogenated castor oil Lactic acid (optional ) 16 5 . 0 40 5 . 0 40 5 . 0 40 5 .0 TOTAL 800 100 % 800 100 % 800 100 % 800 100 % Vehicle 700 88 693 87 692. 5 87 692 87 Lipid 660 83 653 82 652. 5 82 652 82 ??? 100 13 107 15 107 . 5 13 108 14 Ratio API: Lipid 6 .60 6 .60 6 .10 5 . 34 6 .07 6. 07 6 .04 6 .04 Ratio API: Vehicle 7. 00 7. 00 6. 48 5 .67 6. 44 6 .44 6. 41 6. 41 Fumarate Ester (PSD : 200 25 . 0 214 26 . 8 215 26 .9 216 27 .0 d90 s100 um ) Mono- and diglycerides 456 57. 0 442 55. 3 441 55 .1 440 55. 0 Polyvinyl pyrrolidone 24 3. 0 24 3. 0 24 3 .0 24 3. 0 Polyoxyl 40 80 10 . 0 80 10 . 0 80 10 .0 80 10 . 0 hydrogenated castor oil Lactic acid (optional ) 40 5 .0 405 . 0 40 5 . 0 40 5 .0 TOTAL 800 100 % 800 100 % 800 100 % 800 100 % Vehicle 600600 7575 586 73 585 7373 584584 73 Lipid 560 70 546 68 545 68 544 68 ??? 200 25 214 27 215 27 216 27 Ratio API :Lipid 2. 80 2. 80 2. 55 2. 55 2. 53 2. 53 2. 52 2. 52 Ratio API: Vehicle 3 .00 3 .00 2 .74 2 . 74 2 . 72 2. 72 2. 70 2 .70 US 9, 814 ,692 B2 121 122 TABLE 55 Exemplary Fill Composition ( 800 mg) Component mg % wt mg % wt mg % wt mg % wt Fumarate Ester (PSD : 100 12. 5 107 13 .4 107. 5 13 .4 108 13 .5 d90 s100 um ) Soybean oil 660 82 . 5 653 8 1. 6 652 . 5 81. 6 652 81 . 5 Lactic acid (optional ) 40 5 . 0 40 5 . 0 40 5 . 0 40 5 . 0 TOTAL 800 100 % 800 100 % 800 100 % 800 100 % Vehicle 700 88 693 87 692 . 5 87 692 87 Lipid 660 83 653 82 652 . 5 82 652 82 ??? 100 13 107 13 107 . 5 13 108 14 Ratio API: Lipid 6 .60 6 .60 6 . 10 6 . 10 6 . 07 6 .07 6 .04 6 .04 Ratio API: Vehicle 7 . 00 7 . 00 6 .48 6 . 48 6 . 44 6 . 44 6 .41 6 . 41 Fumarate Ester (PSD : 200 25 . 0 214 26 . 8 215 26 .9 216 27 . 0 d90 s100 um ) Soybean oil 560 70 .0 546 68. 3 545 68 .1 544 68 .0 Lactic acid (optional ) 40 5 . 0 40 5 . 0 40 5 . 0 40 5 . 0 TOTAL 800 100 % 800 100 % 800 100 % 800 100 % Vehicle 600 75 586 73 585 73 584 13 Lipid 560 70 546 68 545 68 544 68 ??? 200 25 214 27 215 27 216 27 Ratio API: Lipid 2 .80 2 .80 2 .55 2 . 55 2 . 53 2 .53 2 .52 2 .52 Ratio API: Vehicle 3 .00 3 . 00 2 . 74 2 .74 2 . 722 .72 2 . 70 2 .70

25 Example 30 Soft capsules comprising particles of fumarate esters ( e . g . , monomethyl fumarate , dimethyl fumarate , or a com bination thereof) having particle size distributions of PSD : 30 d90s100 um were prepared with 625 mg, matrix fills as shown in Tables 56 -57 . TABLE 56 Exemplary Fill Composition (625 mg) Component mg % wt mg % wt mg % wt mg % wt Fumarate Ester (PSD : 100 16 . 0 107 17 . 1 107. 5 17 . 2 108 17 . 3 d90 s100 um ) Mono - and di - glycerides 412. 5 66. 0 405. 5 64 . 9 405 64. 8 404. 5 64. 7 Polyvinyl pyrrolidone 18. 8 3 . 0 18 . 8 3 . 0 18 . 8 3 . 0 18 . 8 3 . 0 Polyoxyl 40 62. 5 10 . 0 62 . 5 10 . 0 62. 5 10 . 0 62. 5 10 . 0 hydrogenated castor oil Lactic acid (optional ) 31. 2 5 . 0 31. 2 5 . 0 31. 2 5 .0 31. 2 5 . 0 TOTAL 625 100 % 625 100 % 625 100 % 625 100 % Vehicle 525 84 518 517 . 5 517 83 Lipid 493 . 8 79 486 . 8 78 486 . 3 78 485 . 8 78 ??? 100 16 107 17 107. 5 17 108 17 Ratio API: Lipid 4 . 94 4 . 94 4 .55 4 . 55 4 .52 4 .52 4 .50 4 .50 Ratio API: Vehicle 5 .25 5 .25 4 .84 4 . 84 4 . 81 4 .81 4 .79 4 .79 Fumarate Ester ( PSD : 200 32 .0 214 34 . 2 215 34 . 4 216 34 . 6 d90 s100 um ) Mono - and diglycerides 312 .5 50 . 0 298 . 5 47. 8 297 . 5 47. 6 296 .5 47. 4 Polyvinyl pyrrolidone 18. 75 3 .0 18 .75 3 . 0 18 .75 3. 0 18. 75 3 .0 Polyoxyl 40 62. 5 10 . 0 62 . 5 10. 0 62 . 5 10 . 0 62. 5 10 . 0 hydrogenated castor oil Lactic acid ( optional) 31. 25 5 . 0 31 . 25 5 . 0 31. 25 5. 0 31. 25 5 .0 TOTAL 625 100 % 625 100 % 625 100 % 625 100 % Vehicle 425 68 411 66 410 66 409 65 Lipid 393 . 8 63 379. 8 61 378 . 8 61 377. 8 60 ??? 200 32 214 34 215 34 216 35 Ratio API: Lipid 1. 97 1 .97 1 .77 1 .77 1 .76 1 . 76 1 .75 1 .75 Ratio API: Vehicle 2 . 13 2. 13 1 .92 1 .92 1 .91 1. 91 1 .89 1 .89 US 9, 814 ,692 B2 123 124 TABLE 57 Exemplary Fill Composition (625 mg) Component mg % wt mg % wt mg % wt mg % wt Fumarate Ester ( PSD : 100 16 . 0 107 17 . 1 107 . 5 17 . 2 108 17. 3 d90 s100 um ) Soybean oil 525 84 . 0 518 82. 9 517 . 5 82 . 8 517 82 . 7 TOTAL 625 100 % 625 100 % 625 100 % 625 100 % Lipid 525 84 518 83 517 . 5 83 5 17 83 ??? 100 16 107 17 107 .5 17 108 17 Ratio API: Lipid 5 . 25 5 . 25 4 .84 4 .84 4 .81 4 . 81 4 .79 4 .79 Fumarate Ester ( PSD : 200 32. 0 214 34. 2 215 34 . 4 216 34. 6 d90 s100 um ) Soybean oil 425 68. 0 411 65. 8 410 65. 6 409 6 5. 4 TOTAL 625 100 % 625 100 % 625 100 % 625 100 % Lipid 425 68 411 66 410 66 409 65 API 200 32 214 34 215 34 216 35 Ratio API: Lipid 2 . 13 2 . 13 1. 92 1 .92 1 .91 1 . 91 1 .89 1 .89

Example 31 TABLE 59 -continued Soft capsules comprising particles of a fumarate ester Test 1 Formulation having particle size distributions of PSD : d90s100 um were 25 Component Mass (mg ) Weight % manufactured for clinical investigations. Six different for Polyoxyl 40 Hydrogenated Castor Oil 62. 5 10 . 0 mulations were prepared . See Table 58 . The dosage forms Lactic Acid 31 . 2 5 . 0 comprised two different doses of fumarate ester, two differ ent fill formulations , and two different shell components . TOTAL 625 .0 100 % The doses were either 200 mg or 214 mg of fumarate ester 30 and the fill formulations either comprised a mixture of mono - and diglycerides ( e. g ., Capmul® MCM ) or soybean TABLE 60 oil . Tables 59 -64 . The soft capsules were either an enteric soft capsule (EnteriCare® , Banner Life Sciences) or soft Test 2 Formulation gelatin capsules. See Tables 65 -66 . Both types of capsules 35 Component Mass (mg ) Weight % were manufactured using rotary die encapsulation . Fumarate Ester 200 . 0 34 . 2 After manufacturing and drying, the capsules were coated Capmul ® MCM 279. 0 47 . 8 with a hydroxypropylmethylcellulose undercoat and dried . Povidone K30 17 . 5 3 . 0 The capsules were then coated with an enteric coating 10 Polyoxyl 40 Hydrogenated Castor Oil 58 . 4 10 . 0 containing methacrylic acid , ethyl acrylate copolymer ( e . g . , Lactic Acid 29 . 2 5 . 0 EUDRAGIT® L100 - 55 , Evonik ; Acryl -EZE® , Colorcon ) . TOTAL 584 . 3 100 % Table 67 . Finally , a polyvinyl alcohol moisture barrier top -coating was applied to the enterically coated capsules ( e . g . , Opadry® amb II, Clear , Colorcon ). Table 68 . 45 TABLE 61 TABLE 58 Test 3 Formulation Summary of Clinical Investigation Formulations Component Mass (mg ) Weight % Test 1 Test 2 Test 3 Test 4 Test 5 Test 6 50 Fumarate Ester 214 . 00 34 . 2 Capmul ® MCM 298. 5 47 . 8 Fumarate 214 200 214 214 200 214 Povidone K30 18 . 8 3 . 0 Ester Dose Polyoxyl 40 Hydrogenated Castor Oil 62 . 5 10 . 0 (mg ) Lactic Acid 31 . 2 5 . 0 Formulation Capmul Capmul Capmul Soy - Soybean Soy bean oil oil bean oil TOTAL 625 . 0 100 % Shell Enteric Enteric Softgel Enteric Enteric Softgel 55 SGC SGC SGC SGC TABLE 62

TABLE 59 60 Test 4 Formulation Test 1 Formulation Component Mass (mg ) Weight % Component Mass (mg ) Weight % Fumarate Ester 214 . 0 34 . 2 Soybean oil 411 . 0 65 . 8 Fumarate Ester 214 . 0 34 . 2 Capmul ® MCM 298 . 5 47 . 8 65 TOTAL 625 . 0 100 % Povidone K30 18 . . 8 33 . 00 US 9, 814 ,692 B2 125 126 TABLE 63 TABLE 68 Moisture Barrier Top Coating Composition (Opadry ® amb Test 5 Formulation II , Clear ; Colorcon ) Component Mass (mg ) Weight % Component Mass ( g ) Weight % Fumarate Ester 200200 . 0 34 . 2 2 Polyvinyl alcohol 600 1010 .. 00 Soybean oil 65 . 8 Glyceryl mono -caprylate - caprate 384. 0 Sodium lauryl sulfate Talc TOTAL 584 .0 100 % 10 Titanium Dioxide Water * 5400 9090 . 0 TOTAL 6000 100 . 0 % TABLE 64 * A majority of the water evaporates during the coating process . Test 6 Formulation 15 Component Mass (mg ) Weight % Example 32 Fumarate Ester 214 . 0 34 . 2 A single - dose, randomized , open - label , 4 - way crossover, Soybean oil 411 . 0 65 . 8 pilot comparative bioavailability study of a delayed -release TOTAL 625. 0 100 % fumarate ester at a dose of 200 mg and 214 mg in capsules 2016 and TECFIDERA® 240 mg dimethyl fumarate (DMF ) delayed - release capsules in healthy male and female volun TABLE 65 teers under fasting conditions was performed . This pilot 25 study assessed the tolerability , pharmacokinetics and com EnteriCare ® Enteric soft capsule shell composition parative bioavailability of the fumarate ester in three test Weight % formulations and at two dose strengths ( 200 mg and 214 mg Component Mass ( g ) delayed - release capsules ) and one reference drug, TECFID Gelatin , 150 Bloom 116 . 6 27 . 3 ERA® ( dimethyl fumarate ; Biogen ) 240 mg delayed - release Methacrylic Acid Copolymer Type A 44 . 6 10 .5 Ammonium Hydroxide 6 . 9 1 . 6 30 capsules , in healthy male and female volunteers under Glycerin 72. 2 16 . 9 fasting conditions. A sample size of 24 subjects was selected Triethyl Citrate 5 .0 1 . 2 for this study . The study population included healthy, non Purified water 180 .2 42. 2 smoking , male and non - pregnant female volunteers, 18 Titanium Dioxide 0 . 867 0 . 20 years of age or older, with a body mass index (BMI ) within FD & C Blue # 1 0 .213 0 .05 - 35 18 . 5 - 29. 9 kg/ m² , inclusive . TOTAL 426. 6 100. 0 % Six investigational formulations of a fumarate ester in delayed - release soft capsules were evaluated . Three of these formulations comprise mono - and diglycerides ( e . g . , Cap mul® MCM ; Test Samples 1 -3 ) and three comprise soybean TABLE 66 40 oil ( Test Samples 4 -6 ) . Two dose strengths, 200 mg ( Tests 2 Soft capsule shell composition and 5 ) and 214 mg of fumarate ester ( Tests 1 , 3 , 46 ) , were manufactured using the mono - and di - glyceride and soybean Component Mass ( g ) Weight % oil- based formulations described herein in Example 31 . Gelatin , 195 Bloom 172 . 4 52 . 2 Additionally , two different soft capsule shell formulations Polysorb 85 /70 /00 ( D - Sorbitol/ sorbitans ) 99 . 0 30 . 0 45 were evaluated on the higher ( 214 mg) test formulations as Purified water 58 . 0 17 . 6 indicated by the labels EnteriCare® ( enteric soft capsule ; Titanium Dioxide 0 .8 0 . 24 Tests 1 , 2 , 4 , 5 ) and 195 bloom ( 195 -Bloom gelatin soft FD & C Blue # 1 0 . 2 0 . 06 capsule that is enterically coated ; Tests 3 and 6 ) . The relative TOTAL 330 .4 100 .0 % bioavailability of the three mono - and di - glyceride -based 50 formulations was assessed against the reference listed drug (RLD ) , TECFIDERA? ( dimethyl fumarate ; Biogen ), delayed -release oral capsule , 240 mg, manufactured by TABLE 67 Biogen , Inc . A companion study assessed the soybean oil Enteric Coating Composition ( Acryl -EZE ® , Colorcon ) based formulations against TECFIDERA® . These studies 55 were conducted to evaluate formulations and dose strengths Component Mass ( g ) Weight % that are bioequivalent to TECFIDERA® 240 mg, and to Methacrylic acid , ethyl acrylate copolymer 1826 86 . 6 evaluate the tolerability , including the incidence of flushing Talc and gastrointestinal side effects , of a fumarate ester when Triethyl citrate administered to healthy subjects. Sodium bicarbonate Colloidal anhydrous silica 60 TECFIDERA® (dimethyl fumarate ) is indicated for the Sodium lauryl sulfate treatment of patients with relapsing forms of multiple scle Triethyl citrate * 233 . 8 11 . 4 rosis . See TECFIDERA® product label, incorporated by Water * 8236 399 . 8 reference herein for such teachings. TOTAL 2059 . 8 100 . 0 % The mechanism by which dimethyl fumarate (DMF ) * Additional triethyl citrate added . 65 exerts its therapeutic effect in multiple sclerosis is unknown. " A majority of the water evaporates during the coating process . DMF and its metabolite , monomethyl fumarate (MMF ) , activate the Nuclear factor (erythroid - derived 2 ) - like 2 US 9 ,814 ,692 B2 127 128 (Nrf2 ) pathway in vitro and in vivo in animals and humans. randomized , open - label, 4 - way crossover, four- period , four The Nrf2 pathway is involved in the cellular response to sequence , four - treatment, single -center , comparative bio availability study of three formulations of a fumarate ester at oxidative stress . MMF has been identified as a nicotinic acid doses of 214 mg and 200 mg in delayed - release capsules and receptor agonist in vitro . TECFIDERA? (dimethyl fumarate ) 240 mg delayed - re After oral administration of TECFIDERA® , dimethyl 5 lease capsules ( Biogen , Inc . ) . The formulations were studied fumarate undergoes rapid presystemic hydrolysis by using a crossover design with 24 healthy, non - smoking male esterases and is converted to its active metabolite , monom and non -pregnant female volunteers being administered an ethyl fumarate (MMF ) . Dimethyl fumarate is not quantifi oral dose of 1x214 mg, 1x200 mg, or 1x240 mg delayed able in plasma following oral administration of TECFID release capsule under fasting conditions . There was at least ERA® . Pharmacokinetic analyses related to TECFIDERA? 10 a 2 -day washout period between the study periods. The were performed by evaluating plasma MMF concentrations . washout period of at least 2 days was estimated to be Pharmacokinetic data were obtained in subjects with mul adequate in avoiding carry -over effects of the preceding tiple sclerosis and healthy volunteers. treatments . The median Tmax of MMF is 2 - 2 . 5 hours . The peak plasma Blood samples were obtained by direct venipuncture in concentration (Cmar ) and overall exposure (AUCoverall ) the arm and collected in pre - chilled sodium fluoride / potas increased approximately dose proportionally in the dose 15 sium oxalate 6 mL Vacutainers® . Blood sample collection range studied ( 120 mg to 360 mg) . Following administration times were recorded on the appropriate source documents of TECFIDERA® 240 mg twice a day with food , the mean and reported for each subject. Blood samples were collected Cmax of MMF was 1 .87 mg/ L and AUCoverall was 8 .21 at pre - dose (0 hour) , and at 0 .5 , 1, 1. 5, 2 , 2 .5 , 3, 3 .5 , 4 , 4. 5 , mg .hr / L in MS patients . 5 , 5 .5 , 6 , 8 , 12 and 24 -hours post - dose in each study period . A high - fat, high -calorie meal did not affect the AUC of 20 Subjects were confined to the clinic from at least 10 hours MMF but decreased its Co by 40 % ; the TmarMAX was delayed prior to dosing until at least 24 - hours post- dose in Period 4 , from 2 . 0 hours to 5 . 5 hours . The incidence of flushing was for a total of at least 178 hours (approximately 8 days ) in the reduced by approximately 25 % in the fed state . study . The apparent volume of distribution of MMF varies between 53 and 73 L in healthy subjects . Human plasma The assignment of treatment groups ( randomization protein binding of MMF is 27 -45 % and independent of 25 scheme) was generated by a computer program designed and concentration . run in SAS® Version 9 . 4 . This was an open - label study and In humans, dimethyl fumarate is extensively metabolized subjects as well as clinic staff were not blinded to the by esterases , which are ubiquitous in the gastrointestinal randomization . The analytical laboratory did not have access tract , blood , and tissues , before DMF reaches the systemic to the randomization scheme until the bioanalytical analyses circulation . Furthermetabolism of MMF occurs through the 30 were completed . tricarboxylic acid ( TCA ) cycle , with no involvement of the Subjects who meet the eligibility criteria were randomly cytochrome P450 (CYP ) system . MMF, fumaric acid , citric assigned to receive the study drugs according to one of the acid , and glucose are the major metabolites detectable in four dosing sequences : plasma. Exhalation of CO , is the primary route of elimination , 35 accounting for approximately 60 % of the TECFIDERA? Period 1 Period 2 Period 3 Period 4 DMF dose . Renal and fecal are minor elimination routes , accounting for 16 % and 1 % of the dose , respectively . Trace Sequence 1 T1 T2 T3 amounts of MMF were present in urine . Sequence 2 12T2 T313 Sequence ???3 T3 & The terminal half- life of MMF is approximately 1 hour Sequence 4 and no circulating MMF is present at 24 hours in the 40 T1 TI majority of individuals . Accumulation of MMF does not occur with multiple doses of TECFIDERA? . Each subject was scheduled to have received a total of four This study was conducted in normal healthy male and treatments by the end of the study . non - pregnant female volunteers. This was a single - dose , The treatment labeling scheme was as follows: Treatment Code T1 (Test ) T2 (Test ) T3 ( Test ) R (Reference ) Drug Name : Fumarate Ester Fumarate Ester Fumarate Ester TECFIDERA® (dimethyl fumarate ) Strength : 214 mg 200 mg 214 mg 240 mg Dosage Form : EnteriCare ® DR EnteriCare ® DR 195 Bloom DR Delayed - release Soft Capsules Soft Capsules Soft Capsules Capsules Manufacturer BLS BLS BLS Biogen Dose : 1 x 214 mg 1 x 200 mg 1 x 214 mg 1x 240 mg Fill Capmul , Capmul, Capmul, Table 59 Table 60 Table 61 Treatment Code T4 (Test ) T5 ( Test) T6 ( Test ) R ( Reference ) Drug Name: Fumarate Ester Fumarate Ester Fumarate Ester TECFIDERA? (dimethyl fumarate ) Strength : 214 mg 200 mg 214 mg 240 mg Dosage Form : EnteriCare ® DR EnteriCare ® DR 195 Bloom DR Delayed - release Soft Capsules Soft Capsules Soft Capsules Capsules Manufacturer BLS BLS BLS Biogen Dose : 1 x 214 mg 1 x 200 mg 1 x 214 mg 1 x 240 mg Fill Soybean oil, Soybean oil, Soybean oil , Table 62 Table 63 Table 64 US 9 ,814 ,692 B2 129 130 Pharmacokinetic parameters were calculated using non tration data are plotted in FIGS. 24 and 25 , respectively . The compartmental analysis (NCA ) method using SAS® Version reference drug (Ref ) in both studies is for TECFIDERA? 9 .4 . The following pharmacokinetic parameters were esti (dimethyl fumarate ) 240 mg delayed - release capsules (Bio mated (where possible ) for monomethyl fumarate and gen , Inc . ) . included in the pharmacokinetic and statistical analysis for 5 the subjects in the final data set: TABLE 69 Cmar: The maximal observed plasma concentration . Tmør: Time when the maximal plasma concentration is Mean Plasma Monomethyl Fumarate Concentration as a Function observed . of Time after Dosing Samples T1 -T3 and Reference Drug AUCO - x : Area under the concentration - time curve from 10 time zero until the lastmeasurable concentration or last Sample : sampling time t , whichever occurs first . AUC , is estimated using the trapezoidal method . TOT2 AUC . -- : Area under the concentration - time curve from time zero to infinity , calculated as AUC . -> z + Ciasta , 15 Ti Conc. T3T3 Ref where Ciast is the last measurable concentration . à : Terminal elimination rate constant, estimated by linear Time Conc. Std (ng Std Conc. Std Conc. Std regression analysis of the terminal portion of the natu ( h ) ( ng / mL) Dev . mL) Dev. ( ng/ mL) Dev. ( ng/ mL) Dev. ral log of concentration ( In -concentration ) vs . time plot. ta: Terminal elimination half - life , estimated as ln ( 2 ) . 20 Pre - 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 .0 0 .0 0 . 0 During pharmacokinetic and statistical analyses , drug dosing concentrations below the lower limit of quantitation of the 0 . 5 0 .0 0 .0 0 .0 0 .0 0 .0 0 . 0 138 .3 36 . 4 assay were considered as zero prior to the first measurable 1. 0 415 .3 138. 1 7 . 1 21 . 5 0 . 0 0 .0 2611 . 3 716 . 3 concentration . Drug concentrations that were below the limit 1 .in 5 389 . 8 117. 1 44 .5 77 . 5 453. 9 99 . 7 2421. 5 638 . 9 of quantitation following a measurable result were consid - 25 2 .0 191. 4 53. 6 66 . 1 114 . 2 3467. 1 732 .6 2625 .7 827 . 1 ered as missing during pharmacokinetic calculations and 2 . 5 1386 .6 302. 3 153 . 0 239 . 2 3339. 1 830 . 8 2484 . 6 787. 7 estimations. 3 . 0 2196 . 7 463. 6 197. 1 204 . 1 4062 . 5 977. 3 2487. 7 705 . 2 Missed samples and non - reportable concentrations (e . g . 3 . 5 2124 .5 518 . 7 240 .4 218 . 5 3142 . 7 903. 1 2279. 7 617 .4 quantity not sufficient) from the analytical laboratory were 1988 . 8 532 . 8 450 . 5 453. 0 2548 . 8 781. 8 1686 . 9 466 . 4 treated in the pharmacokinetic analysis as if they had not 30 4 .5 2099. 3 527. 3 635 .5 510 . 2 2583. 9 806. 4 3169 .3 702. 5 been scheduled for collection . 5 .0 2879 . 4 727. 4 909 . 5 488 .7 3747. 9 866 .7 1933 . 2 543 . 2 The à , t1 /2 , and AUC . - - . parameters were not estimated 5 .5 2204 .0 468 .8 698 . 8 288 .3 2092. 5 489 . 6 1718 . 4 440 . 2 for plasma concentration - time profiles where the terminal 6 . 0 1024 . 6 251. 2 487 . 4 268 . 2 1600 . 8 484 .2 655 . 9 167 . 3 linear phase was not clearly defined (R < 0 . 8 ). 8 . 0 697 .6 182. 6 119 . 9 161 . 4 218 . 6 66 . 7 216 . 0 50 . 9 Descriptive statistics (min . ,max ., median , mean , standard 35 12 .0 79 .8 16 . 3 4 .3 15 .7 0 .0 0 . 0 59 .6 15 . 3 deviation , and coefficient of variability ) of all pharmacoki 24. 0 0. 0 0. 0 0 .0 0. 0 0 .0 0. 0 0 .0 0. 0 netic parameters were calculated for monomethyl fumarate for the Test and Reference products . ANOVA including sequence , subjects nested within sequence , period and treatment were performed on the 40 TABLE 70 In - transformed data for AUCO -> , AUC . -- , and Cmax and on Mean Plasma Monomethyl Fumarate Concentration as a Function of the untransformed data for Tmax , à , and t1/ 2 . Tmax was Time after Dosing Samples T4 - T6 and Reference Drug analyzed using an additional non - parametric test (Wilcoxon test ) . Sample : The 90 % Confidence Interval of the Test /Reference ratios 45 of geometric means for AUCo- > , AUC . - 7 . , and Cmax was T4 T5 T6 - Ref calculated based on the LSMEANS and ESTIMATE of the Conc. Conc . Conc. Conc . ANOVA . Additional statistical and alternate tests were per (ng Std (ng Std ( ng Std (ng Std formed as necessary . Time mL) Dev . mL ) Dev. mL) Dev. mL ) Dev . The number and percentage of subjects with adverse 50 Pre -dosing 0 .0 0. 0 0. 0 0 .0 0. 0 0 .0 0 . 0 0 . 0 events was tabulated by body system and preferred term 0 . 5 225 . 6 946 . 3 1 . 2 5 . 6 64 . 0 194 . 0 3 . 6 12 . 2 1 . 0 218 . 5 653. 3 13 . 5 38 . 7 158 . 4 300 . 2 295 . 3 850 . 7 with a breakdown by treatment. A subject with multiple 1 . 5 189 . 3 438 . 7 54 . 0 88 . 1 408 . 9 629 . 2 371. 3 561. 9 adverse events within a body system was only counted once 2 .0 406 . 1 597 . 1 250 . 8 363 . 5 860 . 2 1022 . 3 720 . 1 762. 4 towards the total of this body system . Adverse events were 2. 5 489 .4 469 .2 458 .6 730 . 1 848 . 3 7770 . 931. 3 879 . 1 analyzed using descriptive statistics . Similarly , multiple 55 3. 0 748 . 2 952 . 7 603 . 0 710 . 9 885 . 2 751. 7 1106 . 7 897 . 1 693 . 5 660 . 2 832 . 2 648 . 6 905 . 4 669 . 8 818 . 9 747 . 2 reports of the same preferred term adverse events were 793. 5 523. 0 817 . 4 475 . 4 834 . 4 733. 1 613. 5 553. 5 counted only once at the highest intensity and greatest 4. 5 774 . 9 552. 3 756 . 9 412 . 5 685 . 7 627 . 1 495 . 7 424 . 8 attribution to study treatment. Additional statistical and 5 .0 864 .3 739 . 8 790 . 4 671 . 6 533. 5 521. 5 678 .2 921. 3 alternate tests were performed as necessary . 5 . 5 491 . 7 475 . 2 491 . 9 395 . 6 295 . 5 336 . 3 350 . 0 459 . 7 60 6 .0 274 .6 299 .5 300 . 0 252 . 0 155 . 6 189 . 0 165 .4 193 . 1 8 . 0 18 . 9 50 . 7 44 . 3 95 . 9 6 . 4 17 .6 5 . 5 12 . 6 Example 33 12. 0 1 . 5 7 . 3 0 . 0 0 . 0 0 . 0 0 . 0 1 . 4 6 . 8 Comparative Bioavailability Pilot Study Results 24 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 Mean plasma monomethyl fumarate concentrations from the bioavailability study described in Example 32 are shown 65 Summary pharmacokinetic parameters from the bioavail for Test samples 1- 3 in Table 69 and Test samples 4 - 9 in ability study described in Example 32 are shown for Test Table 70 . The mean plasma monomethyl fumarate concen samples 1 - 3 in Table 71 and Test samples 4 - 9 in Table 72 . US 9, 814 ,692 B2 131 132 TABLE 71 Summary of Comparative Bioavailability Analysis for Plasma Monomethyl Fumarate Randomized , 4 -way crossover, open - label, single -dose , fasting design Geometric Mean * Arithmetic Mean % CV ) AUCO - AUCO- > Cmax AUCO Sample ( h?ng/ mL) ( h?ng/ mL) ( ng/ mL) Tmax (h ) * ta( h) * 1 (1 /h ) * AUCof Reference 3246 . 34 3423 .77 1784 .08 3 . 00 0 . 55 1. 3022 0 . 9791 3397 . 47 3541. 61 1874 .93 ( 1 .00 - 5 .50 ) (20 . 99 ) ( 18 .08 ) ( 1 . 76 ) ( 31. 42 ) ( 31 .08 ) ( 30 .04 ) Test 1 2454 . 38 3078. 63 1206 .93 5 .00 0 . 85 1 . 1127 0 . 9621 2631 .29 3543. 47 1367. 63 ( 2 . 5 - 6 .00 ) (95 .08 ) ( 35 .48 ) ( 4 .66 ) ( 39 .85 ) ( 25 . 13 ) (49 . 77 ) Test 2 2209 . 18 2631 . 23 1110 .01 5 .00 0 . 93 0 . 9467 0 . 9377 2344 . 10 2665 . 26 1176 . 70 ( 2 .52 - 6 . 00 ) (55 .03 ) (45 . 76 ) (6 .24 ) (32 .68 ) ( 26 .01 ) ( 34 . 38 ) Test 3 3318 .08 3522 . 37 2004 . 25 4 .00 0 .51 1 .4526 0 . 9734 3495 .45 3722 . 36 2140 .42 ( 2 .00 - 6 . 00 ) (30 .61 ) ( 20 .63 ) (2 . 23 ) ( 29 .89 ) ( 25 .65 ) ( 37 .54 ) Ratio of Geometric 90 % Confidence Intra - subject CV Means ( T : R ) Interval Test 1 AUCO » 75 .60 67. 42 - 84 .79 23 .48 AUCO 89. 92 77 . 35 - 104 . 53 22. 51 ???? 67. 65 57 . 59 - 79 .47 33 . 44 Test 2 AUCO 68 .05 60 . 68 - 76 . 32 23 . 48 AUCO -> 00 76 . 85 66 . 17 - 89 . 27 22 .51 ???? 62 .22 52 . 96 - 73 .09 33 . 44 Test 3 AUCO 102 . 21 91 . 14 - 114 .62 23. 48 AUCO -> 102 .88 90 . 29 - 117 . 23 22 . 51 Cmax 112. 3 95 .63 - 131. 98 33 . 44 Reference : TECFDERA ® (Biogen Idec ) , 240 mg dimethyl fumarate , enterically coated pellets Test 1 : BLS 214 mg fumarate ester, Capmul fill, EnteriCare ® DR Soft Capsules ; see Table 59 Test 2 , BLS 200 mg fumarate ester Capmul fill, EnteriCare ® DR Soft Capsules; see Table 60 Test 3, BLS 214 mg fumarate ester, Capmul fill, 195 Bloom DR Soft Capsules ; see Table 61 * Arithmetic mean % CV ) only *Median and range only

TABLE 72 Summary of Comparative Bioavailability Analysis for Plasma Monomethyl Fumarate Randomized , 4 - way crossover, open - label, single- dose , fasting design Geometric Mean * Arithmetic Mean ( % CV ) AUCO - AUCO- s , Cmax AUCOT! Sample ( h?ng/ mL) ( h?ng/ mL) ( ng/ mL) Tmax (h ) * t2 (h ) * 1 (1 /h ) * AUC _ * Reference 3175 . 12 3295 .42 1975 .68 2 .85 0 . 57 1 . 2587 0 . 9842 3306 .55 3484 .62 2111. 34 (1 . 02 - 5 .50 ) ( 16 . 97 ) (17 .94 ) ( 1. 24 ) ( 30 .72 ) (29 . 31 ) ( 34 .87 ) Test 4 3103 .71 3258. 09 1657. 53 4 .00 0 .50 1. 4256 0 . 9835 3234 . 00 3478 .19 1848 .96 ( 0 . 52 - 6 .00 ) ( 22 .51 ) (17 .02 ) ( 1 . 27 ) ( 30 .78 ) (29 . 19 ) (53 . 77 ) Test 5 2722 .58 2985 . 13 1322. 51 4 .00 0 .53 1 . 3702 0 . 9830 2878 .77 3206 . 76 1472. 19 ( 2 . 00 - 5 .50 ) (20 .60 ) (20 .61 ) ( 1 .06 ) (35 .92 ) (32 .27 ) ( 47 . 44 ) Test 6 3193 .72 3362 .08 1774 .03 3 . 00 0 .60 1 . 3789 0 .9759 3370 .97 3505. 64 1865 .66 ( 1 . 00 -5 . 08 ) (79 .70 ) ( 25 . 04 ) (2 .53 ) (30 .39 ) (28 .99 ) (33 . 32 ) Ratio of Geometric 90 % Confidence Intra - subject CV Means ( T : R ) Interval Test 4 AUCO 97 .75 91. 08 - 104 . 91 14 . 37 AUCO -> 98 .87 92. 44 - 105 . 74 12 .09 Cmax 83 . 90 70 . 26 - 100 . 19 37 .05 Test 5 AUCOT 85 .75 79 . 89 - 92 . 03 14 . 37 AUCO- > 90 . 58 84 .61 - 96 . 98 12 . 09 Cmax 66 .94 56 . 06 - 79 . 94 37 .05 US 9 ,814 ,692 B2 133 134 TABLE 72 -continued Summary of Comparative Bioavailability Analysis for Plasma Monomethyl Fumarate Randomized , 4 -way crossover, open -label , single -dose , fasting design Test 6 AUCO 100 .59 93. 62 - 108 . 07 14 . 37 AUCO -> 102 .02 95 . 65 - 108. 82 12 .09 Cmax 89 .79 74 . 99 - 107. 51 37. 05 Reference: TECFIDERA ® (Biogen Idec ) , 240 mg dimethyl fumarate , enterically coated pellets Test 4 : BLS 214 mg fumarate ester, soybean oil, EnteriCare ® DR Soft Capsules ; see Table 62 Test 5 : BLS 200 mg fumarate ester, soybean oil, EnteriCare ® DR Soft Capsules ; see Table 63 Test 6 : BLS 214 mg fumarate ester, soybean oil, 195 Bloom DR Soft Capsules ; see Table 64 * Arithmetic mean ( % CV ) only *Median and range only Example 34 15 was encapsulated in soft gelatin capsules comprising 195 Bloom gelatin using rotary die encapsulation . See Table 66 . Six formulations of soft capsules comprising particles of The 90 mg, 95 mg, 100 mg, and 115 mg dosage forms were a fumarate ester having particle size distributions of PSD : 5 oval capsules and the 200 mg and 220 mg dosage forms d90s100 um were manufactured . The dosage forms com - were 12 oval capsules. After manufacturing and drying, the prised six doses of fumarate ester, all with the same fill capsules were coated with a hydroxypropylmethylcellulose composition and the same soft gelatin shell. The doses were “ undercoat and dried . The capsules were then coated with an either 90 mg, 95 mg, 100 mg, 115 mg, 200 mg, or 220 mg enteric coating containing methacrylic acid , ethyl acrylate fumarate ester and comprised 34 % fumarate ester, 48 % of a copolymer ( e . g . , EUDRAGIT® L100 - 55 , Evonik ; Acryl mixture ofmono - and diglycerides ( e . g ., Capmul® MCM ) , EZE® , Colorcon ) . Table 67 . A polyvinyl alcohol moisture 3 % polyvinylpyrrolidone , 10 % polyoxyl 40 hydrogenated barrier top -coating was applied to the enterically coated castor oil, and 5 % lactic acid . Tables 71- 72 . The matrix fill capsules ( e . g ., Opadry® amb II , Clear, Colorcon ) . Table 68 . TABLE 71 Test Formulations 90 mg Dose 95 mg Dose 100 mg Dose Component mg Weight % mg Weight % mg Weight % Fumarate Ester 90 34 . 2 % 95 34 . 2 % 100 34 . 2 % Capmul MCM 125 . 7 47 . 8 % 132 . 5 47 . 8 % 139 . 5 47. 8 % Povidone K30 7 . 9 3 . 0 % 8 . 3 3 . 0 % 8 . 8 3 . 0 % Polyoxyl 40 Hydrogenated 26 . 3 10 . 0 % 27 . 7 10 . 0 % 29 . 2 10 . 0 % Castor Oil Lactic Acid 13 . 1 5 . 0 % 13 . 9 5 . 0 % 14 . 6 5 . 0 % TOTAL 263 100 . 0 % 277 . 4 100 . 0 % 292. 1 100 . 0 % Vehicle 173 66 % 182 . 4 66 % 192 . 1 66 % Lipid 159 . 9 61 % 168 . 5 61 % 177 . 5 61 % ??? 90 34 % 95 34 % 100 34 % 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 Fumarate Ester 0 .62 - 0 .69 0 .66 - 0 .73 0 .69 - 0 . 77

TABLE 72 Test Formulations | 115 mg Dose 200 mg Dose 220 mg Dose Component mg Weight % mg Weight % mg Weight % Fumarate Ester 115 34 . 2 % 200 34 . 2 % 220 34 . 2 % Capmul MCM 160 . 7 47 . 8 % 278 . 9 47 . 8 % 307 . 5 47 . 8 % Povidone K30 10 3 . 0 % 17 . 5 3 . 0 % 19 . 1 3 . 0 % Polyoxyl 40 Hydrogenated 33 . 5 10 . 0 % 58 . 4 10 . 0 % 64 . 5 10 . 0 % Castor Oil Lactic Acid 16 . 8 5 . 0 % 29 . 2 5 . 0 % 32 . 1 5 . 0 % TOTAL 336 100 . 0 % 584 100 . 0 % 643 . 2 100 . 0 % Vehicle 221 66 % 384 66 % 423 . 2 66 % Lipid 204 . 2 61 % 354 . 8 61 % 391 . 1 61 % ??? 115 34 % 200 34 % 220 34 % 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 Fumarate Ester 0 . 80 - 0 . 88 1 . 39 - 1 . 54 1 . 53 - 1 .69 US 9 , 814 ,692 B2 135 136 What is claimed is : 13 . The method of claim 1 , wherein two units of the 1 . A method of treating or reducing symptoms of a composition comprising between about 80 mg to about 115 multiple sclerosis or psoriasis in a subject, the method mg of fumarate ester are simultaneously administered twice comprising contacting peripheral blood mononuclear cells per day . or monocytes of the subject with monomethyl fumarate by 5 14 . The method of claim 1 , wherein 1 unit of the com administering an oral pharmaceutical composition compris position comprising between about 160 mg to about 230 mg ing one or more fumarate esters in an immediate releasing single phase non -aqueous liquid vehicle . of fumarate ester are administered twice per day . 2 . The method of claim 1 , wherein the fumarate ester 15 . The method of claim 1 , wherein upon administration comprises dimethyl fumarate , monomethyl fumarate , pro - 10 toam a subject , the composition activates a nuclear factor drugs thereof , or combinations thereof. pro " erythroid -derived 2- like (Nrf2 ) dependent pathway. 3 . The method of claim 1 , wherein the composition 16 . The method of claim 1 , wherein administering about comprises about 80 mg to about 230 mg of the fumarate 180 mg to about 200 mg of the fumarate ester is bioequiva ester . lent to administering a 240 mg dose of dimethyl fumarate . 4 . The method of claim 1 , wherein the liquid vehicle 15 . 17 . A method of treating or reducing symptoms of mul comprises mono - and diglycerides, polyvinylpyrrolidone , tiple sclerosis or psoriasis in a subject, the method compris and polyoxyl 40 hydrogenated castor oil. ing contacting peripheral blood mononuclear cells or mono 5 . The method of claim 1 , wherein the composition cytes of the subject with monomethyl fumarate by comprises : administering an oral pharmaceutical composition compris about 30 % to about 40 % by weight of the one or more 20 ing about 80 mg to about 230 mg of a prodrug ofmonom fumarate esters ; and ethyl fumarate , dimethyl fumarate , or monomethyl fumarate about 55 % to about 65 % by weight of the liquid vehicle . in an immediate releasing single phase non -aqueous liquid 6 . The method of claim 1 , wherein the composition vehicle . comprises about 5 % by weight of lactic acid . 18 . The method of claim 17, wherein two units of the 7 . The method of claim 1 , wherein the composition is 25 composition comprising between about 80 mg to about 115 encapsulated in a capsule . mg of fumarate ester are simultaneously administered twice 8 . The method of claim 1 , wherein the composition is per day . encapsulated in a capsule comprising one or more subcoat 19 . The method of claim 17 , wherein 1 unit of the ings , enteric coatings , top coatings , or combinations thereof. composition comprising between about 160 mg to about 230 9 . The method of claim 8, wherein the capsule provides 30 delayed release of the fumarate ester. su mg of fumarate ester are administered twice per day . 10 . The method of claim 1 , wherein the subject is admin 20 . A method of activating a nuclear factor erythroid istered one or more units of the composition that cumula derived 2 - like (Nrf2 ) cellular signaling pathway in a subject , tively provide a daily dosage of a fumarate ester from about the method comprising contacting peripheral blood mono 160 mg to about 230 mg fumarate ester . nuclear cells or monocytes of the subject with monomethyl 11 . The method of claim 1 , wherein the subject is admin fumarate by administering an oral pharmaceutical compo istered one or more units of the composition that cumula sition comprising about 80 mg to about 230 mg of a prodrug tively provide a daily dosage of a fumarate ester from about of monomethyl fumarate , dimethyl fumarate , or monom 320 mg to about 460 mg fumarate ester. ethyl fumarate in an immediate releasing single phase non 12 . The method of claim 1 , wherein administration is 40 aqueous liquid vehicle . twice per day. * * * * *