US010179109B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 179 , 109 B2 Bosse et al. ( 45 ) Date of Patent : Jan . 15 , 2019 ( 54 ) PHARMACEUTICAL COMPOSITIONS ( 58 ) Field of Classification Search COMPRISING 5HT RECEPTOR AGONIST CPC . . .. . A01N 43 / 42 ; A61K 31 /44 ; A61K 9 /4808 ; AND ANTIEMETIC PARTICULATES A61K 9 / 5078 ; A61K 9 /1676 See application file for complete search history . (71 ) Applicant: CHARLESTON LABORATORIES, INC ., Jupiter , FL (US ) ( 56 ) References Cited (72 ) Inventors : Paul Bosse , Jupiter, FL (US ); John U . S . PATENT DOCUMENTS Ameling , Jupiter , FL (US ) ; William Kozarek , Jensen Beach , FL (US ) ; 3 ,048 , 526 A 8 / 1962 Boswell Bernard Schachtel , Jupiter, FL (US ) ; 3 , 108 ,046 A 10 / 1963 Harbit John Higgins, Independence , MO (US ) (Continued ) (73 ) Assignee : CHARLESTON LABORATORIES , FOREIGN PATENT DOCUMENTS INC ., Jupiter, FL (US ) CA 2262267 AL 8 / 1999 ( * ) Notice : Subject to any disclaimer , the term of this DE 102005013726 AL 9 /2006 patent is extended or adjusted under 35 (Continued ) U . S .C . 154 (b ) by 0 days. OTHER PUBLICATIONS (21 ) Appl. No. : 15 / 449, 798 Alexander , et al . Comparison of ondansetron and droperidol in reducing postoperative nausea and vomiting associated with patient ( 22 ) Filed : Mar. 3 , 2017 controlled analgesia . Anaesthesia . Dec . 1995 ;50 ( 12 ) : 1086 - 8 . (65 ) Prior Publication Data (Continued ) US 2017 /0252302 A1 Sep . 7 , 2017 Primary Examiner — Carlos A Azpuru Related U . S . Application Data (74 ) Attorney , Agent, or Firm — Wilson Sonsini Goodrich (60 ) Provisional application No . 62/ 415 , 991, filed on Nov. & Rosati 1 , 2016 , provisional application No. 62 / 304 , 074 , filed (57 ) ABSTRACT on Mar. 4 , 2016 . Pharmaceutical compositions and methods are provided to (51 ) Int. CI. treat headache, headache - associated symptoms, photopho A61K 9 / 48 ( 2006 .01 ) bia , or adverse effects associated with the headache. Also AOIN 43/ 42 ( 2006 .01 ) provided herein are small smooth particulates comprising a ( Continued ) 5HT16 /12 receptor agonist. Compositions for oral adminis (52 ) U . S . CI. tration are described herein wherein the compositions com CPC ...... A61K 9 /4808 ( 2013 .01 ); A01N 43 /42 prise a combination of active agents , such as a 5HT1B / 1D (2013 . 01 ) ; A61K 9/ 1611 (2013 . 01 ) ; receptor agonist and one or more antiemetics . ( Continued ) 34 Claims, 3 Drawing Sheets

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( 56 ) References Cited OTHER PUBLICATIONS Zolmitriptan . Orange book : approved drug products with therapeu tic equivalence evaluations. FDA . www .accessdata . fda. gov . Updated Aug . 21 , 2014 . U .S . Appl. No . 15/ 263, 235 Non -Final Office Action dated Feb . 23 , 2018 . Lainez MJ, et al . Optimal management of severe nausea and vomiting in migraine : improving patient outcomes . Patient Relat Outcome Meas. 2013 ; 4 :61 - 73 . Lipton RB , Stewart WF, Diamond S , Diamond ML , Reed M . Prevalence and burden of migraine in the United States : data from the American Migraine Study II. Headache . 2001 ;41 (7 ) :646 -657 . Migraine Information Page . National Institute of Neurological Disorders and Stroke : https: / /www .ninds . nih .gov /Disorders / All Disorders/ Migraine - Information -Page . Accessed Jun . 9 , 2017. [Retrieved Jan . 29 , 2018 ] . U .S . Appl. No. 14 /925 , 669 Supplemental Notice of Allowability dated Jul. 21 , 2017 . International Application No . PCT/ US2017 /020797 International Preliminary Report on Patentability dated Sep . 13 , 2018 . U . S . Appl. No. 15 /452 , 628 Non - Final Office Action dated Jun . 29 , 2018 . U .S . Appl. No . 15 /676 ,761 Non - Final Office Action dated Aug . 10 , 2018 . U . S . Appl. No . 16 /038 , 099 Non -Final Office Action dated Sep . 17, 2018 . * cited by examiner atent Jan . 15 , 2019 Sheet 1 of 3 US 10 , 179 , 109 B2

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FIG . 3 Sugar Core API Layer ** * * * * * * *

Coating Layer US 10 , 179 , 109 B2 PHARMACEUTICAL COMPOSITIONS ratus) rotating at 50 rpm . In some embodiments , the COMPRISING 5HT RECEPTOR AGONIST 5HT B . receptor agonist comprises a triptan or a pharma AND ANTIEMETIC PARTICULATES ceutically acceptable salt thereof. In some embodiments , the triptan or the pharmaceutically acceptable salt thereof com CROSS REFERENCE 5 prises sumatriptan , almotriptan , frovatriptan , eletriptan , riza triptan , naratriptan , or a pharmaceutically acceptable salt This application claims the benefit of U . S . Provisional thereof. In some embodiments , the triptan or the pharma Application Ser. No . 62 / 304 ,074 filed Mar. 4 , 2016 and U . S . ceutically acceptable salt thereof comprises sumatriptan or a Provisional Application Ser. No. 62 / 415 . 991 filed Nov . 1 . pharmaceutically acceptable salt thereof . In some embodi 2016 , the contents of which are hereby incorporated by 10 ments , the pharmaceutically acceptable salt of sumatriptan reference in their entireties . comprises sumatriptan succinate . Provided herein is a particulate , the particulate compris BACKGROUND ing : a 5HT B / D receptor agonist , wherein the particulate comprises from about 55 % to about 65 % of the 5HT1B / ID Available pain medications are typically provided in 15 receptor agonist ( w / w ) , and wherein at least about 80 % of individual doses . The therapeutic effects of these medica - the 5HTB/ 12 receptor agonist is released within about 5 tions may be improved by combining them with other minutes following contact of the particulate with 500 mL of medications capable of providing relief for ailments other a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as than pain , such as nausea and vomiting . In some cases, measured by an Apparatus 2 ( Paddles ) rotating at 50 rpm . In subjects suffering pain experience these additional ailments. 20 some embodiments , the particulate further comprises a phar Accordingly , combination therapies may also address the maceutically acceptable excipient. In some embodiments , need for effective therapeutics for pain relief . the pharmaceutically acceptable excipient is a non - pharma ceutically active ingredient. In some embodiments , the non BRIEF SUMMARY pharmaceutically active ingredient comprises at least one 25 component selected from the group consisting of microc Provided herein is a particulate , the particulate compris - rystalline cellulose , dicalcium phosphate, calcium sulfate , ing : a 5HT16 / 1d receptor agonist ,wherein the particulate has talc , an alkali metal stearate , silicon dioxide, calcium car an average diameter of less than about 500 um , and wherein bonate, and any combinations thereof. In some embodi at least about 80 % of the 5HT , BU receptor agonist is ments , the at least one component is microcrystalline cel released within about 5 minutes following contact of the 30 lulose . In some embodiments , the particulate is in the form particulate with 500 mL of a dissolution fluid ( 0 . 1N HCl, pH of a homogeneous mixture . In some embodiments , the 1 . 1 ) at 37 + / - 0 . 5º C . as measured by an Apparatus 2 particulate comprises about 60 % of the 5HT 1B /10 receptor ( Paddles ) rotating at 50 rpm . In some embodiments , the agonist ( w / w ) . In some embodiments, the particulate has an particulate further comprises a pharmaceutically acceptable average diameter of between about 100 um and about 500 excipient . In some embodiments , the pharmaceutically 35 um . In some embodiments, at least about 81 % of the acceptable excipient is a non - pharmaceutically active ingre - 5HT16 / 10 receptor agonist is released within about 5 minutes dient. In some embodiments , the non - pharmaceutically following contact of the particulate with 500 mL of a active ingredient comprises at least one component selected dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5º C . as from the group consisting of microcrystalline cellulose , measured by an Apparatus 2 (Paddle Apparatus ) rotating at dicalcium phosphate , calcium sulfate , talc , an alkali metal 40 50 rpm . In some embodiments , at least about 89 % of the stearate , silicon dioxide , calcium carbonate , and any com - 5HT3/ 12 receptor agonist is released within about 10 min binations thereof. In some embodiments , the at least one utes following contact of the particulate with 500 mL of a component is microcrystalline cellulose . In some embodi dissolution fluid ( 0 . 1N HCI, pH 1 . 1 ) at 37 + / - 0 . 5° C . as ments , the particulate is in the form of a homogeneous measured by an Apparatus 2 (Paddle Apparatus ) rotating at mixture . In some embodiments , the particulate comprises 45 50 rpm . In some embodiments , at least about 92 % of the about 60 % of the 5HT B /12 receptor agonist ( w / w ). In some 5HT B /1 receptor agonist is released within about 15 min embodiments , the particulate has an average diameter of utes following contact of the particulate with 500 mL of a between about 100 um and about 500 um . In some embodi - dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5º C . as ments , at least about 81 % of the 5HT , 12 receptor agonist measured by an Apparatus 2 (Paddle Apparatus ) rotating at is released within about 5 minutes following contact of the 50 50 rpm . In some embodiments , at least about 94 % of the particulate with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 5HT3/ 12 receptor agonist is released within about 20 min 1. 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle utes following contact of the particulate with 500 mL of a Apparatus ) rotating at 50 rpm . In some embodiments , at dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5º C . as least about 89 % of the 5HT1B / 1d receptor agonist is released measured by an Apparatus 2 (Paddle Apparatus ) rotating at within about 10 minutes following contact of the particulate 55 50 rpm . In some embodiments , the 5HT1B / 1D receptor ago with 500 mL of a dissolution fluid ( 0 . 1N HCl, pH 1 . 1 ) at nist comprises a triptan or a pharmaceutically acceptable salt 37 + / - 0 .5º C . as measured by an Apparatus 2 (Paddle Appa thereof . In some embodiments , the triptan or the pharma ratus ) rotating at 50 rpm . In some embodiments , at least ceutically acceptable salt thereof comprises sumatriptan , about 92 % of the 5HT1B /10 receptor agonist is released almotriptan , frovatriptan , eletriptan , rizatriptan , naratriptan , within about 15 minutes following contact of the particulate 60 or a pharmaceutically acceptable salt thereof. In some with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at embodiments , the triptan or the pharmaceutically acceptable 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - salt thereof comprises sumatriptan or a pharmaceutically ratus ) rotating at 50 rpm . In some embodiments , at least acceptable salt thereof. In some embodiments , the pharma about 94 % of the 5HT , receptor agonist is released ceutically acceptable salt of sumatriptan comprises within about 20 minutes following contact of the particulate 65 sumatriptan succinate . with 500 mL of a dissolution fluid ( 0 .1N HC1, pH 1 . 1 ) at Provided herein is a particulate , the particulate compris 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - ing: a 5HT16 /10 receptor agonist wherein ( a ) the particulate US 10 , 179 , 109 B2 has an average diameter of less than about 500 um ; and ( b ) crystalline cellulose . In some embodiments , each first par the particulate comprises from about 55 % to about 65 % of ticulate comprises about 60 % of the 5HT , BHD receptor the 5HTB/ 12 receptor agonist ( w / w ) . In some embodiments , agonist ( w / w ) . In some embodiments , each first particulate the particulate further comprises a pharmaceutically accept comprises about 40 % of the non - pharmaceutically active able excipient . In some embodiments , the pharmaceutically 5 ingredient ( w / w ) . In some embodiments , each first particu acceptable excipient is a non - pharmaceutically active ingre - late has an average diameter of between about 100 um and dient. In some embodiments , the non - pharmaceutically about 500 um . In some embodiments , the layer enclosing the active ingredient comprises at least one component selected core in each second particulate is directly adjacent to the from the group consisting of microcrystalline cellulose , core . In some embodiments, the core in each second par dicalcium phosphate , calcium sulfate , talc , an alkali metal 10 ticulate does not comprise an antiemetic . In some embodi stearate , silicon dioxide , calcium carbonate , and any com ments , the core in each second particulate comprises a sugar binations thereof. In some embodiments , the at least one sphere . In some embodiments , the layer enclosing the core component is microcrystalline cellulose . In some embodi - in each second particulate comprises one or more pharma ments , the particulate is in the form of a homogeneous ceutically acceptable excipients. In some embodiments , the mixture . In some embodiments , the particulate comprises 15 one or more pharmaceutically acceptable excipients is about 60 % of the 5HT11 / 12 receptor agonist ( w / w ) . In some selected from hydroxypropyl methylcellulose (HPMC ) , embodiments , the particulate has an average diameter of low - substituted hydroxypropyl cellulose ( L -HPC ) , talc , and between about 100 um and about 500 um . In some embodi - any combinations thereof . In some embodiments , each sec ments , at least about 81 % of the 5HT3/12 receptor agonist o nd particulate comprises from about 2 % to about 10 % of is released within about 5 minutes following contact of the 20 hydroxypropyl methylcellulose (HPMC ) (w / w ) . In some particulate with 500 mL of a dissolution fluid (0 . 1N HC1, pH embodiments, each second particulate comprises from about 1 .1 ) at 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle 0 . 1 % to about 2 % of talc ( w / w ). In some embodiments , each Apparatus) rotating at 50 rpm . In some embodiments , at second particulate comprises from about 1 % to about 3 % of least about 89 % of the 5HT, B receptor agonist is released low - substituted hydroxypropyl cellulose ( L -HPC ) ( w / w ) . In within about 10 minutes following contact of the particulate 25 some embodiments , each second particulate comprises from with 500 mL of a dissolution fluid ( 0 . 1N HC1, PH 1 . 1 ) at about 10 % to about 40 % of the antiemetic ( w / w ) . In some 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - embodiments , each second particulate comprises from about ratus ) rotating at 50 rpm . In some embodiments , at least 50 % to about 70 % of a core ( w / w ). In some embodiments , about 92 % of the 5HTM receptor agonist is released each second particulate has an average diameter from about within about 15 minutes following contact of the particulate 30 700 um and about 1200 um . In some embodiments , each first with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at particulate further comprises a first coating . In some 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - embodiments , each second particulate further comprises a ratus ) rotating at 50 rpm . In some embodiments , at least second coating. In some embodiments , each second particu about 94 % of the 5HT1B / 1D receptor agonist is released late comprises from about 5 % to about 15 % of a second within about 20 minutes following contact of the particulate 35 coating (w /w ) . In some embodiments , the first or second with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at coating comprises polyvinyl alcohol, cellulose acetate 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle Appa - phthalate, polyvinyl acetate phthalate, methacrylic acid ratus ) rotating at 50 rpm . In some embodiments , the 5HT BI copolymer, cellulose acetate trimellitate , hydroxypropyl iD receptor agonist comprises a triptan or a pharmaceutically methylcellulose phthalate , hydroxypropyl methylcellulose , acceptable salt thereof. In some embodiments, the triptan or 40 hydroxypropyl methyl cellulose acetate succinate , shellac , the pharmaceutically acceptable salt thereof comprises sodium alginate, zein , or any combinations thereof. In some sumatriptan , almotriptan , frovatriptan , eletriptan , rizatriptan , embodiments , the coating comprises polyvinyl alcohol. In naratriptan , or a pharmaceutically acceptable salt thereof. In some embodiments , the coating is polyvinyl alcohol. In some embodiments , the triptan or the pharmaceutically some embodiments , the 5HT1B / 10 receptor agonist com acceptable salt thereof comprises sumatriptan or a pharma - 45 prises a triptan or a pharmaceutically acceptable salt thereof. ceutically acceptable salt thereof. In some embodiments, the In some embodiments , the triptan or the pharmaceutically pharmaceutically acceptable salt of sumatriptan comprises acceptable salt thereof comprises sumatriptan , almotriptan , sumatriptan succinate. frovatriptan , eletriptan , rizatriptan , naratriptan , or a pharma Provided herein is a pharmaceutical composition com - ceutically acceptable salt thereof. In some embodiments , the prising : a plurality of first particulates, wherein each first 50 triptan or the pharmaceutically acceptable salt thereof com particulate comprises : a 5HT3/ 12 receptor agonist wherein : prises sumatriptan or a pharmaceutically acceptable salt (a ) each first particulate has an average diameter of less than thereof. In some embodiments , the sumatriptan or the phar about 500 um ; or (b ) each first particulate comprises from maceutically acceptable salt thereof is present in an amount about 55 % to about 65 % of the 5HT1B / 10 receptor agonist therapeutically equivalent from about 70 mg to about 110 ( w / w ) ; and a plurality of second particulates , wherein each 55 mg of sumatriptan free base . In some embodiments , the second particulate comprises : (i ) a core ; and (ii ) a layer sumatriptan or the pharmaceutically acceptable salt thereof enclosing the core, wherein said layer comprises an anti - is present in an amount therapeutically equivalent to about emetic . In some embodiments , each first particulate further 90 mg of sumatriptan free base . In some embodiments , the comprises a pharmaceutically acceptable excipient. In some pharmaceutically acceptable salt of the sumatriptan com embodiments , the pharmaceutically acceptable excipient is a 60 prises sumatriptan succinate . In some embodiments, the non - pharmaceutically active ingredient. In some embodi- sumatriptan succinate is present in an amount from about ments , the non -pharmaceutically active ingredient com - 100 mg to about 140 mg. In some embodiments , the prises at least one component selected from the group sumatriptan succinate is present in an amount of about 126 consisting of microcrystalline cellulose , dicalcium phos - mg. In some embodiments , the antiemetic comprises pro phate, calcium sulfate , talc , an alkali metal stearate , silicon 65 methazine , ondansetron , aprepitant, dronabinol, per dioxide , calcium carbonate , and any combinations thereof . phenazine , palonosetron , trimethyobenzamide , metoclopro In some embodiments , the at least one component is micro - mide , domperidone, prochlorperazine, chlorpromazine , US 10 , 179 ,109 B2 trimethobenzamide , granisetron , hydroxyzine , acetylleucine embodiments , at least about 93 % of the 5HTB/ 1 receptor monoethanolamine , alizapride , azasetron , benzquinamide , agonist is released within about 30 minutes following con bietanautine , bromopride , buclizine, clebopride , cyclizine , tact of the pharmaceutical composition with 500 mL of a dimenhydrinate , diphenidol, dolasetron , meclizine , methal dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5º C . as latal, metopimazine , nabilone , oxyperndyl, pipamazine , sco - 5 measured by an Apparatus 2 (Paddle Apparatus ) rotating at polamine , sulpiride , tetrahydrocannabinol, thiethylperazine , 50 rpm . In some embodiments , at least about 98 % of the thioproperazine, tropisetron , droperidol, haloperidol, 5HT B / 1 receptor agonist is released within about 60 min prochloperazine , metoclopramide , diphenhydramine , can - utes following contact of the pharmaceutical composition nabinoid , midazolam , lorazepam , hyoscine, dexamethasone , with 500 mL of a dissolution fluid ( 0 .1N HC1, pH 1 . 1 ) at emetrol, propofol, or a pharmaceutically acceptable salt 10 37 + / - 0 .5º C . as measured by an Apparatus 2 (Paddle Appa thereof. In some embodiments , the antiemetic comprises ratus) rotating at 50 rpm . promethazine or a pharmaceutically acceptable salt thereof. Provided herein is an oral dosage form comprising a In some embodiments , the promethazine or the pharmaceu - pharmaceutical composition comprising: a plurality of first tically acceptable salt thereof is present in an amount particulates, wherein each first particulate comprises: a therapeutically equivalent from about 10 mg to about 60 mg 15 5HT / receptor agonist wherein : ( a ) each first particulate promethazine free base . In some embodiments , the promet - has an average diameter of less than about 500 um ; or ( b ) hazine or the pharmaceutically acceptable salt thereof is each first particulate comprises from about 55 % to about present in an amount therapeutically equivalent to about 11 65 % of the 5HT16 /12 receptor agonist ( w / w ) ; and a plurality mg , about 22 mg, or about 44 mg of promethazine free base . of second particulates, wherein each second particulate In some embodiments , the pharmaceutically acceptable salt 20 comprises: ( i ) a core ; and ( ii ) a layer enclosing the core , of promethazine comprises promethazine hydrochloride . In wherein said layer comprises an antiemetic . In some some embodiments , the promethazine hydrochloride is pres - embodiments , each first particulate further comprises a ent in an amount from about 10 mg to about 60 mg. In some pharmaceutically acceptable excipient. In some embodi embodiments , the promethazine hydrochloride is present in ments , the pharmaceutically acceptable excipient is a non an amount of about 12 . 5 mg, about 25 mg, or about 50 mg. 25 pharmaceutically active ingredient. In some embodiments , In some embodiments , a ratio by weight of the 5HT1B / D the non - pharmaceutically active ingredient comprises at receptor agonist to the antiemetic is from about 1 :2 to about least one component selected from the group consisting of 15 : 1 . In some embodiments , the ratio by weight of the microcrystalline cellulose , dicalcium phosphate , calcium 5HTB11 receptor agonist to the antiemetic is from about sulfate , talc, an alkali metal stearate, silicon dioxide, calcium 3 : 2 to about 11 : 1 . In some embodiments , the ratio by weight 30 carbonate , and any combinations thereof. In some embodi of the 5HT, BI receptor agonist to the antiemetic is from ments , the at least one component is microcrystalline cel about 3 : 1 to about 7 : 1 or from about 1 : 1 to about 5 : 1. In lulose . In some embodiments , each first particulate com some embodiments , the ratio by weight of the 5HTB/ ID prises about 60 % of the 5HT3/ 12 receptor agonist ( w / w ). In receptor agonist to the antiemetic is from about 9 : 2 to about some embodiments , each first particulate comprises about 11 : 2 or from about 4 : 2 to about 6 : 2 . In some embodiments , 35 40 % of the non - pharmaceutically active ingredient ( w / w ) . In the ratio by weight of the 5HT 16 / 1d receptor agonist to the some embodiments , each first particulate has an average antiemetic is about 5 : 1 or about 2 .5 : 1 . In some embodi- diameter of between about 100 um and about 500 um . In ments , at least about 85 % of the antiemetic is released within some embodiments , the layer enclosing the core in each about 5 minutes following contact of the pharmaceutical second particulate is directly adjacent to the core . In some composition with 500 mL of a dissolution fluid ( 0 . 1N HC1, 40 embodiments , the core in each second particulate does not pH 1 . 1 ) at 37 + / - 0 . 5º C . as measured by an Apparatus 2 comprise an antiemetic . In some embodiments , the core in ( Paddle Apparatus ) rotating at 50 rpm . In some embodi- each second particulate comprises a sugar sphere. In some ments , at least about 92 % of the antiemetic is released within embodiments , the layer enclosing the core in each second about 15 minutes following contact of the pharmaceutical particulate comprises one or more pharmaceutically accept composition with 500 mL of a dissolution fluid ( 0 . 1N HCI, 45 able excipients . In some embodiments , the one or more pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an Apparatus 2 pharmaceutically acceptable excipients is selected from ( Paddle Apparatus ) rotating at 50 rpm . In some embodi- hydroxypropyl methylcellulose (HPMC ) , low -substituted ments , at least about 94 % of the antiemetic is released within hydroxypropyl cellulose ( L -HPC ) , talc , and any combina about 30 minutes following contact of the particulate with tions thereof. In some embodiments, each second particulate 500 mL of a dissolution fluid (0 .1N HC1, pH 1 . 1 ) at 50 comprises from about 2 % to about 10 % of hydroxypropyl 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - methylcellulose (HPMC ) ( w / w ) . In some embodiments , ratus ) rotating at 50 rpm . In some embodiments , at least each second particulate comprises from about 0 . 1 % to about about 96 % of the antiemetic is released within about 60 2 % of talc ( w / w ) . In some embodiments, each second minutes following contact of the pharmaceutical composi- particulate comprises from about 1 % to about 3 % of low tion with 500 mL of a dissolution fluid (0 . 1N HCl, pH 1 . 1 ) 55 substituted hydroxypropyl cellulose ( L -HPC ) ( w / w ) . In at 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle some embodiments , each second particulate comprises from Apparatus ) rotating at 50 rpm . In some embodiments, at about 10 % to about 40 % of the antiemetic ( w / w ) . In some least about 75 % of the 5HT , BI receptor agonist is released embodiments , each second particulate comprises from about within about 5 minutes following contact of the pharmaceu 50 % to about 70 % of a core ( w / w ) . In some embodiments , tical composition with 500 mL of a dissolution fluid ( 0 . 1N 60 each second particulate has an average diameter from about HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 700 um and about 1200 um . In some embodiments , each first 2 (Paddle Apparatus ) rotating at 50 rpm . In some embodi- particulate further comprises a first coating. In some ments , at least about 87 % of the 5HT , B receptor agonist embodiments , each second particulate further comprises a is released within about 15 minutes following contact of the second coating . In some embodiments , each second particu pharmaceutical composition with 500 mL of a dissolution 65 late comprises from about 5 % to about 15 % of a second fluid ( 0 . 1N HC1, pH 1 . 1) at 37 + / - 0 .5° C . as measured by an coating ( w / w ) . In some embodiments , the first or second Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some coating comprises polyvinyl alcohol, cellulose acetate US 10 , 179 , 109 B2 phthalate , polyvinyl acetate phthalate , methacrylic acid antiemetic is about 5 : 1 or about 2 . 5 : 1 . In some embodi copolymer, cellulose acetate trimellitate , hydroxypropyl ments , at least about 85 % of the antiemetic is released within methylcellulose phthalate , hydroxypropyl methylcellulose , about 5 minutes following contact of the pharmaceutical hydroxypropyl methyl cellulose acetate succinate , shellac, composition with 500 mL of a dissolution fluid ( 0 . 1N HC1, sodium alginate , zein , or any combinations thereof . In some 5 pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an Apparatus 2 embodiments , the coating comprises polyvinyl alcohol. In (Paddle Apparatus ) rotating at 50 rpm . In some embodi some embodiments , the coating is polyvinyl alcohol . In ments , at least about 92 % of the antiemetic is released within some embodiments, the 5HTB/ D receptor agonist com - about 15 minutes following contact of the pharmaceutical prises a triptan or a pharmaceutically acceptable salt thereof. composition with 500 mL of a dissolution fluid (0 . 1N HC1, In some embodiments , the triptan or the pharmaceutically 10 pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 acceptable salt thereof comprises sumatriptan , almotriptan , (Paddle Apparatus ) rotating at 50 rpm . In some embodi frovatriptan , eletriptan , rizatriptan , naratriptan , or a pharma ments , at least about 94 % of the antiemetic is released within ceutically acceptable salt thereof. In some embodiments, the about 30 minutes following contact of the particulate with triptan or the pharmaceutically acceptable salt thereof com - 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at prises sumatriptan or a pharmaceutically acceptable salt 15 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa thereof. In some embodiments , the sumatriptan or the phar - ratus ) rotating at 50 rpm . In some embodiments , at least maceutically acceptable salt thereof is present in an amount about 96 % of the antiemetic is released within about 60 therapeutically equivalent from about 70 mg to about 110 minutes following contact of the pharmaceutical composi mg of sumatriptan free base . In some embodiments , the tion with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) sumatriptan or the pharmaceutically acceptable salt thereof 20 at 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle is present in an amount therapeutically equivalent to about Apparatus ) rotating at 50 rpm . In some embodiments , at 90 mg of sumatriptan free base . In some embodiments , the least about 75 % of the 5HT B / receptor agonist is released pharmaceutically acceptable salt of the sumatriptan com - within about 5 minutes following contact of the pharmaceu prises sumatriptan succinate . In some embodiments, the tical composition with 500 mL of a dissolution fluid (0 . 1N sumatriptan succinate is present in an amount from about 25 HCI, PH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an Apparatus 100 mg to about 140 mg. In some embodiments , the 2 ( Paddle Apparatus ) rotating at 50 rpm . In some embodi sumatriptan succinate is present in an amount of about 126 ments , at least about 87 % of the 5HT B / D receptor agonist mg . In some embodiments , the antiemetic comprises pro - is released within about 15 minutes following contact of the methazine , ondansetron , aprepitant, dronabinol, per - pharmaceutical composition with 500 mL of a dissolution phenazine , palonosetron , trimethyobenzamide , metoclopro - 30 fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an mide , domperidone , prochlorperazine , chlorpromazine , Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some trimethobenzamide , granisetron , hydroxyzine, acetylleucine embodiments , at least about 93 % of the 5HT1B / 10 receptor monoethanolamine , alizapride , azasetron , benzquinamide , agonist is released within about 30 minutes following con bietanautine , bromopride , buclizine , clebopride , cyclizine , tact of the pharmaceutical composition with 500 mL of a dimenhydrinate , diphenidol, dolasetron , meclizine , methal - 35 dissolution fluid (0 . 1N HCl, pH 1. 1 ) at 37 + / - 0 . 5º C . as latal ,metopimazine , nabilone, oxyperndyl, pipamazine, sco measured by an Apparatus 2 (Paddle Apparatus ) rotating at polamine, sulpiride, tetrahydrocannabinol, thiethylperazine , 50 rpm . In some embodiments , at least about 98 % of the thioproperazine , tropisetron , droperidol, haloperidol, 5HT B / 1 receptor agonist is released within about 60 min prochloperazine , metoclopramide , diphenhydramine , can utes following contact of the pharmaceutical composition nabinoid , midazolam , lorazepam , hyoscine , dexamethasone , 40 with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at emetrol , propofol, or a pharmaceutically acceptable salt 37 + / - 0 .5° C . as measured by an Apparatus 2 ( Paddle Appa thereof. In some embodiments, the antiemetic comprises ratus) rotating at 50 rpm . promethazine or a pharmaceutically acceptable salt thereof. Provided herein is a capsule comprising a pharmaceutical In some embodiments , the promethazine or the pharmaceu - composition comprising: a plurality of first particulates, tically acceptable salt thereof is present in an amount 45 wherein each first particulate comprises : a 5HT B / 1 recep therapeutically equivalent from about 10 mg to about 60 mg tor agonist wherein : ( a ) each first particulate has an average promethazine free base . In some embodiments , the promet - diameter of less than about 500 um ; or ( b ) each first hazine or the pharmaceutically acceptable salt thereof is particulate comprises from about 55 % to about 65 % of the present in an amount therapeutically equivalent to about 11 5HT 16 / 12 receptor agonist ( w / w ) ; and a plurality of second mg, about 22 mg, or about 44 mg of promethazine free base . 50 particulates , wherein each second particulate comprises : ( i ) In some embodiments , the pharmaceutically acceptable salt a core ; and ( ii ) a layer enclosing the core , wherein said layer of promethazine comprises promethazine hydrochloride. In comprises an antiemetic . In some embodiments , each first some embodiments , the promethazine hydrochloride is pres particulate further comprises a pharmaceutically acceptable ent in an amount from about 10 mg to about 60 mg. In some excipient. In some embodiments , the pharmaceutically embodiments, the promethazine hydrochloride is present in 55 acceptable excipient is a non - pharmaceutically active ingre an amount of about 12 . 5 mg, about 25 mg, or about 50 mg. dient. In some embodiments , the non -pharmaceutically In some embodiments , a ratio by weight of the 5HT BID active ingredient comprises at least one component selected receptor agonist to the antiemetic is from about 1 : 2 to about from the group consisting of microcrystalline cellulose , 15 : 1 . In some embodiments , the ratio by weight of the dicalcium phosphate , calcium sulfate , talc , an alkali metal 5HTB11 receptor agonist to the antiemetic is from about 60 stearate , silicon dioxide , calcium carbonate , and any com 3 : 2 to about 11 : 1 . In some embodiments , the ratio by weight binations thereof. In some embodiments , the at least one of the 5HT1B /12 receptor agonist to the antiemetic is from component is microcrystalline cellulose. In some embodi about 3 : 1 to about 7 : 1 or from about 1 : 1 to about 5 : 1 . In ments , each first particulate comprises about 60 % of the some embodiments , the ratio by weight of the 5HTB/ D 5HTB/ D receptor agonist ( w / w ) . In some embodiments , receptor agonist to the antiemetic is from about 9 : 2 to about 65 each first particulate comprises about 40 % of the non 11 : 2 or from about 4 : 2 to about 6 : 2 . In some embodiments , pharmaceutically active ingredient ( w / w ) . In some embodi the ratio by weight of the 5HT16 /10 receptor agonist to the ments , each first particulate has an average diameter of US 10 , 179 , 109 B2 10 between about 100 um and about 500 um . In some embodi cannabinol, thiethylperazine, thioproperazine , tropisetron , ments , the layer enclosing the core in each second particu droperidol, haloperidol, prochloperazine, metoclopramide, late is directly adjacent to the core. In some embodiments , diphenhydramine , cannabinoid , midazolam , lorazepam , the core in each second particulate does not comprise an hyoscine , dexamethasone , emetrol, propofol, or a pharma antiemetic . In some embodiments , the core in each second 5 ceutically acceptable salt thereof . In some embodiments , the particulate comprises a sugar sphere . In some embodiments, antiemetic comprises promethazine or a pharmaceutically the layer enclosing the core in each second particulate acceptable salt thereof. In some embodiments , promethazine comprises one or more pharmaceutically acceptable excipi- or the pharmaceutically acceptable salt thereof is present in ents . In some embodiments , the one or more pharmaceuti - an amount therapeutically equivalent from about 10 mg to cally acceptable excipients is selected from hydroxypropyl 10 about 60 mg promethazine free base . In some embodiments , methylcellulose (HPMC ) , low -substituted hydroxypropyl the promethazine or the pharmaceutically acceptable salt cellulose (L -HPC ) , talc , and any combinations thereof. In thereof is present in an amount therapeutically equivalent to some embodiments , each second particulate comprises from about 11 mg, about 22 mg, or about 44 mg of promethazine about 2 % to about 10 % of hydroxypropyl methylcellulose free base . In some embodiments , the pharmaceutically (HPMC ) ( w / w ) . In some embodiments , each second par - 15 acceptable salt of promethazine comprises promethazine ticulate comprises from about 0 . 1 % to about 2 % of talc hydrochloride . In some embodiments , the promethazine ( w / w ). In some embodiments, each second particulate com - hydrochloride is present in an amount from about 10 mg to prises from about 1 % to about 3 % of low -substituted about 60 mg. In some embodiments , the promethazine hydroxypropyl cellulose ( L -HPC ) ( w / w ) . In some embodi- hydrochloride is present in an amount of about 12 . 5 mg, ments , each second particulate comprises from about 10 % to 20 about 25 mg , or about 50 mg. In some embodiments , a ratio about 40 % of the antiemetic ( w /w ) . In some embodiments , by weight of the 5HT B / 1 receptor agonist to the antiemetic each second particulate comprises from about 50 % to about is from about 1 : 2 to about 15 : 1 . In some embodiments , the 70 % of a core ( w /w ). In some embodiments , each second ratio by weight of the 5HT1B / 10 receptor agonist to the particulate has an average diameter from about 700 um and antiemetic is from about 3 : 2 to about 11 : 1 . In some embodi about 1200 um . In some embodiments , each first particulate 25 ments , the ratio by weight of the 5HT B / 1 receptor agonist further comprises a first coating . In some embodiments , each to the antiemetic is from about 3 : 1 to about 7 : 1 or from about second particulate further comprises a second coating . In 1 : 1 to about 5 : 1 . In some embodiments , the ratio by weight some embodiments , the second particulate comprises from of the 5HT, BI receptor agonist to the antiemetic is from about 5 % to about 15 % of a second coating ( w / w ) . In some about 9 : 2 to about 11 : 2 or from about 4 : 2 to about 6 : 2 . In embodiments , the first or second coating comprises polyvi - 30 some embodiments , the ratio by weight of the 5HT BILD nyl alcohol, cellulose acetate phthalate, polyvinyl acetate receptor agonist to the antiemetic is about 5 : 1 or about 2 .5 : 1 . phthalate, methacrylic acid copolymer, cellulose acetate In some embodiments, at least about 32 % of the antiemetic trimellitate , hydroxypropyl methylcellulose phthalate , is released within about 5 minutes following contact of the hydroxypropyl methylcellulose , hydroxypropyl methyl cel capsule with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH lulose acetate succinate , shellac , sodium alginate , zein , or 35 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle any combinations thereof. In some embodiments , the coat - Apparatus ) rotating at 50 rpm . In some embodiments , at ing comprises polyvinyl alcohol. In some embodiments , the least about 63 % of the antiemetic is released within about 15 coating is polyvinyl alcohol. In some embodiments , the minutes following contact of the capsule with 500 mL of a 5HT16 /10 receptor agonist comprises a triptan or a pharma dissolution fluid (0 . 1N HCI, pH 1 . 1 ) at 37 + / - 0 .5° C . as ceutically acceptable salt thereof. In some embodiments , the 40 measured by an Apparatus 2 ( Paddle Apparatus ) rotating at triptan or the pharmaceutically acceptable salt thereof com - 50 rpm . In some embodiments, at least about 79 % of the prises sumatriptan , almotriptan , frovatriptan , eletriptan , riza antiemetic is released within about 30 minutes following triptan , naratriptan , or a pharmaceutically acceptable salt contact of the capsule with 500 mL of a dissolution fluid thereof. In some embodiments , the triptan or the pharma ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an ceutically acceptable salt thereof comprises sumatriptan or a 45 Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some pharmaceutically acceptable salt thereof. In some embodi- embodiments , at least about 88 % of the antiemetic is ments, the sumatriptan or the pharmaceutically acceptable released within about 60 minutes following contact of the salt thereof is present in an amount therapeutically equiva - capsule with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH lent from about 70 mg to about 110 mg of sumatriptan free 1 . 1 ) at 37 + / - 0 .5° C . as measured by an Apparatus 2 ( Paddle base . In some embodiments , the sumatriptan or the pharma- 50 Apparatus ) rotating at 50 rpm . In some embodiments , at ceutically acceptable salt thereof is present in an amount least about 56 % of the 5HT , BU receptor agonist is released therapeutically equivalent to about 90 mg of sumatriptan within about 5 minutes following contact of the capsule with free base . In some embodiments , the pharmaceutically 500 mL of a dissolution fluid ( 0 . 1N HCl, pH 1 . 1 ) at acceptable salt of the sumatriptan comprises sumatriptan 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle Appa succinate . In some embodiments , the sumatriptan succinate 55 ratus ) rotating at 50 rpm . In some embodiments , at least is present in an amount from about 100 mg to about 140 mg. about 81 % of the 5HT , BILD receptor agonist is released In some embodiments , the sumatriptan succinate is present within about 15 minutes following contact of the capsule in an amount of about 126 mg. In some embodiments, the with 500 mL of a dissolution fluid ( 0 . 1N HCI, pH 1 . 1) at antiemetic comprises promethazine , ondansetron , aprepi- 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle Appa tant , dronabinol, perphenazine, palonosetron , trimethyoben - 60 ratus ) rotating at 50 rpm . In some embodiments , at least zamide , metoclopromide , domperidone , prochlorperazine , about 87 % of the 5HT B / D receptor agonist is released chlorpromazine , trimethobenzamide, granisetron , within about 30 minutes following contact of the capsule hydroxyzine, acetylleucine monoethanolamine , alizapride , with 500 mL of a dissolution fluid (0 . 1N HC1, pH 1 . 1) at azasetron , benzquinamide , bietanautine , bromopride , bucl- 37 + / - 0 . 5° C . as measured by an Apparatus 2 ( Paddle Appa izine , clebopride , cyclizine , dimenhydrinate , diphenidol, 65 ratus ) rotating at 50 rpm . In some embodiments , at least dolasetron , meclizine, methallatal, metopimazine , nabilone , about 92 % of the 5HTB/ D receptor agonist is released oxyperndyl, pipamazine , scopolamine , sulpiride , tetrahydro - within about 60 minutes following contact of the capsule US 10 , 179 , 109 B2 11 12 with 500 mL of a dissolution fluid (0 . 1N HC1, pH 1. 1 ) at mL of a dissolution fluid ( 0 . 1N HC1, pH 1. 1) at 37 + / - 0 .5° C . 37 + / - 0 .5º C . as measured by an Apparatus 2 (Paddle Appa as measured by an Apparatus 2 (Paddle Apparatus ) rotating ratus ) rotating at 50 rpm . at 50 rpm . In some embodiments , after storage at 40° C . for Provided herein is a capsule comprising a pharmaceutical 1 month at least about 92 % of the antiemetic is released composition comprising: a plurality of first particulates, 5 within about 60 minutes following contact of the capsule wherein each first particulate comprises : a 5HT1B / recep with 500 mL of a dissolution fluid ( 0 .1N HC1, pH 1 . 1 ) at tor agonist wherein : ( a ) each first particulate has an average 37 + / - 0 .5° C . as measured by an Apparatus 2 ( Paddle Appa diameter of less than about 500 um ; or (b ) each first ratus ) rotating at 50 rpm . particulate comprises from about 55 % to about 65 % of the Provided herein is a capsule comprising a pharmaceutical 5HTB/ 12 receptor agonist ( w / w ) ; and a plurality of second 10 composition comprising : a plurality of first particulates , particulates, wherein each second particulate comprises: (i ) wherein each first particulate comprises : ( i ) about 100 mg to a core ; and ( ii ) a layer enclosing the core , wherein said layer about 140 mg of sumatriptan succinate ; and ( ii ) about 50 mg comprises an antiemetic ; wherein the dissolution profile of to about 150 mg of microcrystalline cellulose ; and a plural the capsule stored at 40° C . for one month is : at least about ity of second particulates, wherein each second particulate 47 % of the 5HT B receptor agonist is released within 15 comprises : ( i ) about 10 mg to about 60 mg of promethazine about 5 minutes, or at least about 69 % of the 5HT , BILD hydrochloride ; ( ii ) about 30 mg to about 150 mg of a sugar receptor agonist is released within about 15 minutes , or at sphere ; ( iii ) about 2 . 5 mg to about 15 mg of hydroxypropyl least about 80 % of the 5HT B12 receptor agonist is released methylcellulose (HPMC ); ( iv ) about 0 . 5 mg to about 10 mg within about 30 minutes , or at least about 86 % of the of talc ; ( v ) about 0 . 5 mg to about 10 mg of low - substituted 5HT 10 /10 receptor agonist is released within about 60 min - 20 hydroxypropyl cellulose ( L - HPC ) ; and ( vi) about 5 mg to utes following contact of the capsule with 500 mL of a about 30 mg of a coating . In some embodiments, each first dissolution fluid (0 .1N HC1, pH 1 . 1) at 37 + / - 0 .5º C . as particulate has an average diameter of less than about 500 measured by an Apparatus 2 (Paddle Apparatus ) rotating at um . 50 rpm ; and at least about 35 % of the antiemetic is released Provided herein is a capsule comprising a pharmaceutical within about 5 minutes , or at least about 63 % of the 25 composition comprising : a plurality of first particulates , antiemetic is released within about 15 minutes , or at least wherein each first particulate comprises : ( i ) about 126 mg of about 74 % of the antiemetic agonist is released within about sumatriptan succinate ; and ( ii ) about 84 mg of microcrys 30 minutes , or at least about 84 % of the antiemetic is talline cellulose ; wherein each first particulate has an aver released within about 60 minutes following contact of the age diameter of less than about 500 um ; and a plurality of capsule with 500 mL of a dissolution fluid ( 0 . 1N HCl, pH 30 second particulates , wherein each second particulate com 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle prises : ( i ) about 25 mg of promethazine hydrochloride ; ( ii ) Apparatus ) rotating at 50 rpm . In some embodiments, after about 66 .6 mg of a sugar sphere ; ( iii ) about 6 .6 mg of storage at 40° C . for 1 month at least about 60 % of the hydroxypropylmethylcellulose (HPMC ) ; ( iv ) about 1 . 2 mg 5HT1B / 12 receptor agonist is released within about 5 minutes of talc ; ( v ) about 2 . 5 mg of low - substituted hydroxypropyl following contact of the capsule with 500 mL of a dissolu - 35 cellulose ( L -HPC ) ; and (vi ) about 10 . 2 mg of a coating . tion fluid ( 0 . 1N HCI, PH 1 . 1 ) at 37 + / - 0 .5° C . as measured Provided herein is a capsule comprising a pharmaceutical by an Apparatus 2 ( Paddle Apparatus ) rotating at 50 rpm . In composition comprising : a plurality of first particulates , some embodiments , after storage at 40° C . for 1 month at wherein each first particulate comprises : ( i ) about 126 mg of least about 81 % of the 5HT1B / 10 receptor agonist is released sumatriptan succinate ; and ( ii ) about 84 mg of microcrys within about 15 minutes following contact of the capsule 40 talline cellulose ; wherein each first particulate has an aver with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1) at age diameter of less than about 500 um ; and a plurality of 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - second particulates, wherein each second particulate com ratus ) rotating at 50 rpm . In some embodiments , after prises: (i ) about 50 mg of promethazine hydrochloride ; ( ii ) storage at 40° C . for 1 month at least about 88 % of the about 133 . 2 mg of a sugar sphere ; ( iii ) about 13 . 2 mg of 5HT16 / 12 receptor agonist is released within about 30 min - 45 hydroxypropyl methylcellulose (HPMC ); (iv ) about 2 . 4 mg utes following contact of the capsule with 500 mL of a of talc ; ( v ) about 5 mg of low - substituted hydroxypropyl dissolution fluid ( 0 . 1N HC1, pH 1. 1 ) at 37 + / - 0 .5º C . as cellulose ( L -HPC ) ; and (vi ) about 20 . 4 mg of a coating . measured by an Apparatus 2 (Paddle Apparatus ) rotating at Provided herein is a method of treating a headache in a 50 rpm . In some embodiments , after storage at 40° C . for 1 subject in need thereof, comprising administering to the month at least about 93 % of the 5HT16 / 1 receptor agonist 50 subject a pharmaceutical composition comprising : a plural is released within about 60 minutes following contact of the ity of first particulates, wherein each first particulate com capsule with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH prises: a 5HT B / D receptor agonist wherein : ( a ) each first 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle particulate has an average diameter of less than about 500 Apparatus ) rotating at 50 rpm . In some embodiments , after um ; or ( b ) each first particulate comprises from about 55 % storage at 40° C . for 1 month at least about 43 % of the 55 to about 65 % of the 5HT B : receptor agonist ( w / w ) ; and a antiemetic is released within about 5 minutes following plurality of second particulates , wherein each second par contact of the capsule with 500 mL of a dissolution fluid ticulate comprises : ( i) a core ; and ( ii ) a layer enclosing the ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an core , wherein said layer comprises an antiemetic . In some Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some embodiments , each first particulate further comprises a embodiments , after storage at 40° C . for 1 month at least 60 pharmaceutically acceptable excipient . In some embodi about 73 % of the antiemetic is released within about 15 ments , the pharmaceutically acceptable excipient is a non minutes following contact of the capsule with 500 mL of a pharmaceutically active ingredient. In some embodiments , dissolution fluid ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 .5º C . as the non - pharmaceutically active ingredient comprises at measured by an Apparatus 2 ( Paddle Apparatus ) rotating at least one component selected from the group consisting of 50 rpm . In some embodiments , after storage at 40° C . for 1 65 microcrystalline cellulose , dicalcium phosphate , calcium month at least about 84 % of the antiemetic is released within sulfate , talc , an alkali metal stearate , silicon dioxide , calcium about 30 minutes following contact of the capsule with 500 carbonate, and any combinations thereof. In some embodi US 10 , 179 , 109 B2 13 14 ments , the at least one component is microcrystalline cel- mide, domperidone , prochlorperazine , chlorpromazine , lulose . In some embodiments , each first particulate com trimethobenzamide , granisetron , hydroxyzine, acetylleucine prises about 60 % of the 5HT B / 1 receptor agonist ( w / w ) . In monoethanolamine , alizapride, azasetron , benzquinamide , some embodiments , each first particulate comprises about bietanautine , bromopride , buclizine , clebopride , cyclizine , 40 % of the non -pharmaceutically active ingredient ( w / w ) . In 5 dimenhydrinate , diphenidol, dolasetron , meclizine , methal some embodiments, each first particulate has an average latal, metopimazine , nabilone , oxyperndyl, pipamazine , sco diameter of between about 100 um and about 500 um . In polamine, sulpiride , tetrahydrocannabinol, thiethylperazine, some embodiments , the layer enclosing the core in each thioproperazine , tropisetron , droperidol, haloperidol, second particulate is directly adjacent to the core . In some prochloperazine , metoclopramide, diphenhydramine , can embodiments , the core in each second particulate does not 10 nabinoid , midazolam , lorazepam , hyoscine, dexamethasone , comprise an antiemetic . In some embodiments , the core in emetrol, propofol , or a pharmaceutically acceptable salt each second particulate comprises a sugar sphere . In some thereof . In some embodiments, the antiemetic comprises embodiments , the layer enclosing the core in each second promethazine or a pharmaceutically acceptable salt thereof. particulate comprises one or more pharmaceutically accept In some embodiments, the promethazine or the pharmaceu able excipients . In some embodiments , the one or more 15 tically acceptable salt thereof is present in an amount pharmaceutically acceptable excipients is selected from therapeutically equivalent from about 10 mg to about 60 mg hydroxypropyl methylcellulose (HPMC ) , low - substituted promethazine free base . In some embodiments, the promet hydroxypropyl cellulose ( L - HPC ) , talc , and any combina - hazine or the pharmaceutically acceptable salt thereof is tions thereof. In some embodiments , each second particulate present in an amount therapeutically equivalent to about 11 comprises from about 2 % to about 10 % of hydroxypropyl 20 mg, about 22 mg, or about 44 mg of promethazine free base . methylcellulose (HPMC ) ( w / w ) . In some embodiments , In some embodiments , the pharmaceutically acceptable salt each second particulate comprises from about 0 . 1 % to about of promethazine comprises promethazine hydrochloride . In 2 % of talc ( w / w ) . In some embodiments , each second some embodiments, the promethazine hydrochloride is pres particulate comprises from about 1 % to about 3 % of low - ent in an amount from about 10 mg to about 60 mg. In some substituted hydroxypropyl cellulose ( L -HPC ) ( w / w ) . In 25 embodiments , the promethazine hydrochloride is present in some embodiments , each second particulate comprises from an amount of about 12 .5 mg, about 25 mg, or about 50 mg. about 10 % to about 40 % of the antiemetic ( w / w ) . In some In some embodiments , a ratio by weight of the 5HT1B / 1D embodiments , each second particulate comprises from about receptor agonist to the antiemetic is from about 1 : 2 to about 50 % to about 70 % of a core ( w / w ) . In some embodiments, 15 : 1 . In some embodiments , the ratio by weight of the each second particulate has an average diameter from about 30 5HT , B , receptor agonist to the antiemetic is from about 700 um and about 1200 um . In some embodiments , each first 3 : 2 to about 11 : 1 . In some embodiments , the ratio by weight particulate further comprises a first coating. In some of the 5HT , BI receptor agonist to the antiemetic is from embodiments , each second particulate further comprises a about 3 : 1 to about 7 : 1 or from about 1 : 1 to about 5 : 1 . In second coating . In some embodiments , each second particu some embodiments , the ratio by weight of the 5HT1B/ 1D late comprises from about 5 % to about 15 % of a second 35 receptor agonist to the antiemetic is from about 9 : 2 to about coating ( w / w ) . In some embodiments , the first or second 11 : 2 or from about 4 : 2 to about 6 : 2 . In some embodiments , coating comprises polyvinyl alcohol, cellulose acetate the ratio by weight of the 5HTB11 receptor agonist to the phthalate , polyvinyl acetate phthalate , methacrylic acid antiemetic is about 5 : 1 or about 2 . 5 : 1 . In some embodi copolymer, cellulose acetate trimellitate , hydroxypropyl ments , at least about 85 % of the antiemetic is released within methylcellulose phthalate , hydroxypropyl methylcellulose , 40 about 5 minutes following contact of the pharmaceutical hydroxypropyl methyl cellulose acetate succinate , shellac , composition with 500 mL of a dissolution fluid ( 0 . 1N HC1, sodium alginate , zein , or any combinations thereof . In some pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 embodiments, the coating comprises polyvinyl alcohol. In (Paddle Apparatus ) rotating at 50 rpm . In some embodi some embodiments , the coating is polyvinyl alcohol. In ments , at least about 92 % of the antiemetic is released within some embodiments , the 5HT B receptor agonist com - 45 about 15 minutes following contact of the pharmaceutical prises a triptan or a pharmaceutically acceptable salt thereof. composition with 500 mL of a dissolution fluid ( 0 . 1N HC1, In some embodiments , the triptan or the pharmaceutically pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 acceptable salt thereof comprises sumatriptan , almotriptan , ( Paddle Apparatus ) rotating at 50 rpm . In some embodi frovatriptan , eletriptan , rizatriptan , naratriptan , or a pharma - ments , at least about 94 % of the antiemetic is released within ceutically acceptable salt thereof. In some embodiments , the 50 about 30 minutes following contact of the particulate with triptan or the pharmaceutically acceptable salt thereof com - 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at prises sumatriptan or a pharmaceutically acceptable salt 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle Appa thereof. In some embodiments , the sumatriptan or the phar - ratus ) rotating at 50 rpm . In some embodiments , at least maceutically acceptable salt thereof is present in an amount about 96 % of the antiemetic is released within about 60 therapeutically equivalent from about 70 mg to about 110 55 minutes following contact of the pharmaceutical composi mg of sumatriptan free base . In some embodiments , the tion with 500 mL of a dissolution fluid (0 . 1N HCl, pH 1 . 1 ) sumatriptan or the pharmaceutically acceptable salt thereof at 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle is present in an amount therapeutically equivalent to about Apparatus ) rotating at 50 rpm . In some embodiments , at 90 mg of sumatriptan free base . In some embodiments , the least about 75 % of the 5HT3/12 receptor agonist is released pharmaceutically acceptable salt of the sumatriptan com - 60 within about 5 minutes following contact of the pharmaceu prises sumatriptan succinate . In some embodiments , the tical composition with 500 mL of a dissolution fluid ( 0 . 1N sumatriptan succinate is present in an amount from about HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 100 mg to about 140 mg. In some embodiments , the 2 (Paddle Apparatus ) rotating at 50 rpm . In some embodi sumatriptan succinate is present in an amount of about 126 ments , at least about 87 % of the 5HT 8 /12 receptor agonist mg . In some embodiments , the antiemetic comprises pro - 65 is released within about 15 minutes following contact of the methazine , ondansetron , aprepitant, dronabinol, per - pharmaceutical composition with 500 mL of a dissolution phenazine , palonosetron , trimethyobenzamide , metoclopro - fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5º C . as measured by an US 10 , 179 ,109 B2 15 16 Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some particulate comprises a sugar sphere . In some embodiments , embodiments , at least about 93 % of the 5HT1B / 1D receptor the layer enclosing the core in each second particulate agonist is released within about 30 minutes following con comprises one or more pharmaceutically acceptable excipi tact of the pharmaceutical composition with 500 mL of a ents . In some embodiments , the one or more pharmaceuti dissolution fluid (0 . 1N HCl, pH 1 .1 ) at 37 + / - 0 .5º C . as 5 cally acceptable excipients is selected from hydroxypropyl measured by an Apparatus 2 ( Paddle Apparatus ) rotating at methylcellulose (HPMC ) , low -substituted hydroxypropyl 50 rpm . In some embodiments , at least about 98 % of the cellulose ( L -HPC ) , talc , and any combinations thereof . In 5HTB/ 12 receptor agonist is released within about 60 min - some embodiments , each second particulate comprises from utes following contact of the pharmaceutical composition about 2 % to about 10 % of hydroxypropyl methylcellulose with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 10 (HPMC ) ( w / w ) . In some embodiments , each second par 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa ticulate comprises from about 0 . 1 % to about 2 % of talc ratus ) rotating at 50 rpm . In some embodiments, the treat - ( w / w ) . In some embodiments , each second particulate com ment of the headache is acute or prophylactic . In some prise from about 1 % to about 3 % of low - substituted embodiments , the headache is a migraine headache . In some hydroxypropyl cellulose ( L -HPC ) ( w / w ) . In some embodi embodiments , the headache is an acute migraine headache or 15 ments , each second particulate comprises from about 10 % to a chronic migraine headache . In some embodiments , the about 40 % of the antiemetic ( w / w ) . In some embodiments , headache is a migraine headache with or without an aura . In each second particulate comprises from about 50 % to about some embodiments , the headache is a cluster headache . In 70 % of a core ( w / w ) . In some embodiments , each second some embodiments , the pharmaceutical composition , oral particulate has an average diameter from about 700 um and dosage , or capsule is used for treatment of nausea associated 20 about 1200 um . In some embodiments , each first particulate with a headache and vomiting associated with a headache . In further comprises a first coating . In some embodiments , each some embodiments , the pharmaceutical composition , oral second particulate further comprises a second coating . In dosage , or capsule is suitable for use at one , two , or three s ome embodiments , each second particulate comprises from times daily . In some embodiments , the pharmaceutical com about 5 % to about 15 % of a second coating (w /w ). In some position , oral dosage , or capsule is suitable for use at about 25 embodiments , the first or second coating comprises polyvi every 4 to about every 6 hours . In some embodiments , a nyl alcohol, cellulose acetate phthalate , polyvinyl acetate second dose ofthe pharmaceutical composition , oral dosage , phthalate , methacrylic acid copolymer, cellulose acetate or capsule is used after response to a first dose in a subject. trimellitate , hydroxypropyl methylcellulose phthalate , In some embodiments, doses after a first dose of the phar - hydroxypropyl methylcellulose , hydroxypropyl methyl cel maceutical composition , oral dosage , or capsule are sepa - 30 lulose acetate succinate , shellac , sodium alginate , zein , or rated by at least 2 hours . In some embodiments , a maximum any combinations thereof. In some embodiments , the coat dose of the 5HT B /1 receptor agonist over 24 hour does not ing comprises polyvinyl alcohol. In some embodiments, the exceed 200 mg. In some embodiments , a maximum single coating is polyvinyl alcohol. In some embodiments , the dose of the 5HT1B/ 10 receptor agonist does not exceed 50 5HT 15 / 10 receptor agonist comprises a triptan or a pharma mg in a subject with mild to moderate hepatic impairment. 35 ceutically acceptable salt thereof . In some embodiments , the Provided herein is a method of treating a headache in a triptan or the pharmaceutically acceptable salt thereof com subject in need thereof, comprising administering to the prises sumatriptan , almotriptan , frovatriptan , eletriptan , riza subject an oral dosage form comprising a pharmaceutical triptan , naratriptan , or a pharmaceutically acceptable salt composition comprising : a plurality of first particulates, thereof. In some embodiments , the triptan or the pharma wherein each first particulate comprises: a 5HT B / D recep - 40 ceutically acceptable salt thereof comprises sumatriptan or a tor agonist wherein : ( a ) each first particulate has an average pharmaceutically acceptable salt thereof. In some embodi diameter of less than about 500 um ; or ( b ) each first ments , the sumatriptan or the pharmaceutically acceptable particulate comprises from about 55 % to about 65 % of the salt thereof is present in an amount therapeutically equiva 5HT1B / 10 receptor agonist ( w /w ); and a plurality of second lent from about 70 mg to about 110 mg of sumatriptan free particulates , wherein each second particulate comprises : ( i ) 45 base . In some embodiments , the sumatriptan or the pharma a core ; and ( ii ) a layer enclosing the core , wherein said layer ceutically acceptable salt thereof is present in an amount comprises an antiemetic . In some embodiments , each first therapeutically equivalent to about 90 mg of sumatriptan particulate further comprises a pharmaceutically acceptable free base . In some embodiments , the pharmaceutically excipient. In some embodiments , the pharmaceutically acceptable salt of the sumatriptan comprises sumatriptan acceptable excipient is a non - pharmaceutically active ingre - 50 succinate . In some embodiments , the sumatriptan succinate dient. In some embodiments , the non - pharmaceutically is present in an amount from about 100 mg to about 140 mg. active ingredient comprises at least one component selected In some embodiments , the sumatriptan succinate is present from the group consisting of microcrystalline cellulose , in an amount of about 126 mg. In some embodiments , the dicalcium phosphate , calcium sulfate , talc , an alkali metal antiemetic comprises promethazine , ondansetron , aprepi stearate , silicon dioxide , calcium carbonate , and any com - 55 tant, dronabinol, perphenazine , palonosetron , trimethyoben binations thereof. In some embodiments , the at least one zamide , metoclopromide , domperidone, prochlorperazine , component is microcrystalline cellulose. In some embodi- chlorpromazine , trimethobenzamide, granisetron , ments, each first particulate comprises about 60 % of the hydroxyzine, acetylleucine monoethanolamine, alizapride , 5HT1B /10 receptor agonist ( w / w ). In some embodiments , azasetron , benzquinamide, bietanautine , bromopride, bucl each first particulate comprises about 40 % of the non - 60 izine , clebopride , cyclizine , dimenhydrinate , diphenidol, pharmaceutically active ingredient ( w / w ) . In some embodi- dolasetron , meclizine , methallatal, metopimazine , nabilone , ments, each first particulate has an average diameter of oxyperndyl, pipamazine , scopolamine , sulpiride, tetrahydro between about 100 um and about 500 um . In some embodi cannabinol, thiethylperazine , thioproperazine , tropisetron , ments , the layer enclosing the core in each second particu - droperidol, haloperidol, prochloperazine , metoclopramide , late is directly adjacent to the core . In some embodiments , 65 diphenhydramine , cannabinoid , midazolam , lorazepam , the core in each second particulate does not comprise an hyoscine , dexamethasone , emetrol, propofol , or a pharma antiemetic . In some embodiments , the core in each second ceutically acceptable salt thereof. In some embodiments, the US 10 , 179 , 109 B2 17 18 antiemetic comprises promethazine or a pharmaceutically embodiments , the treatment of the headache is acute or acceptable salt thereof. In some embodiments , the promet prophylactic . In some embodiments , the headache is a hazine or the pharmaceutically acceptable salt thereof is migraine headache. In some embodiments, the headache is present in an amount therapeutically equivalent from about an acute migraine headache or a chronic migraine headache . 10 mg to about 60 mg promethazine free base . In some 5 In some embodiments, the headache is a migraine headache embodiments , the promethazine or the pharmaceutically with or without an aura . In some embodiments , the headache acceptable salt thereof is present in an amount therapeuti- is a cluster headache . In some embodiments , the pharma cally equivalent to about 11 mg, about 22 mg, or about 44 ceutical composition , oral dosage , or capsule is used for mg of promethazine free base . In some embodiments , the treatment of nausea associated with a headache and vomit pharmaceutically acceptable salt of promethazine comprises 10 ing associated with a headache. In some embodiments , the promethazine hydrochloride . In some embodiments , the pharmaceutical composition , oral dosage , or capsule is suit promethazine hydrochloride is present in an amount from able for use at one , two , or three times daily . In some about 10 mg to about 60 mg. In some embodiments, the embodiments , the pharmaceutical composition , oral dosage , promethazine hydrochloride is present in an amount of about or capsule is suitable for use at about every 4 to about every 12 . 5 mg, about 25 mg, or about 50 mg. In some embodi - 15 6 hours . In some embodiments , a second dose of the ments, a ratio by weight of the 5HT3/12 receptor agonist to pharmaceutical composition , oral dosage , or capsule is used the antiemetic is from about 1 : 2 to about 15 : 1 . In some after response to a first dose in a subject. In some embodi embodiments , the ratio by weight of the 5HT18 / 10 receptor ments , doses after a first dose of the pharmaceutical com agonist to the antiemetic is from about 3 : 2 to about 11 : 1 . In position , oral dosage , or capsule are separated by at least 2 some embodiments , the ratio by weight of the 5HT1B /1D 20 hours . In some embodiments , a maximum dose of the receptor agonist to the antiemetic is from about 3 : 1 to about 5HT, B , receptor agonist over 24 hour does not exceed 200 7 : 1 or from about 1 : 1 to about 5 : 1 . In some embodiments, mg. In some embodiments, a maximum single dose of the the ratio by weight of the 5HT1B/ 10 receptor agonist to the 5HT1B/ 12 receptor agonist does not exceed 50 mg in a antiemetic is from about 9 : 2 to about 11: 2 or from about 4 : 2 subject with mild to moderate hepatic impairment. to about 6 : 2 . In some embodiments , the ratio by weight of 25 Provided herein is a method of treating a headache in a the 5HT, 12 receptor agonist to the antiemetic is about 5 : 1 subject in need thereof, comprising administering to the or about 2. 5 : 1 . In some embodiments , at least about 85 % of subject a capsule comprising a pharmaceutical composition the antiemetic is released within about 5 minutes following comprising : a plurality of first particulates, wherein each contact of the pharmaceutical composition with 500 mL of first particulate comprises : a 5HTB/ receptor agonist a dissolution fluid ( 0 . 1N HC1, pH 1. 1 ) at 37 + / - 0 .5º C . as 30 wherein : (a ) each first particulate has an average diameter of measured by an Apparatus 2 (Paddle Apparatus ) rotating at less than about 500 um ; or ( b ) each first particulate com 50 rpm . In some embodiments , at least about 92 % of the prises from about 55 % to about 65 % of the 5HT, BD antiemetic is released within about 15 minutes following receptor agonist ( w / w ) ; and a plurality of second particu contact of the pharmaceutical composition with 500 mL of lates , wherein each second particulate comprises : ( i ) a core ; a dissolution fluid (0 .1N HC1, pH 1. 1 ) at 37 + / - 0 . 5º C . as 35 and ( ii ) a layer enclosing the core, wherein said layer measured by an Apparatus 2 ( Paddle Apparatus ) rotating at comprises an antiemetic . In some embodiments, each first 50 rpm . In some embodiments, at least about 94 % of the particulate further comprises a pharmaceutically acceptable antiemetic is released within about 30 minutes following excipient. In some embodiments , the pharmaceutically contact of the particulate with 500 mL of a dissolution fluid acceptable excipient is a non - pharmaceutically active ingre (0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an 40 dient. In some embodiments, the non -pharmaceutically Apparatus 2 ( Paddle Apparatus ) rotating at 50 rpm . In some active ingredient comprises at least one component selected embodiments , at least about 96 % of the antiemetic is from the group consisting of microcrystalline cellulose , released within about 60 minutes following contact of the dicalcium phosphate , calcium sulfate , talc , an alkali metal pharmaceutical composition with 500 mL of a dissolution s tearate, silicon dioxide , calcium carbonate, and any com fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an 45 binations thereof. In some embodiments , the at least one Apparatus 2 ( Paddle Apparatus) rotating at 50 rpm . In some component is microcrystalline cellulose . In some embodi embodiments , at least about 75 % of the 5HTB1 receptor ments , each first particulate comprises about 60 % of the agonist is released within about 5 minutes following contact 5HT BULD receptor agonist ( w / w ) . In some embodiments , of the pharmaceutical composition with 500 mL of a disso - each first particulate comprises about 40 % of the non lution fluid (0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured 50 pharmaceutically active ingredient ( w / w ) . In some embodi by an Apparatus 2 ( Paddle Apparatus ) rotating at 50 rpm . In ments , each first particulate has an average diameter of some embodiments, at least about 87 % of the 5HT BID between about 100 um and about 500 um . In some embodi receptor agonist is released within about 15 minutes follow - ments , the layer enclosing the core in each second particu ing contact of the pharmaceutical composition with 500 mL late is directly adjacent to the core . In some embodiments , of a dissolution fluid ( 0 .1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5º C . as 55 the core in each second particulate does not comprise an measured by an Apparatus 2 ( Paddle Apparatus ) rotating at antiemetic . In some embodiments , the core in each second 50 rpm . In some embodiments , at least about 93 % of the particulate comprises a sugar sphere . In some embodiments , 5HT1B / id receptor agonist is released within about 30 min - the layer enclosing the core in each second particulate utes following contact of the pharmaceutical composition comprises one or more pharmaceutically acceptable excipi with 500 mL of a dissolution fluid (0 . 1N HCl, pH 1. 1 ) at 60 ents . In some embodiments , the one or more pharmaceuti 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - cally acceptable excipients is selected from hydroxypropyl ratus ) rotating at 50 rpm . In some embodiments , at least methylcellulose (HPMC ) , low - substituted hydroxypropyl about 98 % of the 5HT16 / 10 receptor agonist is released cellulose (L -HPC ), talc , and any combinations thereof. In within about 60 minutes following contact of the pharma - some embodiments , each second particulate comprises from ceutical composition with 500 mL of a dissolution fluid 65 about 2 % to about 10 % of hydroxypropyl methylcellulose ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an (HPMC ) ( w /w ) . In some embodiments , each second par Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some ticulate comprises from about 0 . 1 % to about 2 % of talc US 10 , 179 ,109 B2 20 ( w / w ) . In some embodiments , each second particulate com - hydrochloride is present in an amount from about 10 mg to prises from about 1 % to about 3 % of low -substituted about 60 mg . In some embodiments , the promethazine hydroxypropyl cellulose ( L -HPC ) ( w / w ). In some embodi hydrochloride is present in an amount of about 12 . 5 mg, ments, each second particulate comprises from about 10 % to about 25 mg, or about 50 mg. In some embodiments , a ratio about 40 % of the antiemetic ( w / w ) . In some embodiments , 5 by weight of the 5HT1 B / 1 receptor agonist to the antiemetic each second particulate comprises from about 50 % to about is from about 1 : 2 to about 15 : 1 . In some embodiments , the 70 % of a core ( w / w ) . In some embodiments , each second ratio by weight of the 5HT1B / 10 receptor agonist to the particulate has an average diameter from about 700 um and antiemetic is from about 3 : 2 to about 11 : 1 . In some embodi about 1200 um . In some embodiments, each first particulate ments , the ratio by weight of the 5HT , R / 1 receptor agonist further comprises a first coating . In some embodiments , each 10 to the antiemetic is from about 3 : 1 to about 7 : 1 or from about second particulate further comprises a second coating . In 1 : 1 to about 5 : 1 . In some embodiments , the ratio by weight some embodiments , the second particulate comprises from of the 5HT B / D receptor agonist to the antiemetic is from about 5 % to about 15 % of a second coating ( w / w ) . In some about 9 : 2 to about 11 : 2 or from about 4 : 2 to about 6 : 2 . In embodiments , the first or second coating comprises polyvi- some embodiments , the ratio by weight of the 5HT BD nyl alcohol, cellulose acetate phthalate , polyvinyl acetate 15 receptor agonist to the antiemetic is about 5 : 1 or about 2 . 5 : 1 . phthalate , methacrylic acid copolymer, cellulose acetate In some embodiments , at least about 32 % of the antiemetic trimellitate , hydroxypropyl methylcellulose phthalate , is released within about 5 minutes following contact of the hydroxypropyl methylcellulose , hydroxypropyl methyl cel - capsule with 500 mL of a dissolution fluid ( 0 . 1N HCI, PH lulose acetate succinate , shellac , sodium alginate , zein , or 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle any combinations thereof . In some embodiments , the coat - 20 Apparatus ) rotating at 50 rpm . In some embodiments , at ing comprises polyvinyl alcohol. In some embodiments , the least about 63 % of the antiemetic is released within about 15 coating is polyvinyl alcohol. In some embodiments , the minutes following contact of the capsule with 500 mL of a 5HT, receptor agonist comprises a triptan or a pharma - dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as ceutically acceptable salt thereof. In some embodiments , the measured by an Apparatus 2 (Paddle Apparatus ) rotating at triptan or the pharmaceutically acceptable salt thereof com - 25 50 rpm . In some embodiments , at least about 79 % of the prises sumatriptan , almotriptan , frovatriptan , eletriptan , riza - antiemetic is released within about 30 minutes following triptan , naratriptan , or a pharmaceutically acceptable salt contact of the capsule with 500 mL of a dissolution fluid thereof. In some embodiments , the triptan or the pharma- (0 .1N HC1, pH 1. 1 ) at 37 + / - 0 .5º C . as measured by an ceutically acceptable salt thereof comprises sumatriptan or a Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some pharmaceutically acceptable salt thereof . In some embodi - 30 embodiments , at least about 88 % of the antiemetic is ments , the sumatriptan or the pharmaceutically acceptable released within about 60 minutes following contact of the salt thereof is present in an amount therapeutically equiva - capsule with 500 mL of a dissolution fluid (0 . 1N HC1, pH lent from about 70 mg to about 110 mg of sumatriptan free 1 . 1 ) at 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle base . In some embodiments , the sumatriptan or the pharma Apparatus ) rotating at 50 rpm . In some embodiments, at ceutically acceptable salt thereof is present in an amount 35 least about 56 % of the 5HT, BM receptor agonist is released therapeutically equivalent to about 90 mg of sumatriptan within about 5 minutes following contact of the capsule with free base. In some embodiments , the pharmaceutically 500 mL of a dissolution fluid ( 0 . 1N HCI, pH 1 . 1 ) at acceptable salt of the sumatriptan comprises sumatriptan 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle Appa succinate . In some embodiments , the sumatriptan succinate ratus ) rotating at 50 rpm . In some embodiments , at least is present in an amount from about 100 mg to about 140 mg. 40 about 81 % of the 5HT BID receptor agonist is released In some embodiments , the sumatriptan succinate is present within about 15 minutes following contact of the capsule in an amount of about 126 mg. In some embodiments, the with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at antiemetic comprises promethazine , ondansetron , aprepi- 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle Appa tant, dronabinol, perphenazine , palonosetron , trimethyoben ratus ) rotating at 50 rpm . In some embodiments , at least zamide , metoclopromide , domperidone , prochlorperazine , 45 about 87 % of the 5HT B / D receptor agonist is released chlorpromazine , trimethobenzamide, granisetron , within about 30 minutes following contact of the capsule hydroxyzine, acetylleucine monoethanolamine , alizapride , with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at azasetron , benzquinamide , bietanautine , bromopride , bucl - 37 + / - 0 .5º C . as measured by an Apparatus 2 ( Paddle Appa izine , clebopride , cyclizine , dimenhydrinate , diphenidol, ratus ) rotating at 50 rpm . In some embodiments, at least dolasetron , meclizine, methallatal, metopimazine , nabilone , 50 about 92 % of the 5HT , BILD receptor agonist is released oxyperndyl, pipamazine, scopolamine , sulpiride , tetrahydro - within about 60 minutes following contact of the capsule cannabinol, thiethylperazine , thioproperazine , tropisetron , with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at droperidol, haloperidol, prochloperazine , metoclopramide , 37 + / - 0 . 5° C . as measured by an Apparatus 2 ( Paddle Appa diphenhydramine, cannabinoid , midazolam , lorazepam , ratus ) rotating at 50 rpm . In some embodiments , the treat hyoscine, dexamethasone , emetrol, propofol, or a pharma- 55 ment of the headache is acute or prophylactic . In some ceutically acceptable salt thereof. In some embodiments , the embodiments , the headache is a migraine headache . In some antiemetic comprises promethazine or a pharmaceutically embodiments , the headache is an acute migraine headache or acceptable salt thereof . In some embodiments , promethazine a chronic migraine headache . In some embodiments , the or the pharmaceutically acceptable salt thereof is present in headache is a migraine headache with or without an aura . In an amount therapeutically equivalent from about 10 mg to 60 some embodiments , the headache is a cluster headache . In about 60 mg promethazine free base . In some embodiments , some embodiments , the pharmaceutical composition , oral the promethazine or the pharmaceutically acceptable salt dosage , or capsule is used for treatment of nausea associated thereof is present in an amount therapeutically equivalent to with a headache and vomiting associated with a headache . In about 11 mg, about 22 mg, or about 44 mg of promethazine some embodiments , the pharmaceutical composition , oral free base . In some embodiments , the pharmaceutically 65 dosage , or capsule is suitable for use at one , two , or three acceptable salt of promethazine comprises promethazine times daily . In some embodiments , the pharmaceutical com hydrochloride . In some embodiments , the promethazine position , oral dosage , or capsule is suitable for use at about US 10 , 179 , 109 B2 21 every 4 to about every 6 hours . In some embodiments , a about every 6 hours . In some embodiments , a second dose second dose of the pharmaceutical composition , oral dosage , of the pharmaceutical composition , oral dosage , or capsule or capsule is used after response to a first dose in a subject is used after response to a first dose in a subject. In some In some embodiments , doses after a first dose of the phar embodiments , doses after a first dose of the pharmaceutical maceutical composition , oral dosage , or capsule are sepa - 5 composition , oral dosage , or capsule are separated by at least rated by at least 2 hours . In some embodiments , a maximum 2 hours . In some embodiments , a maximum dose of the dose of the 5HT BL receptor agonist over 24 hour does not 5HT B /12 receptor agonist over 24 hour does not exceed 200 exceed 200 mg. In some embodiments , a maximum single mg. In some embodiments , a maximum single dose of the dose of the 5HT B / receptor agonist does not exceed 50 5HTB/ D receptor agonist does not exceed 50 mg in a mg in a subject with mild to moderate hepatic impairment. 10 subject with mild to moderate hepatic impairment . Provided herein is a method of treating a headache in a Provided herein is a method of treating a headache in a subject in need thereof, comprising administering to the subject in need thereof, comprising administering to the subject a capsule comprising a pharmaceutical composition subject a capsule comprising a pharmaceutical composition comprising: a plurality of first particulates, wherein each comprising : a plurality of first particulates , wherein each first particulate comprises : ( i ) about 100 mg to about 140 mg 15 first particulate comprises : a 5HT B / D receptor agonist of sumatriptan succinate ; and ( ii ) about 50 mg to about 150 wherein : ( a ) each first particulate has an average diameter of mg of microcrystalline cellulose ; and a plurality of second less than about 500 um ; or ( b ) each first particulate com particulates, wherein each second particulate comprises : ( i) prises from about 55 % to about 65 % of the 5HT1B/ 1D about 10 mg to about 60 mg of promethazine hydrochloride ; receptor agonist ( w / w ) ; and a plurality of second particu ( ii ) about 30 mg to about 150 mg of a sugar sphere ; ( iii ) 20 lates , wherein each second particulate comprises : ( i ) a core ; about 2 .5 mg to about 15 mg of hydroxypropyl methylcel - and ( ii ) a layer enclosing the core, wherein said layer lulose (HPMC ); ( iv ) about 0 . 5 mg to about 10 mg of talc ; ( v ) comprises an antiemetic ; wherein the dissolution profile of about 0 . 5 mg to about 10 mg of low -substituted hydroxy the capsule stored at 40° C . for one month is : at least about propyl cellulose ( L -HPC ) ; and ( vi ) about 5 mg to about 30 47 % of the 5HTB/ 1 receptor agonist is released within mg of a coating . Provided herein is a method of treating a 25 about 5 minutes , or at least about 69 % of the 5HT , BILD headache in a subject in need thereof , comprising adminis - receptor agonist is released within about 15 minutes , or at tering to the subject a capsule comprising a pharmaceutical least about 80 % of the 5HT , B / receptor agonist is released composition comprising : a plurality of first particulates , within about 30 minutes, or at least about 86 % of the wherein each first particulate comprises : ( i ) about 126 mg of 5HT, B / 1 receptor agonist is released within about 60 min sumatriptan succinate ; and ( ii ) about 84 mg of microcrys - 30 utes following contact of the capsule with 500 mL of a talline cellulose ; wherein each first particulate has an aver - dissolution fluid ( 0 . 1N HCI, pH 1 . 1 ) at 37 + / - 0 . 5° C . as age diameter of less than about 500 um ; and a plurality of measured by an Apparatus 2 ( Paddle Apparatus ) rotating at second particulates , wherein each second particulate com - 50 rpm ; and at least about 35 % of the antiemetic is released prises: (i ) about 25 mg of promethazine hydrochloride ; ( ii ) within about 5 minutes , or at least about 63 % of the about 66 . 6 mg of a sugar sphere ; ( iii ) about 6 . 6 mg of 35 antiemetic is released within about 15 minutes , or at least hydroxypropyl methylcellulose (HPMC ) ; (iv ) about 1 . 2 mg about 74 % of the antiemetic agonist is released within about of talc ; ( v ) about 2 . 5 mg of low - substituted hydroxypropyl 30 minutes , or at least about 84 % of the antiemetic is cellulose ( L -HPC ) ; and ( vi) about 10 . 2 mg of a coating . released within about 60 minutes following contact of the Provided herein is a method of treating a headache in a capsule with 500 mL of a dissolution fluid ( 0 .1N HC1, pH subject in need thereof, comprising administering to the 40 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle subject a capsule comprising a pharmaceutical composition Apparatus ) rotating at 50 rpm . In some embodiments , after comprising : a plurality of first particulates , wherein each storage at 40° C . for 1 month at least about 60 % of the first particulate comprises : ( i ) about 126 mg of sumatriptan 5HT BU receptor agonist is released within about 5 minutes succinate ; and (ii ) about 84 mg ofmicrocrystalline cellulose ; following contact of the capsule with 500 mL of a dissolu wherein each first particulate has an average diameter of less 45 tion fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured than about 500 um ; and a plurality of second particulates, by an Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In wherein each second particulate comprises : ( 1 ) about 50 mg some embodiments , after storage at 40° C . for 1 month at of promethazine hydrochloride; ( ii ) about 133 .2 mg of a least about 81 % of the 5HT1B/ 10 receptor agonist is released sugar sphere ; ( iii ) about 13 . 2 mg of hydroxypropyl methyl- within about 15 minutes following contact of the capsule cellulose (HPMC ) ; ( iv ) about 2 . 4 mg of talc ; ( v ) about 5 mg 50 with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at of low -substituted hydroxypropyl cellulose ( L -HPC ) ; and 37 + / - 0 .5° C . as measured by an Apparatus 2 ( Paddle Appa ( vi ) about 20 . 4 mg of a coating . In some embodiments , each ratus ) rotating at 50 rpm . In some embodiments , after first particulate has an average diameter of less than about storage at 40° C . for 1 month at least about 88 % of the 500 um . In some embodiments , the treatment of the head - 5HTB/ 1 receptor agonist is released within about 30 min ache is acute or prophylactic . In some embodiments , the 55 utes following contact of the capsule with 500 mL of a headache is a migraine headache . In some embodiments , the dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5º C . as headache is an acute migraine headache or a chronic measured by an Apparatus 2 (Paddle Apparatus ) rotating at migraine headache . In some embodiments , the headache is 50 rpm . In some embodiments , after storage at 40° C . for 1 a migraine headache with or without an aura . In some month at least about 93 % of the 5HT B /1 receptor agonist embodiments , the headache is a cluster headache . In some 60 is released within about 60 minutes following contact of the embodiments , the pharmaceutical composition , oral dosage , capsule with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH or capsule is used for treatment of nausea associated with a 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle headache and vomiting associated with a headache . In some Apparatus ) rotating at 50 rpm . In some embodiments , after embodiments , the pharmaceutical composition , oral dosage , storage at 40° C . for 1 month at least about 43 % of the or capsule is suitable for use at one , two , or three times daily . 65 antiemetic is released within about 5 minutes following In some embodiments , the pharmaceutical composition , oral contact of the capsule with 500 mL of a dissolution fluid dosage , or capsule is suitable for use at about every 4 to (0 . 1N HCI, pH 1. 1 ) at 37 + / - 0 .5º C . as measured by an US 10 , 179 , 109 B2 23 24 Apparatus 2 ( Paddle Apparatus) rotating at 50 rpm . In some some embodiments , the layer enclosing the core in each embodiments , after storage at 40° C . for 1 month at least second particulate is directly adjacent to the core . In some about 73 % of the antiemetic is released within about 15 embodiments , the core in each second particulate does not minutes following contact of the capsule with 500 mL of a comprise an antiemetic . In some embodiments , the core in dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5° C . as 5 each second particulate comprises a sugar sphere . In some measured by an Apparatus 2 (Paddle Apparatus ) rotating at embodiments , the layer enclosing the core in each second 50 rpm . In some embodiments , after storage at 40° C . for 1 particulate comprises one or more pharmaceutically accept month at least about 84 % of the antiemetic is released within able excipients. In some embodiments , the one or more about 30 minutes following contact of the capsule with 500 pharmaceutically acceptable excipients is selected from mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . 10 hydroxypropyl methylcellulose (HPMC ) , low -substituted as measured by an Apparatus 2 (Paddle Apparatus ) rotating hydroxypropyl cellulose ( L -HPC ) , talc , and any combina at 50 rpm . In some embodiments , after storage at 40° C . for tions thereof. In some embodiments, each second particulate 1 month at least about 92 % of the antiemetic is released comprises from about 2 % to about 10 % of hydroxypropyl within about 60 minutes following contact of the capsule methylcellulose (HPMC ) ( w / w ) . In some embodiments , with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 15 each second particulate comprises from about 0 . 1 % to about 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - 2 % of talc ( w / w ) . In some embodiments , each second ratus ) rotating at 50 rpm . In some embodiments, the treat - particulate comprises from about 1 % to about 3 % of low ment of the headache is acute or prophylactic . In some substituted hydroxypropyl cellulose (L -HPC ) (w /w ). In embodiments , the headache is a migraine headache . In some some embodiments , each second particulate comprises from embodiments , the headache is an acute migraine headache or 20 about 10 % to about 40 % of the antiemetic ( w / w ) . In some a chronic migraine headache . In some embodiments , the embodiments , each second particulate comprises from about headache is a migraine headache with or without an aura . In 50 % to about 70 % of a core (w /w ). In some embodiments , some embodiments , the headache is a cluster headache. In each second particulate has an average diameter from about some embodiments , the pharmaceutical composition , oral 700 um and about 1200 um . In some embodiments, each first dosage , or capsule is used for treatment of nausea associated 25 particulate further comprises a first coating . In some with a headache and vomiting associated with a headache . In embodiments , each second particulate further comprises a some embodiments , the pharmaceutical composition , oral second coating . In some embodiments , each second particu dosage , or capsule is suitable for use at one , two, or three late comprises from about 5 % to about 15 % of a second times daily . In some embodiments , the pharmaceutical com coating ( w / w ) . In some embodiments , the first or second position , oral dosage , or capsule is suitable for use at about 30 coating comprises polyvinyl alcohol, cellulose acetate every 4 to about every 6 hours. In some embodiments , a phthalate , polyvinyl acetate phthalate , methacrylic acid second dose of the pharmaceutical composition , oral dosage , copolymer, cellulose acetate trimellitate , hydroxypropyl or capsule is used after response to a first dose in a subject . methylcellulose phthalate , hydroxypropyl methylcellulose , In some embodiments , doses after a first dose of the phar- hydroxypropyl methyl cellulose acetate succinate , shellac , maceutical composition , oral dosage , or capsule are sepa - 35 sodium alginate , zein , or any combinations thereof . In some rated by at least 2 hours . In some embodiments , a maximum embodiments , the coating comprises polyvinyl alcohol. In dose of the 5HT1 B / 1 receptor agonist over 24 hour does not some embodiments , the coating is polyvinyl alcohol. In exceed 200 mg. In some embodiments , a maximum single some embodiments , the 5HTB/ D receptor agonist com dose of the 5HT1B / receptor agonist does not exceed 50 prises a triptan or a pharmaceutically acceptable salt thereof. mg in a subject with mild to moderate hepatic impairment. 40 In some embodiments , the triptan or the pharmaceutically Provided herein is a method of treating a photophobia in acceptable salt thereof comprises sumatriptan , almotriptan , a subject in need thereof, comprising administering to the frovatriptan , eletriptan , rizatriptan , naratriptan , or a pharma subject a pharmaceutical composition comprising : a plural- ceutically acceptable salt thereof. In some embodiments , the ity of first particulates, wherein each first particulate com triptan or the pharmaceutically acceptable salt thereof com prises : a 5HT B / D receptor agonist wherein : ( a ) each first 45 prises sumatriptan or a pharmaceutically acceptable salt particulate has an average diameter of less than about 500 thereof. In some embodiments, the sumatriptan or the phar um ; or ( b ) each first particulate comprises from about 55 % maceutically acceptable salt thereof is present in an amount to about 65 % of the 5HTB/ 1 receptor agonist ( w / w ) ; and a therapeutically equivalent from about 70 mg to about 110 plurality of second particulates, wherein each second par - mg of sumatriptan free base . In some embodiments , the ticulate comprises : ( i ) a core ; and ( ii ) a layer enclosing the 50 sumatriptan or the pharmaceutically acceptable salt thereof core , wherein said layer comprises an antiemetic . In some is present in an amount therapeutically equivalent to about embodiments , each first particulate further comprises a 90 mg of sumatriptan free base . In some embodiments , the pharmaceutically acceptable excipient. In some embodi- pharmaceutically acceptable salt of the sumatriptan com ments , the pharmaceutically acceptable excipient is a non - prises sumatriptan succinate . In some embodiments, the pharmaceutically active ingredient. In some embodiments , 55 sumatriptan succinate is present in an amount from about the non - pharmaceutically active ingredient comprises at 100 mg to about 140 mg. In some embodiments , the least one component selected from the group consisting of sumatriptan succinate is present in an amount of about 126 microcrystalline cellulose , dicalcium phosphate, calcium mg. In some embodiments , the antiemetic comprises pro sulfate , talc , an alkali metal stearate , silicon dioxide, calcium methazine, ondansetron , aprepitant, dronabinol, per carbonate , and any combinations thereof. In some embodi - 60 phenazine , palonosetron , trimethyobenzamide , metoclopro ments , the at least one component is microcrystalline cel- mide , domperidone , prochlorperazine, chlorpromazine , lulose . In some embodiments , each first particulate com - trimethobenzamide , granisetron , hydroxyzine , acetylleucine prises about 60 % of the 5HT,B2 receptor agonist ( w / w ) . In monoethanolamine , alizapride , azasetron , benzquinamide , some embodiments , each first particulate comprises about bietanautine , bromopride , buclizine , clebopride , cyclizine , 40 % of the non -pharmaceutically active ingredient ( w / w ) . In 65 dimenhydrinate , diphenidol , dolasetron , meclizine, methal some embodiments, each first particulate has an average latal, metopimazine , nabilone , oxyperndyl, pipamazine , sco diameter of between about 100 um and about 500 um . In polamine, sulpiride , tetrahydrocannabinol, thiethylperazine , US 10 , 179 , 109 B2 25 26 thioproperazine , tropisetron , droperidol, haloperidol, 5HT1B / 1d receptor agonist is released within about 60 min prochloperazine , metoclopramide , diphenhydramine , can utes following contact of the pharmaceutical composition nabinoid , midazolam , lorazepam , hyoscine , dexamethasone, with 500 mL of a dissolution fluid (0 .1N HC1, pH 1. 1 ) at emetrol, propofol, or a pharmaceutically acceptable salt 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa thereof. In some embodiments , the antiemetic comprises 5 ratus ) rotating at 50 rpm . In some embodiments , the treat promethazine or a pharmaceutically acceptable salt thereof. ment of the photophobia is acute or prophylactic . In some In some embodiments , the promethazine or the pharmaceu - embodiments , the pharmaceutical composition , oral dosage , tically acceptable salt thereof is present in an amount or capsule is used for treatment of a light sensitivity . In some therapeutically equivalent from about 10 mg to about 60 mg embodiments , the pharmaceutical composition , oral dosage , promethazine free base . In some embodiments , the promet - 10 or capsule treats nausea associated with a headache or hazine or the pharmaceutically acceptable salt thereof is vomiting associated with a headache . In some embodiments , present in an amount therapeutically equivalent to about 11 the pharmaceutical composition , oral dosage , or capsule mg, about 22 mg, or about 44 mg of promethazine free base . treats nausea associated with a headache and vomiting In some embodiments , the pharmaceutically acceptable salt associated with a headache . In some embodiments , the of promethazine comprises promethazine hydrochloride . In 15 administering is one , two , or three times daily . In some some embodiments , the promethazine hydrochloride is pres - embodiments , the administering is about every 4 to about ent in an amount from about 10 mg to about 60 mg. In some every 6 hours . In some embodiments , the administering is embodiments , the promethazine hydrochloride is present in about every 8 to about every 12 hours . In some embodi an amount of about 12 .5 mg, about 25 mg , or about 50 mg . ments , a second dose of the pharmaceutical composition , In some embodiments , a ratio by weight of the 5HT , BILD 20 oral dosage , or capsule is administered after response to a receptor agonist to the antiemetic is from about 1 : 2 to about first dose in the subject . In some embodiments , doses after 15 : 1 . In some embodiments , the ratio by weight of the a first dose of the pharmaceutical composition , oral dosage , 5HTRA receptor agonist to the antiemetic is from about or capsule are separated by at least 2 hours . In some 3 : 2 to about 11 : 1 . In some embodiments , the ratio by weight embodiments , a maximum dose of the 5HT15 / 12 receptor of the 5HT B / L receptor agonist to the antiemetic is from 25 agonist over 24 hour does not exceed 200 mg. In some about 3 : 1 to about 7 : 1 or from about 1 : 1 to about 5 : 1 . In embodiments , a maximum single dose of the 5HT1B / ID some embodiments , the ratio by weight of the 5HT B / D receptor agonist does not exceed 50 mg in a subject with receptor agonist to the antiemetic is from about 9 : 2 to about mild to moderate hepatic impairment. 11 : 2 or from about 4 :2 to about 6 : 2 . In some embodiments , Provided herein is a method of treating a photophobia in the ratio by weight of the 5HT , B receptor agonist to the 30 a subject in need thereof, comprising administering to the antiemetic is about 5 : 1 or about 2 .5 : 1 . In some embodi- subject an oral dosage form comprising a pharmaceutical ments , at least about 85 % of the antiemetic is released within composition comprising: a plurality of first particulates, about 5 minutes following contact of the pharmaceutical wherein each first particulate comprises : a 5HTB/ 1 recep composition with 500 mL of a dissolution fluid ( 0 . 1N HC1, tor agonist wherein : ( a ) each first particulate has an average pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 35 diameter of less than about 500 um ; or ( b ) each first ( Paddle Apparatus ) rotating at 50 rpm . In some embodi particulate comprises from about 55 % to about 65 % of the ments, at least about 92 % of the antiemetic is released within 5HT B / 1 receptor agonist ( w / w ) ; and a plurality of second about 15 minutes following contact of the pharmaceutical particulates , wherein each second particulate comprises : ( i ) composition with 500 mL of a dissolution fluid ( 0 . 1N HCl, a core; and ( ii ) a layer enclosing the core , wherein said layer pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an Apparatus 2 40 comprises an antiemetic . In some embodiments , each first ( Paddle Apparatus ) rotating at 50 rpm . In some embodi particulate further comprises a pharmaceutically acceptable ments , at least about 94 % of the antiemetic is released within excipient. In some embodiments , the pharmaceutically about 30 minutes following contact of the particulate with acceptable excipient is a non -pharmaceutically active ingre 500 mL of a dissolution fluid (0 . 1N HC1, pH 1 . 1 ) at dient . In some embodiments , the non - pharmaceutically 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - 45 active ingredient comprises at least one component selected ratus ) rotating at 50 rpm . In some embodiments , at least from the group consisting of microcrystalline cellulose , about 96 % of the antiemetic is released within about 60 dicalcium phosphate , calcium sulfate , talc , an alkali metal minutes following contact of the pharmaceutical composi - stearate , silicon dioxide, calcium carbonate , and any com tion with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) binations thereof. In some embodiments , the at least one at 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle 50 component is microcrystalline cellulose . In some embodi Apparatus ) rotating at 50 rpm . In some embodiments , at ments , each first particulate comprises about 60 % of the least about 75 % of the 5HT B / D receptor agonist is released 5HTB/ 1 receptor agonist ( w / w ). In some embodiments , within about 5 minutes following contact of the pharmaceu - each first particulate comprises about 40 % of the non tical composition with 500 mL of a dissolution fluid ( 0 . 1N pharmaceutically active ingredient ( w / w ). In some embodi HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 55 ments , each first particulate has an average diameter of 2 (Paddle Apparatus ) rotating at 50 rpm . In some embodi - between about 100 um and about 500 um . In some embodi ments , at least about 87 % of the 5HT B / D receptor agonist ments , the layer enclosing the core in each second particu is released within about 15 minutes following contact of the late is directly adjacent to the core . In some embodiments , pharmaceutical composition with 500 mL of a dissolution the core in each second particulate does not comprise an fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an 60 antiemetic . In some embodiments , the core in each second Apparatus 2 ( Paddle Apparatus) rotating at 50 rpm . In some particulate comprises a sugar sphere . In some embodiments , embodiments , at least about 93 % of the 5HTB receptor the layer enclosing the core in each second particulate agonist is released within about 30 minutes following con comprises one or more pharmaceutically acceptable excipi tact of the pharmaceutical composition with 500 mL of a ents . In some embodiments , the one or more pharmaceuti dissolution fluid (0 .1N HCl, pH 1 . 1) at 37 + / - 0 .5º C . as 65 cally acceptable excipients is selected from hydroxypropyl measured by an Apparatus 2 (Paddle Apparatus ) rotating at methylcellulose (HPMC ) , low - substituted hydroxypropyl 50 rpm . In some embodiments , at least about 98 % of the cellulose ( L -HPC ) , talc , and any combinations thereof . In US 10 , 179 ,109 B2 27 28 some embodiments , each second particulate comprises from cally equivalent to about 11 mg, about 22 mg, or about 44 about 2 % to about 10 % of hydroxypropyl methylcellulose mg of promethazine free base . In some embodiments, the (HPMC ) ( w / w ) . In some embodiments , each second par pharmaceutically acceptable salt of promethazine comprises ticulate comprises from about 0 . 1 % to about 2 % of talc promethazine hydrochloride . In some embodiments , the ( w / w ) . In some embodiments , each second particulate com - 5 promethazine hydrochloride is present in an amount from prises from about 1 % to about 3 % of low -substituted about 10 mg to about 60 mg. In some embodiments , the hydroxypropyl cellulose ( L -HPC ) ( w / w ) . In some embodi- promethazine hydrochloride is present in an amount of about ments , each second particulate comprises from about 10 % to 12 . 5 mg, about 25 mg, or about 50 mg. In some embodi about 40 % of the antiemetic ( w / w ) . In some embodiments , ments, a ratio by weight of the 5HT1B / 10 receptor agonist to each second particulate comprises from about 50 % to about 10 the antiemetic is from about 1 : 2 to about 15 : 1 . In some 70 % of a core ( w / w ) . In some embodiments , each second embodiments , the ratio by weight of the 5HT16 / 12 receptor particulate has an average diameter from about 700 um and agonist to the antiemetic is from about 3 : 2 to about 11 : 1 . In about 1200 um . In some embodiments, each first particulate some embodiments , the ratio by weight of the 5HT1B / 1D further comprises a first coating . In some embodiments , each receptor agonist to the antiemetic is from about 3 : 1 to about second particulate further comprises a second coating . In 15 7 : 1 or from about 1 : 1 to about 5 : 1 . In some embodiments , some embodiments , each second particulate comprises from the ratio by weight of the 5HT 16 /12 receptor agonist to the about 5 % to about 15 % of a second coating ( w / w ) . In some antiemetic is from about 9 : 2 to about 11 : 2 or from about 4 : 2 embodiments , the first or second coating comprises polyvi- to about 6 : 2 . In some embodiments , the ratio by weight of nyl alcohol, cellulose acetate phthalate, polyvinyl acetate the 5HT3/ 12 receptor agonist to the antiemetic is about 5 : 1 phthalate , methacrylic acid copolymer, cellulose acetate 20 or about 2 . 5 : 1 . In some embodiments , at least about 85 % of trimellitate , hydroxypropyl methylcellulose phthalate , the antiemetic is released within about 5 minutes following hydroxypropylmethylcellulose , hydroxypropyl methyl cel contact of the pharmaceutical composition with 500 mL of lulose acetate succinate , shellac , sodium alginate , zein , or a dissolution fluid ( 0 .1N HC1, pH 1. 1 ) at 37 + / - 0 . 5° C . as any combinations thereof. In some embodiments , the coat measured by an Apparatus 2 (Paddle Apparatus ) rotating at ing comprises polyvinyl alcohol. In some embodiments , the 25 50 rpm . In some embodiments , at least about 92 % of the coating is polyvinyl alcohol. In some embodiments, the antiemetic is released within about 15 minutes following 5HT1B / 1d receptor agonist comprises a triptan or a pharma contact of the pharmaceutical composition with 500 mL of ceutically acceptable salt thereof. In some embodiments , the a dissolution fluid ( 0 .1N HC1, pH 1 .1 ) at 37 +/ - 0 . 5º C . as triptan or the pharmaceutically acceptable salt thereof com - measured by an Apparatus 2 (Paddle Apparatus ) rotating at prises sumatriptan , almotriptan , frovatriptan , eletriptan , riza - 30 50 rpm . In some embodiments, at least about 94 % of the triptan , naratriptan , or a pharmaceutically acceptable salt antiemetic is released within about 30 minutes following thereof. In some embodiments, the triptan or the pharma - contact of the particulate with 500 mL of a dissolution fluid ceutically acceptable salt thereof comprises sumatriptan or a (0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 . 5º C . as measured by an pharmaceutically acceptable salt thereof . In some embodi - Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some ments , the sumatriptan or the pharmaceutically acceptable 35 embodiments , at least about 96 % of the antiemetic is salt thereof is present in an amount therapeutically equiva - released within about 60 minutes following contact of the lent from about 70 mg to about 110 mg of sumatriptan free pharmaceutical composition with 500 mL of a dissolution base . In some embodiments , the sumatriptan or the pharma- fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5º C . as measured by an ceutically acceptable salt thereof is present in an amount Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some therapeutically equivalent to about 90 mg of sumatriptan 40 embodiments , at least about 75 % of the 5HT , 8 : receptor free base . In some embodiments , the pharmaceutically agonist is released within about 5 minutes following contact acceptable salt of the sumatriptan comprises sumatriptan of the pharmaceutical composition with 500 mL of a disso succinate. In some embodiments , the sumatriptan succinate lution fluid ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured is present in an amount from about 100 mg to about 140 mg. by an Apparatus 2 ( Paddle Apparatus ) rotating at 50 rpm . In In some embodiments , the sumatriptan succinate is present 45 some embodiments , at least about 87 % of the 5HT BILD in an amount of about 126 mg. In some embodiments , the receptor agonist is released within about 15 minutes follow antiemetic comprises promethazine , ondansetron , aprepi ing contact of the pharmaceutical composition with 500 mL tant, dronabinol, perphenazine , palonosetron , trimethyoben - of a dissolution fluid ( 0 . 1N HC1, pH 1. 1 ) at 37 + / - 0 .5º C . as zamide, metoclopromide, domperidone , prochlorperazine, measured by an Apparatus 2 (Paddle Apparatus ) rotating at chlorpromazine , trimethobenzamide , granisetron , 50 50 rpm . In some embodiments , at least about 93 % of the hydroxyzine, acetylleucine monoethanolamine , alizapride , 5HT3/ 12 receptor agonist is released within about 30 min azasetron , benzquinamide, bietanautine , bromopride , bucl - utes following contact of the pharmaceutical composition izine , clebopride, cyclizine , dimenhydrinate , diphenidol, with 500 mL of a dissolution fluid (0 .1N HC1, pH 1. 1 ) at dolasetron , meclizine , methallatal, metopimazine , nabilone , 37 + / - 0 .5º C . as measured by an Apparatus 2 ( Paddle Appa oxyperndyl, pipamazine, scopolamine, sulpiride , tetrahydro - 55 ratus ) rotating at 50 rpm . In some embodiments , at least cannabinol, thiethylperazine , thioproperazine , tropisetron , about 98 % of the 5HT B / D receptor agonist is released droperidol, haloperidol, prochloperazine, metoclopramide, within about 60 minutes following contact of the pharma diphenhydramine , cannabinoid , midazolam , lorazepam , ceutical composition with 500 mL of a dissolution fluid hyoscine , dexamethasone , emetrol, propofol, or a pharma - ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an ceutically acceptable salt thereof. In some embodiments , the 60 Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some antiemetic comprises promethazine or a pharmaceutically embodiments , the treatment of the photophobia is acute or acceptable salt thereof. In some embodiments , the promet prophylactic . In some embodiments , the pharmaceutical hazine or the pharmaceutically acceptable salt thereof is composition , oral dosage , or capsule is used for treatment of present in an amount therapeutically equivalent from about a light sensitivity . In some embodiments, the pharmaceutical 10 mg to about 60 mg promethazine free base . In some 65 composition , oral dosage , or capsule treats nausea associated embodiments , the promethazine or the pharmaceutically with a headache or vomiting associated with a headache. In acceptable salt thereof is present in an amount therapeuti some embodiments , the pharmaceutical composition , oral US 10 , 179 , 109 B2 29 30 dosage , or capsule treats nausea associated with a headache about 1200 um . In some embodiments , each first particulate and vomiting associated with a headache. In some embodi further comprises a first coating. In some embodiments , each ments , the administering is one , two , or three times daily . In second particulate further comprises a second coating. In some embodiments , the administering is about every 4 to some embodiments , the second particulate comprises from about every 6 hours . In some embodiments, the administer - 5 about 5 % to about 15 % of a second coating ( w / w ) . In some ing is about every 8 to about every 12 hours. In some embodiments , the first or second coating comprises polyvi embodiments , a second dose of the pharmaceutical compo - nyl alcohol, cellulose acetate phthalate , polyvinyl acetate sition , oral dosage , or capsule is administered after response phthalate , methacrylic acid copolymer , cellulose acetate to a first dose in the subject. In some embodiments , doses trimellitate , hydroxypropyl methylcellulose phthalate , after a first dose of the pharmaceutical composition , oral 10 hydroxypropyl methylcellulose , hydroxypropyl methyl cel dosage , or capsule are separated by at least 2 hours . In some lulose acetate succinate , shellac , sodium alginate , zein , or embodiments , a maximum dose of the 5HT B / D receptor any combinations thereof. In some embodiments , the coat agonist over 24 hour does not exceed 200 mg. In some ing comprises polyvinyl alcohol. In some embodiments, the embodiments , a maximum single dose of the 5HT15 / 1D coating is polyvinyl alcohol. In some embodiments , the receptor agonist does not exceed 50 mg in a subject with 15 5HT B / D receptor agonist comprises a triptan or a pharma mild to moderate hepatic impairment. ceutically acceptable salt thereof. In some embodiments , the Provided herein is a method of treating a photophobia in triptan or the pharmaceutically acceptable salt thereof com a subject in need thereof, comprising administering to the prises sumatriptan , almotriptan , frovatriptan , eletriptan , riza subject a capsule comprising a pharmaceutical composition triptan , naratriptan , or a pharmaceutically acceptable salt comprising: a plurality of first particulates , wherein each 20 thereof. In some embodiments , the triptan or the pharma first particulate comprises : a 5HT1B / 10 receptor agonist ceutically acceptable salt thereof comprises sumatriptan or a wherein : ( a ) each first particulate has an average diameter of pharmaceutically acceptable salt thereof . In some embodi less than about 500 um ; or (b ) each first particulate com - ments , the sumatriptan or the pharmaceutically acceptable prises from about 55 % to about 65 % of the 5HT , BILD. salt thereof is present in an amount therapeutically equiva receptor agonist ( w / w ) ; and a plurality of second particu - 25 lent from about 70 mg to about 110 mg of sumatriptan free lates , wherein each second particulate comprises : ( i ) a core ; base . In some embodiments , the sumatriptan or the pharma and ( ii ) a layer enclosing the core , wherein said layer ceutically acceptable salt thereof is present in an amount comprises an antiemetic . In some embodiments , each first therapeutically equivalent to about 90 mg of sumatriptan particulate further comprises a pharmaceutically acceptable free base . In some embodiments , the pharmaceutically excipient . In some embodiments , the pharmaceutically 30 acceptable salt of the sumatriptan comprises sumatriptan acceptable excipient is a non -pharmaceutically active ingre - succinate. In some embodiments , the sumatriptan succinate dient. In some embodiments , the non - pharmaceutically is present in an amount from about 100 mg to about 140 mg. active ingredient comprises at least one component selected In some embodiments , the sumatriptan succinate is present from the group consisting of microcrystalline cellulose , in an amount of about 126 mg. In some embodiments, the dicalcium phosphate , calcium sulfate , talc , an alkali metal 35 antiemetic comprises promethazine , ondansetron , aprepi stearate , silicon dioxide , calcium carbonate , and any com tant, dronabinol, perphenazine , palonosetron , trimethyoben binations thereof. In some embodiments , the at least one zamide , metoclopromide, domperidone , prochlorperazine, component is microcrystalline cellulose . In some embodi- chlorpromazine , trimethobenzamide , granisetron , ments , each first particulate comprises about 60 % of the hydroxyzine , acetylleucine monoethanolamine , alizapride, 5HT1B / 1d receptor agonist ( w / w ) . In some embodiments, 40 azasetron , benzquinamide , bietanautine , bromopride , bucl each first particulate comprises about 40 % of the non - izine , clebopride , cyclizine , dimenhydrinate , diphenidol, pharmaceutically active ingredient ( w / w ) . In some embodi- dolasetron , meclizine , methallatal , metopimazine , nabilone, ments , each first particulate has an average diameter of oxyperndyl, pipamazine , scopolamine , sulpiride , tetrahydro between about 100 um and about 500 um . In some embodi cannabinol, thiethylperazine , thioproperazine, tropisetron , ments , the layer enclosing the core in each second particu - 45 droperidol, haloperidol, prochloperazine , metoclopramide , late is directly adjacent to the core . In some embodiments , diphenhydramine , cannabinoid , midazolam , lorazepam , the core in each second particulate does not comprise an hyoscine , dexamethasone , emetrol, propofol, or a pharma antiemetic . In some embodiments , the core in each second ceutically acceptable salt thereof. In some embodiments , the particulate comprises a sugar sphere . In some embodiments , antiemetic comprises promethazine or a pharmaceutically the layer enclosing the core in each second particulate 50 acceptable salt thereof. In some embodiments , promethazine comprises one or more pharmaceutically acceptable excipi- or the pharmaceutically acceptable salt thereof is present in ents . In some embodiments , the one or more pharmaceuti- an amount therapeutically equivalent from about 10 mg to cally acceptable excipients is selected from hydroxypropyl about 60 mg promethazine free base . In some embodiments , methylcellulose (HPMC ), low -substituted hydroxypropyl the promethazine or the pharmaceutically acceptable salt cellulose ( L -HPC ) , talc , and any combinations thereof . In 55 thereof is present in an amount therapeutically equivalent to some embodiments , each second particulate comprises from about 11 mg, about 22 mg, or about 44 mg of promethazine about 2 % to about 10 % of hydroxypropyl methylcellulose free base . In some embodiments , the pharmaceutically (HPMC ) ( w / w ) . In some embodiments , each second par - acceptable salt of promethazine comprises promethazine ticulate comprises from about 0 . 1 % to about 2 % of talc hydrochloride . In some embodiments , the promethazine ( w / w ) . In some embodiments , each second particulate com - 60 hydrochloride is present in an amount from about 10 mg to prises from about 1 % to about 3 % of low -substituted about 60 mg. In some embodiments , the promethazine hydroxypropyl cellulose ( L - HPC ) ( w / w ) . In some embodi- hydrochloride is present in an amount of about 12 . 5 mg, ments , each second particulate comprises from about 10 % to about 25 mg, or about 50 mg. In some embodiments , a ratio about 40 % of the antiemetic ( w / w ) . In some embodiments , by weight of the 5HT B / 12 receptor agonist to the antiemetic each second particulate comprises from about 50 % to about 65 is from about 1 : 2 to about 15 : 1 . In some embodiments , the 70 % of a core ( w / w ) . In some embodiments , each second ratio by weight of the 5HTB/ D receptor agonist to the particulate has an average diameter from about 700 um and antiemetic is from about 3 : 2 to about 11 : 1 . In some embodi US 10 , 179 , 109 B2 31 32 ments , the ratio by weight of the 5HT1B /10 receptor agonist receptor agonist does not exceed 50 mg in a subject with to the antiemetic is from about 3 : 1 to about 7 : 1 or from about mild to moderate hepatic impairment. 1 : 1 to about 5 :1 . In some embodiments , the ratio by weight Provided herein is a method of treating a photophobia in of the 5HTB/ D receptor agonist to the antiemetic is from a subject in need thereof, comprising administering to the about 9 : 2 to about 11 : 2 or from about 4 : 2 to about 6 : 2 . In 5 subject a capsule comprising a pharmaceutical composition some embodiments , the ratio by weight of the 5HT1B / 1D comprising : a plurality of first particulates , wherein each receptor agonist to the antiemetic is about 5 : 1 or about 2 . 5 : 1 . first particulate comprises : ( i) about 100 mg to about 140 mg In some embodiments , at least about 32 % of the antiemetic is released within about 5 minutes following contact of the of sumatriptan succinate ; and ( ii ) about 50 mg to about 150 capsule with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 10 mg of microcrystalline cellulose ; and a plurality of second 1 . 1) at 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle particulates, wherein each second particulate comprises: ( i ) Apparatus ) rotating at 50 rpm . In some embodiments, at about 10 mg to about 60 mg of promethazine hydrochloride ; least about63 % of the antiemetic is released within about 15 ( ii ) about 30 mg to about 150 mg of a sugar sphere ; (iii ) minutes following contact of the capsule with 500 mL of a about 2 . 5 mg to about 15 mg of hydroxypropyl methylcel dissolution fluid ( 0 . 1N HCI. pH 1 . 1 ) at 37 + / - 0 . 5° C . as 15 lulose (HPMC ) ; ( iv ) about 0 . 5 mg to about 10 mg of talc ; ( v ) measured by an Apparatus 2 (Paddle Apparatus) rotating at about 0 . 5 mg to about 10 mg of low - substituted hydroxy 50 rpm . In some embodiments , at least about 79 % of the propyl cellulose ( L -HPC ) ; and (vi ) about 5 mg to about 30 antiemetic is released within about 30 minutes following mg of a coating. In some embodiments , each first particulate contact of the capsule with 500 mL of a dissolution fluid has an average diameter of less than about 500 um . Provided ( 0 . 1N HCl, pH 1. 1 ) at 37 + / - 0 .5º C . as measured by an 20 herein is a method of treating a photophobia in a subject in Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some need thereof, comprising administering to the subject a embodiments , at least about 88 % of the antiemetic is capsule comprising a pharmaceutical composition compris released within about 60 minutes following contact of the ing : a plurality of first particulates , wherein each first capsule with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH particulate comprises : ( i ) about 126 mg of sumatriptan 1 . 1 ) at 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle 25 succinate ; and ( ii ) about 84 mg ofmicrocrystalline cellulose ; Apparatus ) rotating at 50 rpm . In some embodiments, at wherein each first particulate has an average diameter of less least about 56 % of the 5HT B / receptor agonist is released than about 500 um ; and a plurality of second particulates, within about 5 minutes following contact of the capsule with wherein each second particulate comprises : ( i) about 25 mg 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at of promethazine hydrochloride ; ( ii ) about 66 .6 mg of a sugar 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - 30 sphere ; ( iii ) about 6 .6 mg of hydroxypropyl methylcellulose ratus ) rotating at 50 rpm . In some embodiments , at least (HPMC ) ; ( iv ) about 1 . 2 mg of talc ; ( v ) about 2 . 5 mg of about 81 % of the 5HT , BH receptor agonist is released low - substituted hydroxypropyl cellulose ( L -HPC ) ; and ( vi ) within about 15 minutes following contact of the capsule about 10 . 2 mg of a coating. Provided herein is a method of with 500 mL of a dissolution fluid (0 . 1N HC1, pH 1. 1) at treating a photophobia in a subject in need thereof, com 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - 35 prising administering to the subject a capsule comprising a ratus ) rotating at 50 rpm . In some embodiments , at least pharmaceutical composition comprising : a plurality of first about 87 % of the 5HTB11 receptor agonist is released particulates , wherein each first particulate comprises : (i ) within about 30 minutes following contact of the capsule about 126 mg of sumatriptan succinate ; and ( ii ) about 84 mg with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at of microcrystalline cellulose ; wherein each first particulate 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle Appa - 40 has an average diameter of less than about 500 um ; and a ratus ) rotating at 50 rpm . In some embodiments , at least plurality of second particulates , wherein each second par about 92 % of the 5HT , BH receptor agonist is released ticulate comprises : ( i ) about 50 mg of promethazine hydro within about 60 minutes following contact of the capsule chloride ; ( ii ) about 133 . 2 mg of a sugar sphere ; ( iii ) about with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 13 . 2 mg of hydroxypropyl methylcellulose (HPMC ) ; ( iv ) 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - 45 about 2 . 4 mg of talc ; ( v ) about 5 mg of low - substituted ratus ) rotating at 50 rpm . In some embodiments, the treat - hydroxypropyl cellulose ( L -HPC ); and (vi ) about 20 . 4 mg of ment of the photophobia is acute or prophylactic . In some a coating. In some embodiments , the treatment of the embodiments , the pharmaceutical composition , oral dosage , photophobia is acute or prophylactic . In some embodiments , or capsule is used for treatment of a light sensitivity . In some the pharmaceutical composition , oral dosage , or capsule is embodiments, the pharmaceutical composition , oral dosage , 50 used for treatment of a light sensitivity . In some embodi or capsule treats nausea associated with a headache or m ents , the pharmaceutical composition , oral dosage , or vomiting associated with a headache . In some embodiments, capsule treats nausea associated with a headache or vomiting the pharmaceutical composition , oral dosage , or capsule associated with a headache . In some embodiments , the treats nausea associated with a headache and vomiting pharmaceutical composition , oral dosage , or capsule treats associated with a headache. In some embodiments , the 55 nausea associated with a headache and vomiting associated administering is one , two , or three times daily . In some with a headache . In some embodiments , the administering is embodiments , the administering is about every 4 to about one , two, or three times daily . In some embodiments , the every 6 hours . In some embodiments , the administering is administering is about every 4 to about every 6 hours . In about every 8 to about every 12 hours. In some embodi- some embodiments , the administering is about every 8 to ments , a second dose of the pharmaceutical composition , 60 about every 12 hours . In some embodiments , a second dose oral dosage , or capsule is administered after response to a of the pharmaceutical composition , oral dosage , or capsule first dose in the subject . In some embodiments , doses after is administered after response to a first dose in the subject . a first dose of the pharmaceutical composition , oral dosage, In some embodiments , doses after a first dose of the phar or capsule are separated by at least 2 hours . In some maceutical composition , oral dosage , or capsule are sepa embodiments, a maximum dose of the 5HTB/ 12 receptor 65 rated by at least 2 hours . In some embodiments , a maximum agonist over 24 hour does not exceed 200 mg. In some dose of the 5HT1B /12 receptor agonist over 24 hour does not embodiments, a maximum single dose of the 5HTB/ 1D exceed 200 mg. In some embodiments , a maximum single US 10 , 179 , 109 B2 33 34 dose of the 5HT1B / 10 receptor agonist does not exceed 50 about 30 minutes following contact of the capsule with 500 mg in a subject with mild to moderate hepatic impairment. mL of a dissolution fluid ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 .5° C . Provided herein is a method of treating a photophobia in as measured by an Apparatus 2 (Paddle Apparatus ) rotating a subject in need thereof, comprising administering to the at 50 rpm . In some embodiments , after storage at 40° C . for subject a capsule comprising a pharmaceutical composition 5 1 month at least about 92 % of the antiemetic is released comprising: a plurality of first particulates, wherein each first particulate comprises: a 5HT16 / 12 receptor agonist within about 60 minutes following contact of the capsule wherein : ( a ) each first particulate has an average diameter of with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at less than about 500 um ; or (b ) each first particulate com 37 + / - 0 . 5º C . as measured by an Apparatus 2 (Paddle Appa prises from about 55 % to about 65 % of the 5HT1B / 10 10 ratus ) rotating at 50 rpm . In some embodiments , the treat receptor agonist (w /w ); and a plurality of second particu ment of the photophobia is acute or prophylactic . In some lates , wherein each second particulate comprises: ( i) a core ; embodiments , the pharmaceutical composition , oral dosage , and (ii ) a layer enclosing the core , wherein said layer or capsule is used for treatment of a light sensitivity . In some comprises an antiemetic ; wherein the dissolution profile of embodiments , the pharmaceutical composition , oral dosage , the capsule stored at 40° C . for one month is : at least about 15 or capsule treats nausea associated with a headache or 47 % of the 5HT1B / 10 receptor agonist is released within vomiting associated with a headache . In some embodiments , about 5 minutes, or at least about 69 % of the 5HT , the pharmaceutical composition , oral dosage , or capsule receptor agonist is released within about 15 minutes , or at treats nausea associated with a headache and vomiting least about 80 % of the 5HT3/ 1 receptor agonist is released associated with a headache . In some embodiments , the within about 30 minutes, or at least about 86 % of the 20 administering is one , two, or three times daily . In some 5HT16 /10 receptor agonist is released within about 60 min embodiments , the administering is about every 4 to about utes following contact of the capsule with 500 mL of a every 6 hours . In some embodiments , the administering is dissolution fluid ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 .5° C . as about every 8 to about every 12 hours. In some embodi measured by an Apparatus 2 (Paddle Apparatus ) rotating at ments , a second dose of the pharmaceutical composition , 50 rpm ; and at least about 35 % of the antiemetic is released 25 oral dosage , or capsule is administered after response to a within about 5 minutes, or at least about 63 % of the first dose in the subject. In some embodiments , doses after antiemetic is released within about 15 minutes , or at least a first dose of the pharmaceutical composition , oral dosage , about 74 % of the antiemetic agonist is released within about or capsule are separated by at least 2 hours . In some 30 minutes, or at least about 84 % of the antiemetic is embodiments , a maximum dose of the 5HT B / D receptor released within about 60 minutes following contact of the 30 agonist over 24 hour does not exceed 200 mg. In some capsule with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH embodiments , a maximum single dose of the 5HTB/ 1D 1 . 1 ) at 37 + / - 0 . 5º C . as measured by an Apparatus 2 (Paddle receptor agonist does not exceed 50 mg in a subject with Apparatus ) rotating at 50 rpm . In some embodiments , after mild to moderate hepatic impairment. storage at 40° C . for 1 month at least about 60 % of the Provided herein are particulates, compositions, and cap 5HT, RA receptor agonist is released within about 5 minutes 35 sules comprising an antiemetic , wherein the antiemetic is in following contact of the capsule with 500 mL of a dissolu - a rapid release matrix . In some embodiments, the antiemetic tion fluid (0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured is promethazine or a pharmaceutically acceptable salt by an Apparatus 2 ( Paddle Apparatus ) rotating at 50 rpm . In thereof. In some embodiments , the promethazine is promet some embodiments , after storage at 40° C . for 1 month at hazine hydrocholoride . In some embodiments , the promet least about 81 % of the 5HT , B receptor agonist is released 40 hazine is present in an amount of from about 12 .5 mg to within about 15 minutes following contact of the capsule about 60 mg. In some embodiments, the promethazine with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at hydrochloride is present in an amount of from about 12 . 5 mg 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - to about 60 mg. In some embodiments, the promethazine ratus ) rotating at 50 rpm . In some embodiments , after hydrochloride is present in an amount of 25 mg or 50 mg. storage at 40° C . for 1 month at least about 88 % of the 45 In some embodiments , the promethazine base is present in 5HT B . receptor agonist is released within about 30 min - an amount of 22 mg or 44 mg . In some embodiments , a utes following contact of the capsule with 500 mL of a capsule comprises from about 50 mg to about 150 mg of dissolution fluid ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 .5° C . as sumatriptan or a pharmaceutically acceptable salt thereof measured by an Apparatus 2 (Paddle Apparatus ) rotating at and from about 12 . 5 to about 60 mg of promethazine or a 50 rpm . In some embodiments , after storage at 40° C . for 1 50 pharmaceutically acceptable salt thereof . In some embodi month at least about 93 % of the 5HT16 /12 receptor agonist ments , the capsule comprises from about 50 mg to about 150 is released within about 60 minutes following contact of the mg of sumatriptan succinate and from about 12 . 5 to about 60 capsule with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH mg of promethazine hydrochloride . In some embodiments , 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle the capsule comprises about 126 mg of sumatriptan succi Apparatus ) rotating at 50 rpm . In some embodiments , after 55 nate and about 50 mg of promethazine hydrochloride . storage at 40° C . for 1 month at least about 43 % of the antiemetic is released within about 5 minutes following BRIEF DESCRIPTION OF THE DRAWINGS contact of the capsule with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an FIG . 1 illustrates an exemplary capsule , unfilled ( left , in Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some 60 side and bottom view ) or filled ( right) with particulates . embodiments , after storage at 40° C . for 1 month at least Particulates are not drawn to scale . about 73 % of the antiemetic is released within about 15 FIG . 2 illustrates another exemplary capsule, unfilled minutes following contact of the capsule with 500 mL of a ( left , in top , side and bottom view ) or filled ( right ) with dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as particulates . Particulates are not drawn to scale . measured by an Apparatus 2 (Paddle Apparatus ) rotating at 65 FIG . 3 illustrates an exemplary particulate comprising an 50 rpm . In some embodiments , after storage at 40° C . for 1 inner sugar core , a layer comprising an active pharmaceu month at least about 84 % of the antiemetic is released within tical ingredient ( “ API” ), and an optional coating layer. US 10 , 179 , 109 B2 35 36 INCORPORATION BY REFERENCE um ; and a plurality of second particulates comprising : about 25 mg of promethazine hydrochloride; about 66 . 6 mg of a All publications, patents , and patent applications sugar sphere ; about 6 . 6 mg of hydroxypropyl methylcellu described herein are incorporated by reference to the same lose (HPMC ); about 1. 2 mg of talc ; about 2. 5 mg of extent as if each individual publication , patent, or patent 5 low - substituted hydroxypropyl cellulose ( L - HPC ) ; and application was specifically and individually indicated to be about 10 . 2 mg of a coating . In some embodiments , a incorporated by reference . In the event of a conflict between pharmaceutical composition described herein comprises a a term disclosed herein and a term in an incorporated plurality of first particulates comprising : about 126 mg of reference , the term herein controls . sumatriptan succinate ; and about 84 mg of microcrystalline 10 cellulose ; wherein each first particulate has an average DETAILED DESCRIPTION diameter of less than about 500 um ; and a plurality of second particulates comprising : about 50 mg of promethazine This disclosure is generally directed to compositions hydrochloride ; about 133. 2 mg of a sugar sphere ; about 13 . 2 comprising multiple pharmaceutically active agents for the mg of hydroxypropyl methylcellulose (HPMC ); about 2. 4 alleviation , abatement or elimination of one or more condi- 15 mg of talc ; about 5 mg of low - substituted hydroxypropyl tions in a subject in need thereof, as further described herein cellulose ( L -HPC ); and about 20. 4 mg of a coating . below . 5HT16 / 1D Receptor Agonists Definitions In some embodiments, the pharmaceutical composition A “ therapeutically effective amount” when used in con - disclosed herein comprises a 5HT 16 /1D receptor agonist . nection with a pharmaceutical composition described herein 20 Exemplary 5HT1B / 1d receptor agonists include, without is an amount of one or more pharmaceutically active limitation , ergotamine and triptan family compounds . agent( s ) sufficient to produce a therapeutic result in a subject Exemplary triptans include, without limitation , sumatriptan , in need thereof. For example, a therapeutic result includes, almotriptan , frovatriptan , eletriptan , rizatriptan , and but is not limited to , treating pain , migraine headache , naratriptan . In some embodiments , the pharmaceutical com nausea , vomiting, photophobia , phonophobia or osmopho - 25 position disclosed herein comprises a triptan or triptan bia by a subject. analog . Triptan analogs are generally a family of tryptamine “ Therapeutically equivalent” when used in connection based drugs used for the treatment of migraines and head with a pharmaceutical composition described herein refers aches . Their action is attributed to their binding to serotonin to an amount or quantity of a pharmaceutically acceptable receptors in nerve ending and in cranial blood vessels salt of a pharmaceutically active agent that is equivalent to 30 (causing their constriction ) and subsequent inhibition of the therapeutically effective amount of the free base of the pro - inflammatory neuropeptide release . Exemplary triptans pharmaceutically active agent. include, sumatriptan , almotriptan , forvatriptan , rizatriptan , Unless specifically stated or obvious from context, as zolmitriptan , eletriptan , and naratriptan , and pharmaceuti used herein , the term “ about" in reference to a number or cally acceptable salts thereof. In some embodiments , triptan range of numbers is understood to mean the stated number 35 is used in the pharmaceutical composition disclosed herein and numbers + / - 10 % thereof, or 10 % below the lower listed is a free base or in the form of pharmaceutically acceptable limit and 10 % above the higher listed limit for the values salt thereof, for example , in the form of succinate . In some listed for a range. embodiments , the triptan is sumatriptan or a pharmaceuti In some embodiments , a pharmaceutical composition cally acceptable salt thereof. described herein comprises a plurality of first particulates 40 In some embodiments , the pharmaceutical composition comprising a therapeutically effective amount of a first disclosed herein comprises a triptan or a pharmaceutically pharmaceutically active agent; and a plurality of second acceptable salt thereof that is present at a dose from about particulates comprising a therapeutically effective amount of 1 . 0 mg to about 200 mg , including , but not limited to , from a second pharmaceutically active agent. Pharmaceutically about 25 mg to about 100 mg, from about 35 mg to about active agents disclosed herein are capable of use in a 45 140 mg, from about 70 mg to about 140 mg, from about 80 pharmaceutical composition as described herein . In some mg to about 135 mg, from about 1 . 0 mg to about 25 mg, embodiments , a pharmaceutically active agent is a 5HT , BHD from about 25 mg to about 50 mg, from about 50 mg to receptor agonist or an antiemetic . about 100 mg, from about 100 mg to about 150 mg, from In some embodiments , a pharmaceutical composition about 150 mg to about 200 mg, from about 1 . 0 mg to about described herein comprises a plurality of first particulates , 50 35 mg, from about 35 mg to about 70 mg, from about 70 mg wherein each first particulate comprises : about 100 mg to to about 105 mg, from about 105 mg to about 140 mg, from about 140 mg of sumatriptan succinate ; and about 50 mg to about 140 mg to about 175 mg, or from about 175 mg to about 150 mg of microcrystalline cellulose ; and a plurality about 200 mg. In some embodiments , the pharmaceutical of second particulates, wherein each second particulate composition disclosed herein comprises a triptan or a phar comprises : about 10 mg to about 60 mg of promethazine 55 maceutically acceptable salt thereof that is present at a hydrochloride ; about 30 mg to about 150 mg of a sugar dosage from about 1 . 0 mg to about 200 mg, including, but sphere ; about 2 . 5 mg to about 15 mg of hydroxypropyl not limited to , about 1 . 0 mg, about 1 . 5 mg, about 2 . 5 mg, methylcellulose (HPMC ) ; about 0 . 5 mg to about 10 mg of about 3 . 0 mg, about 3 . 5 mg , about 4 . 0 mg, about 4 . 5 mg, talc ; about 0 . 5 mg to about 10 mg of low -substituted about 5 . 0 mg, about 5 . 5 mg, about 6 . 0 mg , about 6 . 5 mg, hydroxypropyl cellulose (L -HPC ) ; and about 5 mg to about 60 about 7 . 0 mg, about 7 . 5 mg, about 8 . 0 mg, about 8 . 5 mg, 30 mg of a coating . In some embodiments , each first about 9 . 0 mg, about 9 . 5 mg, about 10 . 0 mg, about 10 . 5 mg, particulate has an average diameter of less than about 500 about 11 . 0 mg , about 11. 5 mg , about 12 . 0 mg, about 12 . 5 um . In some embodiments , a pharmaceutical composition mg, about 13 . 0 mg, about 13 . 5 mg, about 14 .0 mg, about described herein comprises a plurality of first particulates 14 . 5 mg, about 15 . 0 mg, about 15 . 5 mg, about 16 mg, about comprising: about 126 mg of sumatriptan succinate ; and 65 16 . 5 mg, about 17 mg, about 17 . 5 mg, about 18 mg , about about 84 mg ofmicrocrystalline cellulose ; wherein each first 18 . 5 mg, about 19 mg, about 19 . 5 mg, about 20 mg, about particulate has an average diameter of less than about 500 20 . 5 mg, about 21 mg, about 21. 5 mg, about 22 mg, about US 10 , 179 , 109 B2 37 38 22 . 5 mg, about 23 mg , about 23 . 5 mg, about 24 mg, about cally acceptable salt thereof, that is present at a dose from 24 . 5 mg, about 25 mg, about 25 .5 mg, about 26 mg, about about 1 . 0 mg to about 50 mg, including , but not limited to , 26 . 5 mg, about 27 mg , about 27 .5 mg, about 28 mg, about about 1 .0 mg to about 30 mg, about 5 . 0 mg to about 25 mg, 28 . 5 mg, about 29 mg, about 29 . 5 mg, about 30 mg, about about 5 . 0 mg to about 15 mg, about 1 . 0 mg to about 5 . 0 mg, 30 . 5 mg, about 31 mg, about 31 . 5 mg, about 32 mg, about 5 about 5 . 0 mg to about 10 . 0 mg, about 10 . 0 mg to about 15 32 . 5 mg, about 33 mg, about 33 . 5 mg, about 34 mg, about mg, about 15 mg to about 20 mg, about 20 mg to about 25 34 . 5 mg, about 35 mg, about 35 .5 mg, about 36 mg, about mg, about 25 mg to about 30 mg, about 35 mg to about 40 36 . 5 mg, about 37 mg, about 37 . 5 mg, about 38 mg, about mg, about 40 mg to about 45 mg, or about 45 mg to about 38 . 5 mg, about 39 mg, about 39 . 5 mg, about 40 mg, about 50 mg. In some embodiments , the pharmaceutical compo 40 . 5 mg, about 41 mg, about 41 . 5 mg, about 42 mg, about 10 sition described herein comprises almotriptan or a pharma 42 . 5 mg, about 43 mg, about 43 .5 mg, about 44 mg, about ceutically acceptable salt thereof, that is present at a dose 44 .5 mg, about 45 mg , about 45 . 5 mg, about 46 mg, about from about 1 . 0 mg to about 50 mg, including, but not limited 46 . 5 mg, about 47 mg, about 47 . 5 mg, about 48 mg, about to , about 1 . 0 mg, about 1 . 5 mg, about 2 . 0 mg, about 2 . 5 mg, 48 . 5 mg, about 49 mg, about 49 .5 mg, about 50 mg, about about 3 . 0 mg , about 3 . 5 mg, about 4 . 0 mg, about 4 . 5 mg , 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 15 about 5 . 0 mg, about 5 . 5 mg, about 6 . 0 mg, about 6 . 5 mg, mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 7 . 0 mg, about 7 . 5 mg, about 8 . 0 mg , about 8 . 5 mg, about 100 , about 105 mg, about 110 mg , about 115 mg, about 9 . 0 mg, about 9 . 5 mg , about 10 . 0 mg, about 10 . 5 mg, about 120 mg, about 120 .5 mg, about 121 mg, about 121. 5 about 11. 0 mg, about 11. 5 mg, about 12 .0 mg, about 12 . 5 mg, about 122 mg, about 122 . 5 mg, about 123 mg, about mg, about 13 mg, about 13 . 5 mg , about 14 mg, about 14 . 5 123 . 5 mg, about 124 mg, about 124 . 5 mg, about 125 mg, 20 mg, about 15 mg, about 15 . 5 mg, about 16 mg , about 16 . 5 about 125 . 5 mg , about 126 mg, about 126 . 5 mg, about 127 mg, about 17 mg, about 17 . 5 mg , about 18 mg, about 18 . 5 mg, about 127 . 5 mg, about 128 mg, about 128 . 5 mg, about mg, about 19 mg, about 19 . 5 mg, about 20 mg, about 20 . 5 129 mg, about 129 . 5 mg, about 130 mg, about 135 mg, about mg, about 21 mg, about 21. 5 mg, about 22 mg, about 22 . 5 140 mg, about 145 mg, about 150 mg, about 155 mg, about mg, about 23 mg, about 23 . 5 mg , about 24 mg , about 24 . 5 160 mg, about 165 mg, about 170 mg, about 175 mg, about 25 mg, about 25 mg, about 25 .5 mg , about 26 mg, about 26 . 5 180 mg, about 185 mg , about 190 mg, about 195 mg , or mg, about 27 mg, about 27 . 5 mg, about 28 mg , about 28 . 5 about 200 mg. In some embodiments , the triptan is sumatrip - mg, about 29 mg, about 29 .5 mg, about 30 mg, about 30 . 5 tan or a pharmaceutically acceptable salt thereof. In some mg, about 31 mg, about 31 . 5 mg , about 32 mg, about 32 . 5 embodiments , the pharmaceutical composition disclosed mg, about 33 mg, about 33 . 5 mg, about 34 mg, about 34 . 5 herein comprises a pharmaceutically acceptable salt of trip - 30 mg, about 35 mg, about 35 .5 mg, about 36 mg, about 36 . 5 tan in a quantity therapeutically equivalent to triptan dosages mg, about 37 mg, about 37 . 5 mg, about 38 mg, about 38. 5 disclosed herein . In some embodiments , the pharmaceutical mg, about 39 mg, about 39 .5 mg, about 40 mg, about 40 . 5 composition disclosed herein comprises a pharmaceutically mg, about 41 mg, about 41 . 5 mg, about 42 mg, about 42 . 5 acceptable salt of sumatriptan in a quantity therapeutically mg, about 43 mg, about 43 . 5 mg, about 44 mg, about 44 . 5 equivalent to about 90 mg of sumatriptan free base . 35 mg, about 45 mg , about 45 . 5 mg , about 46 mg , about 46 . 5 In some embodiments , the amount of sumatriptan or a mg, about 47 mg, about 47 . 5 mg, about 48 mg , about 48 . 5 pharmaceutically acceptable salt thereof present in the phar- mg, about 49 mg, about 49 . 5 mg, or about 50 mg. In some maceutical composition disclosed herein is equivalent to embodiments , the pharmaceutically acceptable salt of about 4 mg , about 6 mg, about 10 mg, about 25 mg, about almotriptan is almotriptan malate . 50 mg, about 85 mg, about 90 mg, or about 100 mg of 40 In some embodiments, the pharmaceutical composition sumatriptan free base . In some embodiments, the pharma - disclosed herein comprises eletriptan or a pharmaceutically ceutically acceptable salt of sumatriptan is sumatriptan acceptable salt thereof, that is present at a dose from about succinate . In some embodiments , the amount of sumatriptan 10 . 0 mg to about 100 mg, including , but not limited to , about succinate present in the pharmaceutical composition dis - 10 . 0 mg to about 75 mg, about 10 . 0 mg to about 50 mg, closed herein is about 35 mg, about 70 mg, about 126 mg, 45 about 10 mg to about 30 mg, about 30 mg to about 50 mg, or about 140 mg. In some embodiments , an amount of about 50 mg to about 70 mg, about 70 mg to about 90 mg , sumatriptan free base present in the pharmaceutical compo - about 10 . 0 mg to about 20 mg, about 20 mg to about 30 mg, sition disclosed herein is from about 25 mg and about 50 mg , about 30 mg to about 40 mg, about 40 mg to about 50 mg, from about 50 mg to about 100 mg, or from about 75 mg to about 50 mg to about 60 mg , about 60 mg to about 70 mg, about 100 mg. 50 about 70 mg to about 80 mg, about 80 mg to about 90 mg, In some embodiments , the pharmaceutical composition or about 90 mg to about 100 mg. In some embodiments, the disclosed herein comprises sumatriptan , or a pharmaceuti - pharmaceutical composition described herein comprises cally acceptable salt thereof, that is present at a free base eletriptan or a pharmaceutically acceptable salt thereof , that dose from about 10 mg to about 200 mg, including , but not is present at a dose from about 10 . 0 mg to about 100 mg, limited to , from about 25 mg to about 100 mg, from about 55 including, but not limited to , about 10 . 0 mg, about 10 . 5 mg, 35 mg to about 140 mg, from about 70 mg to about 140 mg, about 11. 0 mg, about 12 . 0 mg, about 12 . 5 mg, about 13 . 0 from about 80 mg to about 135 mg, from about 10 mg to mg, about 13 . 5 mg, about 14 . 0 mg, about 14 . 5 mg, about about 25 mg, from about 25 mg to about 50 mg, from about 15 . 0 mg, about 15 . 5 mg, about 16 mg, about 16 . 5 mg, about 50 mg to about 100 mg, from about 100 mg to about 150 mg, 17 mg , about 17 . 5 mg, about 18 mg, about 18 .5 mg, about from about 150 mg to about 200 mg, from about 10 mg to 60 19 mg , about 19 . 5 mg, about 20 mg, about 20 .5 mg, about about 35 mg, from about 35 mg to about 70 mg , from about 21 mg , about 21 . 5 mg, about 22 mg , about 22 . 5 mg, about 70 mg to about 105 mg, from about 105 mg to about 140 mg, 23 mg, about 23 . 5 mg, about 24 mg, about 24 .5 mg, about from about 140 mg to about 175 mg, or from about 175 mg 25 mg, about 25 . 5 mg, about 26 mg, about 26 . 5 mg, about to about 200 mg. In some embodiments , the pharmaceuti - 27 mg, about 27 . 5 mg, about 28 mg, about 28 .5 mg, about cally acceptable salt of sumatriptan is sumatriptan succinate . 65 29 mg, about 29 .5 mg, about 30 mg, about 30 . 5 mg , about In some embodiments , the pharmaceutical composition 31 mg, about 31 . 5 mg, about 32 mg, about 32 . 5 mg , about disclosed herein comprises almotriptan or a pharmaceuti 33 mg, about 33 .5 mg , about 34 mg, about 34 .5 mg, about US 10 , 179, 109 B2 39 40 35 mg, about 35 . 5 mg, about 36 mg, about 36 . 5 mg, about about 31 . 5 mg, about 32 mg, about 32 . 5 mg, about 33 mg, 37 mg, about 37 . 5 mg, about 38 mg , about 38 . 5 mg, about about 33 . 5 mg, about 34 mg, about 34 . 5 mg, about 35 mg, 39 mg, about 39 . 5 mg, about 40 mg , about 40 . 5 mg, about about 35 . 5 mg, about 36 mg, about 36 . 5 mg, about 37 mg, 41 mg, about 41. 5 mg, about 42 mg , about 42 . 5 mg, about about 37 . 5 mg, about 38 mg, about 38 . 5 mg, about 39 mg, 43 mg, about 43 . 5 mg, about 44 mg , about 44 . 5 mg, about 5 about 39 . 5 mg, about 40 mg, about 40 . 5 mg, about 41 mg, 45 mg, about 45 . 5 mg, about 46 mg , about 46 . 5 mg, about about 41 . 5 mg, about 42 mg, about 42 . 5 mg, about 43 mg, 47 mg, about 47. 5 mg, about 48 mg , about 48 . 5 mg, about about 43 . 5 mg, about 44 mg, about 44 . 5 mg, about 45 mg, 49 mg, about 49 . 5 mg , about 50 mg, about 55 mg, about 60 about 45 . 5 mg, about 46 mg, about 46 . 5 mg, about 47 mg, mg , about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 47 . 5 mg, about 48 mg, about 48 . 5 mg, about 49 mg , about 85 mg, about 90 mg, about 95 mg , or about 100 mg. 10 about 49 . 5 mg, or about 50 mg. In some embodiments , the In some embodiments , the pharmaceutically acceptable salt pharmaceutically acceptable salt of rizatriptan is rizatriptan of eletriptan is eletriptan hydrobromide . benzoate . In some embodiments , the pharmaceutical composition In some embodiments , the pharmaceutical composition disclosed herein comprises frovatriptan or a pharmaceuti - disclosed herein comprises zolmitriptan or a pharmaceuti cally acceptable salt thereof, that is present at a dose from 15 cally acceptable salt thereof, that is present at a dose from about 0 . 5 mg to about 10 . 0 mg, including , but not limited to , about 1 . 0 mg to about 25 mg, including , but not limited to , about 0 . 5 mg to about 5 . 0 mg , about 1 . 0 mg to about 3 . 0 mg, about 1 . 0 mg to about 15 mg, about 1 . 0 mg to about 10 mg, about 0 . 5 mg to about 1 . 5 mg, about 1 . 5 mg to about 3 . 0 mg, about 1 . 0 mg to about 7 . 5 mg, about 1 . 0 mg to about 7 . 0 mg, about 3 .0 mg to about 4 . 5 mg, about 4 . 5 mg to about 6 . 0 mg, about 7 . 0 mg to about 14 mg, about 14 mg to about 25 mg, about 6 . 0 mg to about 7 . 5 mg , about 7 . 5 mg to about 9 . 0 mg, 20 about 1 . 0 mg to about 2 . 5 mg, about 2 . 5 mg to about 5 . 0 mg, about 9 . 0 mg to about 10 . 0 mg, about 0 . 5 mg to about 1 . 0 about 5 . 0 mg to about 7 . 5 mg, about 7 . 5 mg to about 10 mg, mg about 1 . 0 mg to about 2 . 0 mg, about 2 . 0 mg to about 3 . 0 about 10 mg to about 12 . 5 mg, about 12 . 5 mg to about 15 mg , about 3 . 0 mg to about 4 .0 mg, about 4 . 0 mg to about 5 . 0 mg, about 15 mg to about 17 . 5 mg, about 17 . 5 mg to about mg, about 5 . 0 mg to about 6 . 0 mg , about 6 . 0 mg to about 7 . 0 20 mg , or about 20 mg to about 25 mg. In some embodi mg , about 7 . 0 mg to about 8 . 0 mg, or about 8 . 0 mg to about 25 ments , the pharmaceutical composition described herein 9 . 0 mg. In some embodiments, the pharmaceutical compo - comprises zolmitriptan or a pharmaceutically acceptable salt sition described herein comprises frovatriptan or a pharma - thereof, that is present at a dose from about 1 . 0 mg to about ceutically acceptable salt thereof, that is present at a dose 25 mg, including , but not limited to , about 1. 0 mg, about 1. 5 from about 0 . 5 mg to about 10 . 0 mg, including, but not mg, about 2 . 0 mg, about 2 . 5 mg, about 3 . 0 mg, about 3 . 5 mg, limited to , about 0 . 5 mg, about 1 . 0 mg, about 1 . 5 mg, about 30 about 4 . 0 mg, about 4 . 5 mg, about 5 . 0 mg, about 5 . 5 mg, 2 . 0 mg, about 2 . 5 mg, about 3 . 0 mg, about 3 . 5 mg, about 4 . 0 about 6 . 0 mg, about 6 . 5 mg, about 7 . 0 mg, about 7 . 5 mg, mg, about 4 . 5 mg, about 5 . 0 mg, about 5 . 5 mg, about 6 . 0 mg, about 8 . 0 mg, about 8 . 5 mg, about 9 . 0 mg, about 9 . 5 mg, about 6 . 5 mg, about 7 . 0 mg, about 7 . 5 mg, about 8 . 0 mg, about 10 . 0 mg, about 10 . 5 mg, about 11 . 0 mg, about 11 . 5 about 8 . 5 mg, about 9 . 0 mg, about 9 . 5 mg, or about 10 . 0 mg. mg, about 12 . 0 mg, about 12 . 5 mg, about 13 mg, about 13. 5 In some embodiments , the pharmaceutically acceptable salt 35 mg, about 14 mg, about 14 .5 mg , about 15 mg, about 15 . 5 of frovatriptan is frovatriptan succinate . mg, about 16 mg, about 16 . 5 mg, about 17 mg, about 17 . 5 In some embodiments , the pharmaceutical composition mg, about 18 mg, about 18 . 5 mg, about 19 mg, about 19 . 5 disclosed herein comprises rizatriptan or a pharmaceutically mg, about 20 mg, about 20 . 5 mg , about 21 mg, about 21. 5 acceptable salt thereof, that is present at a dose from about mg, about 22 mg, about 22 . 5 mg, about 23 mg, about 23 . 5 1 . 0 mg to about 50 mg, including , but not limited to , about 40 mg, about 24 mg, about 24 . 5 mg , or about 25 mg. 1. 0 mg to about 75 mg, about 1 .0 mg to about 50 mg, about In some embodiments , the pharmaceutical composition 1. 0 mg to about 25 mg, about 1 .0 mg to about 15 mg, about disclosed herein comprises naratriptan or a pharmaceutically 15 mg to about 30 mg, about 30 mg to about 45 mg, about acceptable salt thereof, that is present at a dose from about 1 . 0 mg to about 5 . 0 mg, about 5 . 0 mg to about 10 . 0 mg, 0 . 5 mg to about 25 mg, including , but not limited to , about about 10 . 0 mg to about 15 mg, about 15 mg to about 20 mg, 45 0 . 5 mg to about 10 mg, about 0 . 5 mg to about 7 . 5 mg, about about 20 mg to about 25 mg, about 25 mg to about 30 mg, 0 . 5 mg to about 5 . 0 mg, about 0 . 5 mg to about 4 . 0 mg, about about 30 mg to about 35 mg, about 35 mg to about 40 mg, 0 . 5 mg to about 3 . 0 mg, about 3 . 0 mg to about 5 . 0 mg, about about 40 mg to about 45 mg, or about 45 mg to about 50 mg. 5 . 0 mg to about 10 . 0 mg, about 10 . 0 mg to about 15 mg, In some embodiments , the pharmaceutical composition about 15 mg to about 20 mg , about 20 mg to about 25 mg, described herein comprises rizatriptan or a pharmaceutically 50 about 1 . 0 mg to about 4 . 0 mg, about 4 . 0 mg to about 7 . 0 mg, acceptable salt thereof, that is present at a dose from about or about 7 . 0 mg to about 10 . 0 mg. In some embodiments , the 1 . 0 mg to about 50 mg, including , but not limited to , about pharmaceutical composition described herein comprises 1 . 0 mg, about 1 . 5 mg, about 2 . 0 mg, about 2 . 5 mg, about 3 . 0 naratriptan or a pharmaceutically acceptable salt thereof, mg, about 3 . 5 mg, about 4 . 0 mg, about 4 . 5 mg, about 5 . 0 mg, that is present at a dose from about 1 . 0 mg to about 25 mg, about 5 . 5 mg, about 6 . 0 mg, about 6 . 5 mg, about 7 . 0 mg, 55 including, but not limited to , about 0 . 5 mg , about 0 . 6 mg, about 7 . 5 mg, about 8 . 0 mg, about 8 . 5 mg , about 9 . 0 mg, about 0 . 7 mg , about 0 . 8 mg, about 0 . 9 mg, about 1 . 0 mg, about 9 . 5 mg, about 10 . 0 mg, about 10 . 5 mg, about 11. 0 mg, about 1 . 5 mg, about 2 . 0 mg, about 2 . 5 mg, about 3 . 0 mg, about 11 . 5 mg, about 12 . 0 mg, about 12 . 5 mg, about 13 mg, about 3 . 5 mg, about 4 . 0 mg, about 4 . 5 mg, about 5 . 0 mg, about 13 . 5 mg, about 14 mg, about 14 . 5 mg, about 15 mg, about 5 . 5 mg, about 6 . 0 mg, about 6 . 5 mg , about 7 . 0 mg, about 15 . 5 mg, about 16 mg, about 16 . 5 mg, about 17 mg, 60 about 7 . 5 mg, about 8 . 0 mg, about 8 . 5 mg, about 9 . 0 mg, about 17 . 5 mg, about 18 mg, about 18 . 5 mg, about 19 mg, about 9 . 5 mg, about 10 . 0 mg, about 10 . 5 mg, about 11 . 0 mg, about 19 . 5 mg, about 20 mg, about 20 . 5 mg, about 21 mg, about 11 . 5 mg , about 12 . 0 mg, about 12 . 5 mg, about 13 mg, about 21 . 5 mg, about 22 mg, about 22 . 5 mg, about 23 mg, about 13 . 5 mg, about 14 mg, about 14 . 5 mg, about 15 mg, about 23 . 5 mg, about 24 mg, about 24 . 5 mg, about 25 mg, about 15 . 5 mg, about 16 mg , about 16 . 5 mg , about 17 mg, about 25 . 5 mg, about 26 mg, about 26 . 5 mg, about 27 mg, 65 about 17 . 5 mg, about 18 mg, about 18 . 5 mg, about 19 mg, about 27 . 5 mg, about 28 mg, about 28 . 5 mg, about 29 mg, about 19 . 5 mg, about 20 mg, about 20 . 5 mg, about 21 mg, about 29. 5 mg, about 30 mg, about 30 . 5 mg, about 31 mg, about 21. 5 mg, about 22 mg, about 22 . 5 mg, about 23 mg, US 10 , 179 , 109 B2 42 about 23 . 5 mg , about 24 mg , about 24 . 5 mg , or about 25 mg. 39 mg, about 40 mg , about 41 mg, about 42 mg, about 43 In some embodiments , the pharmaceutically acceptable salt mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, of naratriptan is naratriptan hydrochloride . about 48 mg , about 49 mg, about 50 mg, about 55 mg, about Antiemetics 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 In some embodiments , pharmaceutical compositions dis - 5 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 closed herein comprise one or more antiemetics . Exemplary mg. In some embodiments , the antiemetic is promethazine antiemetics include , aprepitant, dronabinol, perphenazine , or a pharmaceutically acceptable salt thereof . In some palonosetron , trimethyobenzamide , metoclopromide , dom - embodiments , the antiemetic is provided at a dose to prevent peridone , prochlorperazine , promethazine , chlorpromazine , or reduce sedation . In some embodiments , the pharmaceu trimethobenzamide , ondansetron , granisetron , hydroxyzine , 10 tical composition described herein comprises a pharmaceu acetylleucinemonoethanolamine , alizapride , azasetron , ben - tically acceptable salt of an antiemetic in a quantity thera zquinamide , bietanautine , bromopride , buclizine , clebo - peutically equivalent to antiemetic dosages disclosed herein . pride , cyclizine , dimenhydrinate , diphenidol, dolasetron , In some embodiments , the pharmaceutical composition meclizine , methallatal, metopimazine, nabilone , oxypern described herein comprises a pharmaceutically acceptable dyl, pipamazine, scopolamine , sulpiride, tetrahydrocannabi- 15 salt of promethazine in a quantity therapeutically equivalent nol, thiethylperazine, thioproperazine, tropisetron , droperi - to about 11 mg promethazine free base . In some embodi dol, haloperidol, prochloperazine , metoclopramide , ments , the pharmaceutical composition described herein diphenhydramine, cannabinoid , midazolam , lorazepam , comprises a pharmaceutically acceptable salt of promethaz hyoscine , dexamethasone , emetrol , propofol , and pharma i ne in a quantity therapeutically equivalent to about 22 mg ceutically acceptable salts thereof. Antiemetics also include 20 promethazine free base . In some embodiments , the pharma H1 agonists , H1 antagonists , H2 agonists , H2 antagonists , ceutical composition described herein comprises a pharma H3 agonists , H3 antagonists , H4 agonists , and H4 antago - ceutically acceptable salt of promethazine in a quantity nists . Examples of such agonists and antagonists include , but therapeutically equivalent to about 44 mg promethazine free are not limited to , 2 - ( m - fluoropheny ) -histamine , azelastine, base . In some embodiments, the pharmaceutical composi buclizine , carbinoxamine, cetrizine , clemastine , cyprohep - 25 tion described herein comprises a pharmaceutically accept tadine , desloratidine , dimenhydrinate , diphenhydramine , able salt of promethazine in a quantity therapeutically emedastine , fexofenadine , hydroxyzine , ketotifen , levoca equivalent to about 22 . 3 mg promethazine free base . In some bastine , olopatadine , phenindamine, promethazine, chlo embodiments , the pharmaceutical composition described rpheniramine , scopolamine , mepyramine , terfenadine , herein comprises a pharmaceutically acceptable salt of pro astemizole , triprolidine , dimaprit , impromidine , amthamine , 30 methazine in a quantity therapeutically equivalent to about cimetidine , ranitidine , nizatidine , famotidine , R - alpha -meth - 44 . 6 mg promethazine free base . ylhistamine , imetit, immepip , thioperamide, iodophenpropit, Pharmaceutically Acceptable Salts clobenpropit , clozapine , and a pharmaceutically acceptable In some embodiments , an agent used in a composition salt thereof. In some embodiments , the second pharmaceu - disclosed herein is the form of a free base , pharmaceutically tically active agent is an antiemetic . In some embodiments , 35 acceptable salt , prodrug , analog or complex . In some the antiemetic is promethazine or a pharmaceutically accept- instances , a pharmaceutically active agent comprises the able salt thereof. form of a pharmaceutically acceptable salt . In various In some embodiments , the pharmaceutical composition embodiments , with respect to a pharmaceutically active disclosed herein comprises an antiemetic or a pharmaceuti agent in a composition , a pharmaceutically acceptable salt cally acceptable salt thereof that is present at a dose from 40 includes , but is not limited to , metal salts , such as sodium about 0 . 5 mg to about 100 mg, including but not limited to , salts , potassium salts , and lithium salts ; alkaline earth met from about 0 .5 mg to about 12 . 5 mg , from about 12. 5 mg to a ls , such as calcium salts , magnesium salts , and the like ; about 50 mg, from about 50 mg to about 75 mg, from about organic amine salts , such as triethylamine salts , pyridine 75 mg to about 100 mg, from about 0 . 5 mg to about 15 mg, salts , picoline salts , ethanolamine salts, triethanolamine from about 15 mg to about 35 mg, from about 20 mg to 45 salts , dicyclohexylamine salts , N , N - dibenzylethylenedi about 30 mg, from about 35 mg to about 55 mg, from about a mine salts , and the like ; inorganic acid salts such as 55 mg to about 75 mg, or from about 75 mg to about 95 mg. hydrochloride salts , hydrobromide salts , sulfate salts , phos In some embodiments , the pharmaceutical composition phate salts, and the like; organic acid salts such as formate described herein comprises an antiemetic that is present at a salts , acetate salts , trifluoroacetate salts , maleate salts , tar dose from about 0 .5 mg to about 100 mg, including but not 50 trate salts , and the like ; sulfonate salts such as methanesul limited to , about 0 .5 mg, about 1 .0 mg, about 1 . 5 mg, about fonate salts , benzenesulfonate salts , p - toluenesulfonate salts , 2 . 0 mg, about 2 . 5 mg, about 3 . 0 mg, about 3 . 5 mg, about 4 .0 and the like ; and amino acid salts , such as arginate salts , mg, about 4 . 5 mg, about 5 . 0 mg, about 5 . 5 mg, about 6 . 0 mg, asparginate salts , glutamate salts , and the like . about 6 . 5 mg, about 7 . 0 mg, about 7 . 5 mg, about 8 . 0 mg, In some embodiments , pharmaceutically acceptable salts about 8 . 5 mg, about 9 . 0 mg, about 9 . 5 mg, about 10 . 0 mg, 55 include bitartrate , bitartrate hydrate , hydrochloride , p - tolu about 10 . 5 mg, about 11 . 0 mg, about 11 . 5 mg, about 12 . 0 enesulfonate , phosphate , sulfate , trifluoroacetate , bitartrate mg, about 12 . 5 mg, about 13 mg, about 13 . 5 mg, about 14 hemipentahydrate , pentafluoropropionate , hydrobromide, mg, about 14 . 5 mg, about 15 mg, about 15 . 5 mg, about 16 mucate , oleate , phosphate dibasic , phosphate monobasic , mg, about 16 . 5 mg, about 17 mg, about 17. 5 mg, about 18 acetate trihydrate, bis (heptafluorobutyrate ), bis (pentafluoro mg , about 18 . 5 mg, about 19 mg, about 19 . 5 mg, about 20 60 propionate ), bis( pyridine carboxy late ) , bis ( trifluoroacetate ) , mg, about 20 . 5 mg, about 21 mg, about 21 . 5 mg, about 22 chlorhydrate , and sulfate pentahydrate . In some embodi mg, about 22 . 5 mg, about 23 mg, about 23 . 5 mg, about 24 ments , an agent is promethazine , a pharmaceutically accept mg, about 24 . 5 mg, about 25 mg, about 25 . 5 mg, about 26 able salt or its thiosemicarbazone, p -nitrophenylhydrazone , mg , about 26 .5 mg, about 27 mg, about 27 . 5 mg, about 28 O -methyloxime , semicarbazone , or bis (methylcarbamate ) . mg, about 28 . 5 mg, about 29 mg, about 29 . 5 mg, about 30 65 Other representative pharmaceutically acceptable salts mg, about 31 mg, about 32 mg , about 33 mg, about 34 mg, include , e . g . , water -soluble and water - insoluble salts, such about 35 mg, about 36 mg, about 37 mg, about 38 mg, about as the acetate , amsonate ( 4 , 4 - diaminostilbene- 2 , 2 - disul US 10 , 179 , 109 B2 43 44 fonate ), benzenesulfonate , benzonate , bicarbonate , bisulfate , dextrin , tragacanth , trehalose , xylitol, or combinations bitartrate , borate , butyrate , calcium edetate , camphorsul thereof . In some embodiments , the pharmaceutically accept fonate , camsy late , carbonate, citrate , clavulariate, dihydro - able excipient is hydroxypropyl methylcellulose (HPMC ) . chloride , edetate, edisylate , estolate , esylate , fiunarate , In some embodiments , the pharmaceutically acceptable fumarate , gluceptate , gluconate , glutamate , glycollylarsa - 5 excipient is low substituted hydroxypropyl cellulose nilate, hexafluorophosphate , hexylresorcinate , hydrabamine , ( L -HPC ) . In some embodiments , the pharmaceutically hydrobromide , hydrochloride, hydroxynaphthoate , iodide , acceptable excipient is talc. In some embodiments, the isothionate, lactate , lactobionate , laurate , malate , maleate , pharmaceutically acceptable excipient is microcrystalline mandelate , mesylate , methylbromide , methylnitrate , meth - cellulose . ylsulfate , mucate , napsylate , nitrate , N -methylglucamine 10 First Particulate ammonium salt , 3 - hydroxy - 2 -naphthoate , oleate , oxalate , Disclosed herein is a first particulate comprising a palmitate , pamoate ( 1 , 1 -methene - bis - 2 -hydroxy - 3 - naph - 5HTB112 receptor agonist. In some embodiments , each first thoate , einbonate ) , pantothenate , phosphate / diphosphate , particulate further comprises a non -pharmaceutically active picrate , polygalacturonate , propionate , p - toluenesulfonate , ingredient. In some embodiments , the first particulates are salicylate , stearate , subacetate , succinate , sulfate , sulfosali - 15 beads, granules , spherules , or pellets ( e . g . , micropellets, or culate , suramate , tannate , tartrate , teoclate , tosylate , triethio - minipellets ) . dide , and valerate salts . A hydrate is another example of a Size pharmaceutically acceptable salt. In some embodiments , the In some embodiments , each first particulate are of differ second pharmaceutically active agent is capable of reducing ent sizes . In some embodiments , each first particulate are of or eliminating an adverse effect of the first pharmaceutically 20 the same size . In some embodiments, target and maximum active agent. particulate size , including particulate size distribution , is Pharmaceutically Acceptable Excipients determined through analytical sieving in accordance with In some aspects , the pharmaceutical composition dis - USP < 786 > or other appropriately validated methods . closed herein comprises one or more pharmaceutically Exemplary filters used in particulate size generation include , acceptable excipients . Exemplary pharmaceutically accept- 25 without limitation , # 30 , # 40 , # 60 , # 100 , and # 140 size mesh able excipients for the purposes of pharmaceutical compo - screens, corresponding to 590 um , 420 um , 250 um , 149 um , sitions disclosed herein include, but are not limited to , and 105 um in diameter , respectively . In some embodiments , binders , disintegrants , superdisintegrants , lubricants , the average diameter of each first particulate ranges from diluents , fillers, flavors , glidants , sorbents , solubilizers , about 50 um to about 1000 um , including, but not limited to , chelating agents , emulsifiers , thickening agents , dispersants, 30 about 50 um , about 60 um , about 70 um , about 80 um , about stabilizers , suspending agents , adsorbents , granulating 90 um , about 100 um , about 110 um , about 120 um , about agents , preservatives, buffers, coloring agents and sweeten 130 um , about 140 um , about 150 um , about 160 um , about ers or combinations thereof . Examples of binders include 170 um , about 180 um , about 190 um , about 200 um , about microcrystalline cellulose , hydroxypropyl methylcellulose , 210 um , about 220 um , about 230 um , about 240 um , about carboxyvinyl polymer, polyvinylpyrrolidone, polyvinylpo - 35 250 um , about 260 um , about 270 um , about 280 um , about lypyrrolidone , carboxymethylcellulose calcium , carboxym - 290 um , about 300 um , about 310 um , about 320 um , about ethylcellulose sodium , ceratonia , chitosan , cottonseed oil, 330 um , about 340 um , about 350 um , about 360 um , about dextrates, dextrin , ethylcellulose , gelatin , glucose , glyceryl 370 um , about 380 um , about 390 um , about 400 um , about behenate , galactomannan polysaccharide , hydroxyethyl cel - 410 um , about 420 um , about 430 um , about 440 um , about lulose , hydroxyethylmethyl cellulose , hydroxypropyl cellu - 40 450 um , about 460 um , about 470 um , about 480 um , about lose , hypromellose , inulin , lactose , magnesium aluminum 490 um , about 500 um , about 510 um , about 520 um , about silicate , maltodextrin , methylcellulose , poloxamer , polycar - 530 um , about 540 um , about 550 um , about 560 um , about bophil , polydextrose , polyethylene glycol, polyethylene 570 um , about 580 um , about 590 um , about 600 um , about oxide , polymethacrylates , sodium alginate , sorbitol, starch , 610 um , about 620 um , about 630 um , about 640 um , about sucrose , sunflower oil , vegetable oil , tocofersolan , zein , or 45 650 um , about 660 um , about 670 um , about 680 um , about combinations thereof . Examples of disintegrants include 690 um , about 700 um , about 710 um , about 720 um , about hydroxypropyl methylcellulose (HPMC ) , low substituted 730 um , about 740 um , about 750 um , about 760 um , about hydroxypropyl cellulose ( L -HPC ) , croscarmellose sodium , 770 um , about 780 um , about 790 um , about 800 um , about sodium starch glycolate , lactose , magnesium aluminum sili - 810 um , about 820 um , about 830 um , about 840 um , about cate , methylcellulose , polacrilin potassium , sodium alginate , 50 850 um , about 860 um , about 870 um , about 880 um , about starch , or combinations thereof. Examples of a lubricant 890 um , about 900 um , about 910 um , about 920 um , about include stearic acid , sodium stearyl fumarate , glyceryl 930 um , about 940 um , about 950 um , about 960 um , about behenate , calcium stearate , glycerin monostearate , glyceryl 970 um , about 980 um , about 990 um , or about 1000 um . In palmitostearate , magnesium lauryl sulfate , mineral oil , some embodiments , the average diameter of each first par palmitic acid , myristic acid , poloxamer , polyethylene glycol, 55 ticulate is less than about 500 um . In some embodiments , the sodium benzoate , sodium chloride , sodium lauryl sulfate , average diameter of the each particulate range from 100 um talc, zinc stearate , potassium benzoate , magnesium stearate to about 500 um , including , but not limited to , from about or combinations thereof. Examples of diluents include talc , 100 um to about 200 um , from about 100 um to about 300 ammonium alginate , calcium carbonate , calcium lactate , um , from about 100 um to about 400 um , from about 200 um calcium phosphate , calcium silicate, calcium sulfate , cellu - 60 to about 300 um , from about 200 um to about 400 um , from lose , cellulose acetate , corn starch , dextrates , dextrin , dex about 200 um to about 500 um , from about 300 um to about trose , erythritol, ethylcellulose, fructose , fumaric acid , glyc - 500 um , or from about 400 um to about 500 um . eryl palmitostearate , isomalt, kaolin , lactitol, lactose , Composition magnesium carbonate , magnesium oxide , maltodextrin , Core maltose , mannitol, microcrystalline cellulose , polydextrose , 65 In some embodiments , each first particulate comprises a polymethacrylates , simethicone , sodium alginate , sodium 5HTB/ D receptor agonist . In some embodiments , the chloride , sorbitol, starch , sucrose, sulfobutylether ß - cyclo - 5HT16 / 1d receptor agonist is sumatriptan or a pharmaceuti US 10 , 179 ,109 B2 45 46 cally acceptable salt thereof. In some embodiments , each ing material comprises or is PVA . In some embodiments , the first particulate comprises at least about 50 % of a 5HT, BILD coating material comprises or is HPMC . An exemplary receptor agonist ( w / w ) . In some embodiments , the amount PVA -based coating material includes Opadry II. In some of the 5HT16 / 10 receptor agonist in the first particulate range instances , the coating material is about 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , from about 50 % to about 90 % ( w / w ) , including but not 5 9 , or 10 % of the weight of each first particulate . In some limited to , from about 50 % to about 80 % ( w / w ) , from about instances , the coating material represent between about 1 % 50 % to about 70 % ( w / w ) , from about 50 % to about 60 % and about 15 % of the total weight of each first particulate , ( w / w ) , from about 60 % to about 90 % ( w / w ) , from about including, but not limited to , between about 5 % and about 70 % to about 90 % ( w / w ), from about 80 % to about 90 % 10 % , between about 6 % and about 10 % , between about 7 % ( w / w ) , from about 55 % to about 65 % ( w / w ) , from about 10 and about 10 % , between about 8 % and about 10 % , or 55 % to about 75 % ( w / w ) , or from about 55 % to about 85 % between about 9 % and about 10 % . In some instances, the ( w / w ) . In some embodiments , the amount of the 5HT B / D coating material is greater than about 2 % , greater than about receptor agonist in the first particulate range from about 50 % 3 % , greater than about 4 % , greater than about 5 % , greater to about 90 % ( w / w ) , including , but not limited to , about 50 % than about 6 % , greater than about 7 % , greater than about ( w / w ) , about 55 % ( w / w ) , about 60 % ( w / w ) , about 65 % 15 8 % , greater than about 9 % , or greater than about 10 % of the ( w / w ) , about 70 % ( w / w ) , about 75 % ( w / w ) , about 80 % weight of each first particulate . In some instances , the ( w / w ), about 85 % ( w / w ) , or about 90 % ( w / w ) . coating material is less than about 2 % , less than about 3 % , In some embodiments, each first particulate comprises a less than about 4 % , less than about 5 % , less than about 6 % , ndnon -pharmaceutically active ingredient. In some embodi- less than about 7 % , less than about 8 % , less than about 9 % , ments , the non -pharmaceutically active ingredient is 20 or less than about 10 % of the weight of each first particulate . selected from the group consisting of microcrystalline cel Dissolution lulose , dicalcium phosphate , calcium sulfate, talc , an alkali A n example of a method to measure dissolution profiles metal stearate , silicon dioxide , calcium carbonate , and any is provided at Examples 4 and 5 . In some aspects , dissolu combinations thereof. In some embodiments , the non - phar - tion rates are measured by a USP Apparatus 2 (Paddle maceutically active ingredient is microcrystalline cellulose . 25 Apparatus ) at a speed of 50 rpm in a dissolution fluid of 500 In some embodiments , each first particulate comprises at ml de- aerated 0 . 1 N HCl ( i . e . , pH 1 . 1 ) at 37 . 0 + 0 .5° C . In most about 50 % of a non -pharmaceutically active ingredient some instances , dissolution samples are analyzed by HPLC . ( w / w ) . In some embodiments , the amount of the non - In some embodiments , at least about 80 % of the 5HT BID pharmaceutically active ingredient in the first particulate receptor agonist is released within about 5 minutes follow range from about 10 % to about 50 % ( w / w ) , including but 30 ing contact of the particulate with 500 mL of a dissolution not limited to , from about 10 % to about 40 % ( w / w ) , from fluid ( 0 . 1N HCI, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an about 10 % to about 30 % ( w / w ) , from about 10 % to about Apparatus 2 ( Paddles ) rotating at 50 rpm . In some embodi 20 % ( w / w ) , from about 20 % to about 50 % ( w / w ) , from ments , at least about 81 % of the 5HTB/ 1 receptor agonist about 30 % to about 50 % ( w / w ), or from about 40 % to about is released within about 5 minutes following contact of the 50 % ( w / w ) . In some embodiments , the amount of the 35 first particulate with 500 mL of a dissolution fluid ( 0 . 1N non - pharmaceutically active ingredient in each first particu - HC1, pH 1 . 1 ) at 37 + / - 0 . 5º C . as measured by an Apparatus late range from about 10 % to about 50 % ( w / w ) , including , 2 (Paddle Apparatus ) rotating at 50 rpm . In some embodi but not limited to , about 10 % ( w /w ), about 15 % ( w / w ) , ments, at least about 89 % of the 5HT 15 /1D receptor agonist about 20 % ( w / w ), about 25 % ( w / w ) , about 30 % ( w / w ) , is released within about 10 minutes following contact of the about 35 % ( w /w ) , about 40 % (w /w ) , about 45 % ( w / w ) , or 40 first particulate with 500 mL of a dissolution fluid ( 0 . 1N about 50 % ( w / w ) . HC1, pH 1 . 1 ) at 37 + / - 0 . 5º C . as measured by an Apparatus Coating 2 (Paddle Apparatus ) rotating at 50 rpm . In some embodi In some cases , the first particulate disclosed herein is ments , at least about 92 % of the 5HT1B/ receptor agonist coated with a coating material , e . g . , a sealant. In some is released within about 15 minutes following contact of the embodiments , the coating material is water soluble . In some 45 first particulate with 500 mL of a dissolution fluid ( 0 . 1N embodiments , the coating material comprises a polymer, HC1, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an Apparatus plasticizer, a pigment, or any combination thereof. In some 2 (Paddle Apparatus ) rotating at 50 rpm . In some embodi embodiments , the coating material is a form of a film ments , at least about 94 % of the 5HT R1 receptor agonist coating , e . g . , a glossy film , a pH independent film coating, is released within about 20 minutes following contact of the an aqueous film coating , a dry powder film coating ( e . g ., 50 first particulate with 500 mL of a dissolution fluid (0 . 1N complete dry powder film coating ), or any combination HC1, pH 1 . 1 ) at 37 + / - 0 .5º C . as measured by an Apparatus thereof. In some embodiments , the coatingmaterial is highly 2 ( Paddle Apparatus ) rotating at 50 rpm . adhesive . In some embodiments , the coating material pro - Second Particulate vides low level of water permeation . In some embodiments , Disclosed herein is a second particulate comprising a core the coating material provides oxygen barrier protection . In 55 and a layer enclosing the core , wherein the layer comprises some embodiments , the coating material allows immediate an antiemetic . In some embodiments , the second particulates disintegration for fast release of drug actives . In some are beads, granules , spherules , or pellets ( e. g ., micropellets , embodiments , the coating material is pigmented , clear, or or minipellets ) . In some embodiments , the second particu white . In some embodiments , the coating material is clear. lates comprise a coating . Exemplary coating materials include , without limitation , 60 Size polyvinyl alcohol (PVA ), cellulose acetate phthalate (CAP ), In some embodiments , each second particulate is of polyvinyl acetate phthalate (PVAP ) , methacrylic acid copo different sizes. In some embodiments , each second particu lymers , cellulose acetate trimellitate (CAT ) , hydroxypropyl late is of the same size . In some embodiments , target and methylcellulose phthalate (HPMCP ) , hydroxypropyl meth - maximum particulate size , including particulate size distri ylcellulose (HPMC ), hydroxypropyl methyl cellulose 65 bution , is determined through analytical sieving in accor acetate succinate (hypromellose acetate succinate ) , shellac , dance with USP < 786 > or other appropriately validated sodium alginate , and zein . In some embodiments , the coat methods. Exemplary filters used in particulate size genera US 10 , 179 , 109 B2 47 48 tion include , without limitation , # 16 , # 18 , # 20 , and # 25 size um , between about 300 um and about 500 um , between mesh screens, corresponding to 1190 um , 1000 um , 840 um , about 500 um and about 710 um , or between about 710 um and 710 um in diameter , respectively. In some embodiments , and about 850 um . the average diameter of each second particulate range from In some embodiments , the core represents between about about 500 um to about 1500 um , including , but not limited 5 40 % and about 90 % of the total weight of the second to , about 500 um , about 510 um , about 520 um , about 530 particulate ( w / w ) , e . g . , between about 40 % and about 80 % um , about 540 um , about 550 um , about 560 um , about 570 ( w / w ) , between about 40 % and about 70 % ( w / w ) , between um , about 580 um , about 590 um , about 600 um , about 610 about 50 % and about 70 % (w /w ), between about 40 % and um , about 620 um , about 630 um , about 640 um , about 650 about 60 % ( w / w ) , between about 40 % and about 50 % um , about 660 um , about 670 um , about 680 um , about69010 ( w / w ) , between about 50 % and about 90 % (w / w ) , between um , about 700 um , about 710 um , about 720 um , about 730 about 50 % and about 60 % ( w /w ), between about 60 % and jum , about 740 um , about 750 um , about 760 um , about 770 about 90 % ( w / w ), between about 70 % and about 90 % um , about 780 um , about 790 um , about 800 um , about 810 ( w / w ) , or between about 70 % and about 80 % ( w / w ) . In some um , about 820 um , about 830 um , about 840 um , about 850 i embodiments , the core represents between about 40 % and um , about 860 um , about 870 um , about 880 um , about 890 about 90 % of the total weight of the second particulate um , about 900 um , about 910 um , about 920 um , about 930 ( w / w ) , e . g . , about 40 % ( w / w ) , about 45 % ( w / w ), about 50 % um , about 940 um , about 950 um , about 960 um , about 970 ( w / w ), about 55 % ( w / w ), about 60 % ( w / w ), about 65 % um , about 980 um , about 990 um , about 1000 um , about ( w / w ), about 70 % ( w / w ), about 75 % ( w / w ), about 80 % 1010 um , about 1020 um , about 1030 um , about 1040 um , 20 ( w / w ) , about 85 % ( w / w ), or about 90 % ( w / w ) . about 1050 um , about 1060 um , about 1070 um , about 1080 Layer Enclosing the Core um , about 1090 um , about 1100 um , about 1110 um , about In some embodiments , each second particulate comprises 1120 um , about 1130 um , about 1140 um , about 1150 um , an active ingredient layer enclosing the core . In some about 1160 um , about 1170 um , about 1180 um , about 1190 embodiments , the active ingredient layer enclosing the core um , about 1200 um , about 1210 um , about 1220 um , about 25 is directly adjacent to the core . In some embodiments , the 1230 um , about 1240 um , about 1250 um , about 1260 um , active ingredient layer comprises multiple active ingredi about 1270 um , about 1280 um , about 1290 um , about 1300 ents . In some embodiments , the active ingredient layer um , about 1310 um , about 1320 um , about 1330 um , about comprises an antiemetic as disclosed herein . In some 1340 um , about 1350 um , about 1360 um , about 1370 um , embodiments , the active ingredient layer comprises promet about 1380 um , about 1390 um , about 1400 um , about 1410 30 hazine or a pharmaceutically acceptable salt thereof. In some um , about 1420 um , about 1430 um , about 1440 um , about embodiments , the active ingredient layer further comprises 1450 um , about 1460 um , about 1470 um , about 1480 um , pharmaceutically acceptable excipients . In some embodi about 1490 um , or about 1500 um . In some embodiments , ments , the active ingredient layer is applied onto the inert the average diameter of each second particulate range from 35 core by methods known in the art . In some embodiments , the 700 um to about 1200 um , including , but not limited to , from active ingredient layer is applied by solution or suspension about 700 um to about 1100 um , from about 700 um to about layering. In some embodiments , the active ingredient and 1000 um , from about 700 um to about 900 um , from about pharmaceutically acceptable excipients are dissolved or sus 700 um to about 800 um , from about 800 um to about 1200 pended in water or an organic solvent. In some embodi um , from about 900 um to about 1200 um , from about 1000 40 ments , the pharmaceutically acceptable excipients comprise um to about 1200 um , or from about 1100 um to about 1200 disintegrants , lubricants , binders , diluents and the like. In um . some embodiments , the pharmaceutically acceptable excipi Composition ents comprise hydroxypropyl methylcellulose (HPMC ) , low Core substituted hydroxypropyl cellulose ( L -HPC ), talc , and any In some embodiments , each second particulate comprises 45 combinations thereof. a core . In some embodiments , the core is an inert core such In some embodiments, each second particulate comprises as a sugar sphere ( non -pareils ) or a microcrystalline cellu - an antiemetic . In some embodiments , the antiemetic is lose sphere . In some embodiments , the inert core is a sugar promethazine or a pharmaceutically acceptable salt thereof. sphere (such as SugletsTM or SureSpheresTM ) . In some In some embodiments , the amount of the antiemetic in the embodiments , the sugar sphere comprises sucrose or a 50 second particulates range from about 5 % to about 40 % mixture of sucrose and starch . In some embodiments , the ( w / w ) , including but not limited to , from about 5 % to about sugar sphere comprises multiple layers . In some embodi - 30 % ( w / w ) , from about 5 % to about 25 % ( w / w ), from about ments, the sugar sphere comprises a sucrose core , a sucrose 10 % to about 40 % ( w / w ), from about 10 % to about 30 % layer and a corn starch layer . In some embodiments , the ( w / w ) , from about 20 % to about 40 % ( w / w ) , from about sugar sphere diameter is between about 212 um and about 55 20 % to about 30 % ( w / w ) , or from about 20 % to about 25 % 850 um . In some embodiments , the sugar sphere diameter is ( w / w ) . In some embodiments , the amount of the antiemetic between about 250 um and about 355 um , between about in the second particulates range from about 5 % to about 40 % 355 um and about 500 um , between about 425 um and about ( w / w ) , including , but not limited to , about 5 % ( w / w ) , about 500 um , between about 500 um and about 600 um , between 6 % ( w / w ) , about 7 % ( w / w ) , about 8 % ( w / w ) , about 9 % about 610 um and about 710 um , between about 710 um and 60 ( w / w ) , about 10 % ( w / w ) , about 11 % ( w / w ) , about 12 % about 850 um , between about 850 um and about 1000 um , ( w / w ), about 13 % (w /w ) , about 14 % ( w / w ), about 15 % between about 850 um and about 1180 um , or between about ( w / w ) , about 16 % ( w / w ) , about 17 % ( w / w ), about 18 % 1000 um and about 1400 um . In some embodiments , the ( w / w ) , about 19 % ( w /w ) , about 20 % ( w / w ), about 21 % inert core is a microcrystalline cellulose sphere (such as ( w / w ) , about 22 % ( w / w ) , about 23 % ( w / w ) , about 24 % CelletsTM or CelphereTM ) . In Some embodiments , the micro - 65 ( w /w ) , about 25 % ( w /w ), about 26 % ( w /w ), about 27 % crystalline cellulose sphere diameter is between about 106 ( w / w ) , about 28 % ( w / w ) , about 29 % ( w / w ) , about 30 % um and about 212 um , between about 150 um and about 300 ( w / w ) , about 31 % ( w / w ) , about 32 % ( w / w ), about 33 % US 10 , 179 , 109 B2 49 50 ( w / w ) , about 34 % ( w / w ) , about 35 % ( w / w ) , about 36 % limited to , from about 5 % to about 9 % ( w / w ) , from about ( w / w ), about 37 % (w /w ), about 38 % ( w / w ), about 39 % 6 % to about 8 % ( w / w ), from about 4 % to about 8 % (w /w ), ( w / w ) , or about 40 % ( w / w ) . or from about 6 % to about 9 % ( w / w ). In some embodiments , the amount of the antiemetic in the Coating drug layer range from about 50 % to about 90 % ( w / w ) , 5 In some cases, the second particulates disclosed herein are including but not limited to , from about 50 % to about 80 % coated with a coating material, e . g ., a sealant. In some ( w / w ) , from about 60 % to about 80 % ( w / w ), from about embodiments , the coating material is water soluble . In some 50 % to about 70 % ( w / w ) , from about 65 % to about 75 % embodiments , the coating material comprises a polymer, ( w /w ), or from about 55 % to about 85 % ( w / w ) . plasticizer, a pigment, or any combination thereof. In some In some embodiments , each second particulate comprises 10 embodiments , the coating material is a form of a film pharmaceutically acceptable excipients . In some embodi- coating , e . g . , a glossy film , a pH independent film coating , ments , the pharmaceutically acceptable excipients repre - an aqueous film coating , a dry powder film coating ( e . g . , sents between about 2 % and about 15 % of the total weight complete dry powder film coating) , or any combination of the second particulates, including , but not limited to , thereof . In some embodiments , the coating material is highly between about 5 % and about 15 % ( w / w ), between about 5 % 15 adhesive . In some embodiments , the coating material pro and about 10 % ( w / w ) , or between about 5 % and about 9 % vides low level of water permeation . In some embodiments , ( w / w ). In some embodiments , the amount of pharmaceuti - the coating material provides oxygen barrier protection . In cally acceptable excipients in the drug layer of the second some embodiments , the coating material allows immediate particulates range from about 10 % to about 50 % ( w / w ), disintegration for fast release of drug actives . In some including but not limited to , from about 10 % to about 40 % 20 embodiments , the coating material is pigmented , clear , or ( w / w ) , from about 20 % to about 40 % ( w / w ) , from about white . In some embodiments, the coating material is clear. 25 % to about 35 % ( w / w ), or from about 15 % to about 45 % Exemplary coating materials include, without limitation , ( w / w ) . polyvinyl alcohol ( PVA ), cellulose acetate phthalate (CAP ) , In some embodiments , the pharmaceutically acceptable polyvinyl acetate phthalate ( PVAP ) , methacrylic acid copo excipients comprised in each second particulate comprise 25 lymers , cellulose acetate trimellitate (CAT ) , hydroxypropy I hydroxypropyl methylcellulose (HPMC ) , low substituted methylcellulose phthalate (HPMCP ), hydroxypropyl meth hydroxypropyl cellulose ( L - HPC ) , talc , and any combina ylcellulose (HPMC ) , hydroxy propyl methyl, cellulose tions thereof. acetate succinate (hypromellose acetate succinate ) , shellac , In some embodiments , one of the pharmaceutically sodium alginate , and zein . In some embodiments , the coat acceptable excipient comprised in each second particulate is 30 ing material comprises or is PVA . In some embodiments , the hydroxypropyl methylcellulose (HPMC ) . In some embodi - coating material comprises or is HPMC . An exemplary ments, hydroxypropyl methylcellulose represents between PVA -based coating material includes Opadry II . In some about 2 % and about 10 % of the total weight of the second instances, the coating material is about 1, 2 , 3 , 4 , 5 , 6 , 7 , 8 , particulate , including , but not limited to , between about 5 % 9 , or 10 % of the weight of the second particulates. In some and about 10 % ( w / w ) , between about 5 % and about 9 % 35 instances , the coating material represent between about 1 % ( w / w ), between about 5 % and about 8 % ( w / w ) , or between and about 15 % of the total weight of the second particulates , about 5 % and about 7 % ( w / w ) . In some embodiments, the including, but not limited to , between about 5 % and about amount of hydroxypropyl methylcellulose in the drug layer 10 % , between about 6 % and about 10 % , between about 7 % of the second particulates range from about 10 % to about and about 10 % , between about 8 % and about 10 % , or 30 % ( w / w ) , including but not limited to , from about 10 % to 40 between about 9 % and about 10 % . In some instances, the about 25 % ( w / w ), from about 10 % to about 20 % ( w / w ) , coating material is greater than about 2 % , greater than about from about 15 % to about 25 % ( w /w ), or from about 15 % to 3 % , greater than about 4 % , greater than about 5 % , greater about 20 % (w / w ). than about 6 % , greater than about 7 % , greater than about In some embodiments , one of the pharmaceutically 8 % , greater than about 9 % , or greater than about 10 % of the acceptable excipient comprised in the second particulates is 45 weight of the second particulates . In some instances, the talc . In some embodiments , talc represents between about coating material is less than about 2 % , less than about 3 % , 0 . 5 % and about 3 % of the total weight of the second less than about 4 % , less than about 5 % , less than about 6 % , particulate , including , but not limited to , between about less than about 7 % , less than about 8 % , less than about 9 % , 0 . 5 % and about 2 . 5 % ( w / w ) , between about 0 . 5 % and about or less than about 10 % of the weight of the second particu 2 % ( w /w ), between about 0 .5 % and about 1. 5 % (w /w ), or 50 lates . between about 1 % and about 1 .5 % ( w / w ) . In some embodi Dissolution ments , the amount of talc in the drug layer of the second An example of a method to measure dissolution profiles particulate range from about 1 % to about 5 % ( w / w ) , includ - is provided at Examples 4 and 5 . In some aspects , dissolu ing but not limited to , from about 1 % to about 4 % ( w / w ) , tion rates are measured by a USP Apparatus 2 (Paddle from about 2 % to about 4 % ( w / w ), from about 2 % to about 55 Apparatus ) at a speed of 50 rpm in a dissolution fluid of 500 3 . 5 % ( w / w ), or from about 2 . 5 % to about 3 . 5 % ( w / w ) . ml de - aerated 0 . 1 N HCl (i . e . , pH 1 . 1 ) at 37 . 0 + 0 . 5° C . In In some embodiments , one of the pharmaceutically some instances , dissolution samples are analyzed by HPLC . acceptable excipient comprised in the second particulates isS In some embodiments , at least about 95 % of the anti low substituted hydroxypropyl cellulose ( L -HPC ) . In some emetic is released within about 5 minutes following contact embodiments , L -HPC represents between about 1 % and 60 of the first particulate with 500 mL of a dissolution fluid about 5 % of the total weight of the second particulates , ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an including, but not limited to , between about 1 % and about Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some 4 % ( w / w ), between about 1 % and about 3 % ( w / w ) , between embodiments , at least about 100 % of the antiemetic is about 2 % and about 3 % ( w / w ) , or between about 1 . 5 % and released within about 15 minutes following contact of the about 2 . 5 % ( w / w ). In some embodiments , the amount of 65 first particulate with 500 mL of a dissolution fluid ( 0 . 1N L -HPC in the drug layer of the second particulates range HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus from about 4 % to about 10 % ( w / w ) , including but not 2 (Paddle Apparatus) rotating at 50 rpm . US 10 , 179 , 109 B2 51 52 Provided herein are particulates , compositions , and cap and sweeteners , sugars , gastroresistant substances , or com sules comprising an antiemetic , wherein the antiemetic is in binations thereof. In some embodiments , the capsule is a rapid release matrix . In some embodiments , the antiemetic coated . In some embodiments , the coating covering the is promethazine or a pharmaceutically acceptable salt capsule includes, but is not limited to , immediate release thereof. In some embodiments , the promethazine is promet - 5 coatings , protective coatings , enteric or delayed release hazine hydrocholoride . In some embodiments , the promet - coatings , sustained release coatings, barrier coatings, seal hazine is present in an amount of from about 12 . 5 mg to coatings , or combinations thereof. In some embodiments , a about 60 mg. In some embodiments , the promethazine capsule herein is hard or soft . In some embodiments , the hydrochloride is present in an amount of from about 12 . 5 mg capsule is seamless . In some embodiments , the capsule is to about 60 mg. In some embodiments , the promethazine 10 broken such that the particulates are sprinkled on soft foods hydrochloride is present in an amount of 25 mg or 50 mg . and swallowed without chewing . In some embodiments , the In some embodiments , the promethazine base is present in shape and size of the capsule also vary . Examples of capsule an amount of 22 mg or 44 mg. In some embodiments , a shapes include , but are not limited to , round , oval, tubular, capsule comprises from about 50 mg to about 150 mg of oblong , twist off, or a non - standard shape . The size of the sumatriptan or a pharmaceutically acceptable salt thereof 15 capsule may vary according to the volume of the particu and from about 12 . 5 to about 60 mg of promethazine or a lates . In some embodiments , the size of the capsule is pharmaceutically acceptable salt thereof. In some embodi - adjusted based on the volume of the particulates and pow ments , the capsule comprises from about 50 mg to about 150 ders . Hard or soft gelatin capsules may be manufactured in mg of sumatriptan succinate and from about 12 . 5 to about 60 accordance with conventional methods as a single body unit mg of promethazine hydrochloride. In some embodiments , 20 comprising the standard capsule shape . A single - body soft the capsule comprises about 126 mg of sumatriptan succi- gelatin capsule typically may be provided , for example , in nate and about 50 mg of promethazine hydrochloride . sizes from 3 to 22 minims ( 1 minims being equal to 0 .0616 Capsules ml) and in shapes of oval, oblong or others . The gelatin In some aspects , the pharmaceutical composition dis - capsule may also be manufactured in accordance with closed herein is encapsulated into discrete units . In some 25 conventional methods , for example , as a two -piece hard embodiments , the discrete units are capsules or packets. In gelatin capsule , sealed or unsealed , typically in standard some embodiments, the pharmaceutical composition dis - shape and various standard sizes, conventionally designated closed herein is enclosed in a capsule. In embodiments, the as ( 000 ) , (00 ) , (0 ) , ( 1 ) , ( 2 ) , ( 3 ) , ( 4 ) , and ( 5 ) . The largest pharmaceutical composition disclosed herein comprises plu - number corresponds to the smallest size . In some embodi ralities of particulates . In some embodiments , the pharma- 30 ments , the pharmaceutical composition disclosed herein ceutical composition comprises a plurality of first particu - ( e . g ., capsule ) is swallowed as a whole . In some embodi lates and a plurality of second particulates . In some ments , the pharmaceutical composition disclosed herein embodiments , the plurality of first particulates comprises a ( e . g ., capsule ) does not completely disintegrate in mouth 5HT1B / 10 receptor agonist . In some embodiments, the plu - within about: 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11, 12 , 13 , 14 , 15 , 16 , rality of first particulates comprises a triptan or a pharma - 35 17 , 18 , 19 , or 20 minutes . In some embodiments , the ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition disclosed herein is not a film . In plurality of first particulates comprises sumatriptan or a some embodiments , the pharmaceutical composition dis pharmaceutically acceptable salt thereof . In some embodi- closed herein is not for buccal administration . In some ments, the plurality of first particulates comprises sumatrip embodiments , the pharmaceutical composition disclosed tan succinate . In some embodiments , the plurality of second 40 herein ( e . g . , capsule ) dissolves in stomach or intestine . particulates comprises an antiemetic . In some embodiments , In some embodiments, a capsule disclosed herein has a the plurality of second particulates comprises promethazine net weight of ranging from 28 mg to 125 mg, e . g . , from or a pharmaceutically acceptable salt thereof. In some about 90 mg to about 102 mg, about 100 mg to about 114 embodiments , the plurality of second particulates comprises mg, about 103 mg to about 117 mg, about 76 mg to about promethazine hydrochloride . FIGS . 1 and 2 illustrate exem - 45 86 mg, about 71 mg to about 81 mg, about 61 mg to about plary capsules containing two types of beads , one bead 71 mg, about 57 mg to about 65 mg, about 45 mg to about comprising an antiemetic described herein and the other 51 mg, about 37 mg to about 43 mg, about 35 mg to about bead comprising a 5HT B / D receptor agonist described 41 mg, or about 26 mg to about 30 mg. In some cases , the herein . In some embodiments , the pharmaceutical compo - capsule has a net weight of about 118 mg, about 107 mg, sition disclosed herein comprises a plurality of third par - 50 about 110 mg, about 95 mg, about 81 mg , about 75 mg , ticulates . In some embodiments the plurality of third par - about 66 mg , about 60 mg, about 47 mg , about 40 mg, about ticulates comprises an antiemetic different than that present 38 mg, or about 28 mg. In some cases , a capsule has a in the plurality of second particulates . volume ranging from about 0 . 1 to 0 . 9 ml, e . g . , about 0 . 6 ml Amounts and weight ratios disclosed herein for the first to about 0 . 8 ml, about 0 . 4 ml to about 0 . 6 ml, about 0 . 3 ml particulates and the second particulates provide an advan - 55 to about 0 . 5 ml, about 0 . 2 ml to about 0 . 4 ml, or about 0 . 1 tageous feature for the treatment of a headache ( e . g . , a ml to about 0 . 3 ml. In some cases , the capsule has a volume migraine or cluster headache ) . Amounts and weight ratios of about 0 . 9 ml, about 0 . 8 ml, about 0 . 7 ml, about 0 . 6 ml, disclosed herein for the first particulates and the second about 0 . 5 ml, about 0 .4 ml, about 0 . 35 ml, about 0 . 3 ml, particulates also provide an advantageous feature for the about 0 .25 ml, about 0 . 2 ml, about 0 . 15 ml, or about 0 . 1 ml. treatment of nausea associated with a migraine and / or vom - 60 In some cases , a body of the capsule ranges from about 9 iting associated with a migraine . In some embodiments , the mm to about 20 mm long , e . g ., about 17 mm to about 20 mm capsule is formed using materials which include, but are not long , about 17 mm to about 19 mm long , about 16 mm to limited to , natural or synthetic gelatin , pectin , casein , col- about 20 mm long , about 15 mm to about 19 mm long, about lagen , protein , modified starch , polyvinylpyrrolidone , 14 mm to about 18 mm long , about 13 mm to about 17 mm acrylic polymers , cellulose derivatives , or combinations 65 long, about 12 mm to about 16 mm long, about 11 mm to thereof. In some embodiments , the capsule is formed using about 15 mm long , about 10 mm to about 14 mm long, about preservatives , coloring and opacifying agents , flavorings 9 mm to about 13 mm long, about 9 mm to about 12 mm US 10 , 179 ,109 B2 53 54 long , about 9 mm to about 11 mm long , or about 9 mm to In some embodiments , the pharmaceutical composition about 10 mm long. In some cases , the body of the capsule described herein comprises sumatriptan or a pharmaceuti is about 18 mm long , about 17 mm long , about 16 mm long , cally acceptable salt thereof and promethazine or a pharma about 15 mm long , about 14 mm long, about 13 mm long , ceutically acceptable salt thereof. In some embodiments , the about 12 mm long, about 11 mm long , about 10 mm long , 5 sumatriptan or a pharmaceutically acceptable salt thereof is or about 9 mm long. In some cases, a cap of the capsule present at a dose from about 10 mg to about 200 mg, including , but not limited to , about 10 . 0 mg, about 10 . 5 mg, ranges from about 6 mm to about 12 mm long , e . g . , about 10 about 11 . 0 mg, about 11. 5 mg, about 12 . 0 mg, about 12 . 5 mm to 12 mm long , about 9 mm to about 11 mm long , about mg , about 13 . 0 mg, about 13 . 5 mg, about 14 . 0 mg, about 8 mm to about 10 mm long , about 7 mm to about 9 mm long, 10 14 . 5 mg, about 15 . 0 mg, about 15 . 5 mg, about 16 mg, about or about 6 mm to about 8 mm long. In some cases , the cap 16 . 5 mg , about 17 mg , about 17. 5 mg, about 18 mg, about of the capsule is about 11 mm long, about 10 mm long , about 18 . 5 mg, about 19 mg, about 19 . 5 mg, about 20 mg, about 9 mm long , about 8 mm long, about 7 mm long , or about 6 20 .5 mg, about 21 mg , about 21 . 5 mg , about 22 mg, about mm long . In some cases, the body of the capsule has an 22. 5 mg, about 23 mg , about 23. 5 mg, about 24 mg , about external diameter ranging from about 4 mm to aboutut 9 mm , 15 24 . 5 mg, about 25 mg, about 25. 5 mg, about 26 mg, about e . g ., about 6 mm to about 8 mm , about 7 mm to about 9 mm , 26 . 5 mg, about 27 mg, about 27 . 5 mg, about 28 mg , about about 7 mm to about 8 mm , about 5 mm to about 7 mm , or 28 . 5 mg, about 29 mg, about 29. 5 mg, about 30 mg, about about 4 mm to about 6 mm . In some cases , the body of the 30 . 5 mg, about 31 mg, about 31. 5 mg, about 32 mg, about capsule has an external diameter of about 9 mm , about 8 32 . 5 mg, about 33 mg, about 33 . 5 mg, about 34 mg, about mm , about 7 mm , about 6 mm , about 5 mm , or about 4 mm . 20 34. 5 mg, about 35 mg, about 35 . 5 mg, about 36 mg, about In some cases, a cap of the capsule has an external diameter 36 . 5 mg , about 37 mg, about 37 . 5 mg, about 38 mg, about ranging from about 4 mm to about 9 mm , e . g . , about 7 mm 38 . 5 mg, about 39 mg, about 39 . 5 mg, about 40 mg, about to about 9 mm , about 6 mm to about 9 mm , about 7 mm to 40 . 5 mg, about 41 mg, about 41. 5 mg, about 42 mg, about about 8 mm , about 5 mm to about 7 mm , or about 4 mm to 42 . 5 mg , about 43 mg, about 43 .5 mg, about 44 mg, about about 6 mm . In some cases , the cap of the capsule has an 25 44 . 5 mg, about 45 mg, about 45 . 5 mg, about 46 mg, about external diameter of about 9 mm , about 8 mm , about 7 mm , 46 . 5 mg , about 47 mg, about 47 . 5 mg, about 48 mg, about about 6 mm , about 5 mm , or about 4 mm . In some cases , an 48 . 5 mg , about 49 mg, about 49. 5 mg, about 50 mg, about overall closed length of the capsule ranges from about 10 55 mg , about 60 mg, about 65 mg, about 70 mg, about 75 mm to about 24 mm , e . g . , about 20 mm to about 24 mm , or mg, about 80 mg , about 85 mg, about 90 mg, about 95 mg, about 21 mm to about 23 mm , about 20 mm to about 22 mm , 30 about 100 , about 105 mg, about 110 mg, about 115 mg, about 19 mm to about 21 mm , about 18 mm to about 20 mm , about 120 mg, about 120 .5 mg, about 121 mg, about 121. 5 about 17 mm to about 19 mm , about 16 mm to about 18 mm , mg, about 122 mg, about 122 . 5 mg , about 123 mg, about about 15 mm to about 17 mm , about 14 mm to about 16 mm , 123 . 5 mg, about 124 mg, about 124 . 5 mg, about 125 mg, about 13 mm to about 15 mm , about 12 mm to about 14 mm , about 125 .5 mg, about 126 mg, about 126 . 5 mg, about 127 about 11 mm to about 13 mm , or about 10 mm to about 12 35 mg, about 127 . 5 mg, about 128 mg, about 128 . 5 mg, about mm . In some cases, the overall closed length of the capsule 129 mg, about 129 . 5 mg , about 130 mg, about 135 mg , about is about 22 mm , about 24 mm , about 23 mm , about 21 mm , 140 mg, about 145 mg, about 150 mg, about 155 mg, about about 20 mm , about 19 mm , about 18 mm , about 17 mm , 160 mg , about 165 mg, about 170 mg, about 175 mg, about about 16 mm , about 15 mm , about 14 mm , about 13 mm , 180 mg, about 185 mg, about 190 mg, about 195 mg, about about 12 mm , about 11 mm , or about 10 mm . In some cases , 40 200 mg, about 25 mg to about 100 mg, about 35 mg to about the capsule has a capacity of about 50 mg to about 800 mg, 140 mg, about 70 mg to about 140 mg, about 80 mg to about e . g . , about 400 mg to about 800 mg, about 350 mg to about 135 mg, about 10 mg to about 25 mg, about 25 mg to about 450 mg, about 300 mg to about 500 mg, about 300 mg to 50 mg, about 50 mg to about 100 mg, about 100 mg to about about 400 mg, about 250 mg to about 350 mg, about 200 mg 150 mg, about 150 mg to about 200 mg, about 10 mg to to about 300 mg, about 200 mg to about 250 mg, about 150 45 about 35 mg, about 35 mg to about 70 mg , about 70 mg to mg to about 200 mg, about 100 mg to about 200 mg, about about 105 mg, about 105 mg to about 140 mg, about 140 mg 100 mg to about 150 mg, about 50 mg to about 100 mg, to about 175 mg, or about 175 mg to about 200 mg and the about 600 g , about 500 mg, about 450 mg, about 425 mg, promethazine or a pharmaceutically acceptable salt thereof about 400 mg, about 375 mg, about 350 mg, about 325 mg, is present at a dose from about 0 . 5 mg to about 100 mg, about 300 mg, about 275 mg, about 250 mg, about 225 mg, 50 including, but not limited to , about 0 . 5 mg , about 1 . 0 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about 1 . 5 mg, about 2 . 0 mg, about 2 . 5 mg , about 3 . 0 mg, about 100 mg, or about 75 mg, and a powder density of about 3 . 5 mg, about 4 . 0 mg, about 4 . 5 mg, about 5 . 0 mg, about 0 . 6 g /ml to about 1 . 2 g /ml , e . g . , about 0 . 6 g /ml , g /ml about 5 . 5 mg, about 6 . 0 mg, about 6 . 5 mg, about 7 . 0 mg, 0 .8 g /ml , g /ml 1 g /ml , or g /ml 1 . 2 g /ml . In some cases, the about 7 . 5 mg, about 8 . 0 mg, about 8 . 5 mg , about 9 . 0 mg, capsule is oblong . 55 about 9 . 5 mg, about 10 . 0 mg, about 10 . 5 mg, about 11 . 0 mg, Dosages in Capsule about 11 . 5 mg, about 12 . 0 mg, about 12 . 5 mg, about 13 mg, In some aspects , the pharmaceutical composition dis - about 13 . 5 mg, about 14 mg, about 14 . 5 mg, about 15 mg, closed herein comprises multiple pharmaceutically active about 15 . 5 mg, about 16 mg, about 16 . 5 mg, about 17 mg, agents at the same or different dosages . In some embodi- about 17 . 5 mg, about 18 mg, about 18 . 5 mg, about 19 mg, ments , the pharmaceutical composition disclosed herein 60 about 19 . 5 mg, about 20 mg, about 20 . 5 mg, about 21 mg, comprises a 5HTB/ 12 receptor agonist disclosed herein and about 21 . 5 mg, about 22 mg, about 22 . 5 mg , about 23 mg, an antiemetic disclosed herein . In some embodiments , a about 23 . 5 mg, about 24 mg, about 24 . 5 mg, about 25 mg, pharmaceutically active agent such as 5HT B / D receptor about 25 . 5 mg, about 26 mg, about 26 . 5 mg, about 27 mg, agonist varies in dosages as further described herein , and the about 27 . 5 mg, about 28 mg , about 28 . 5 mg, about 29 mg, dosage of a pharmaceutically active agent such as an anti - 65 about 29 . 5 mg, about 30 mg, about 31 mg , about 32 mg, emetic is adjusted according to the particular 5HT1B /ID about 33 mg, about 34 mg, about 35 mg, about 36 mg, about receptor agonist used . 37 mg , about 38 mg, about 39 mg, about 40 mg, about 41 US 10 , 179 , 109 B2 55 56 mg, about 12 mg, about 43 mg, about 44 mg, about 45 mg, mg, about 20 mg, about 20. 5 mg, about 21 mg, about 21. 5 about 46 mg, about 47 mg, about 48 mg, about 49 mg, about mg, about 22 mg, about 22 .5 mg , about 23 mg, about 23 . 5 50 mg , about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 24 mg, about 24 . 5 mg , about 25 mg, about 25 . 5 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, mg, about 26 mg, about 26 . 5 mg, about 27 mg, about 27 . 5 about 95 mg, about 100 mg, about 0 .5 mg to about 12 . 5 mg, 5 mg, about 28 mg, about 28 .5 mg , about 29 mg, about 29 . 5 about 12 . 5 mg to about 50 mg, about 50 mg to about 75 mg, mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 75 mg to about 100 mg, about 0 . 5 mg to about 15 mg, about 34 mg, about 35 mg , about 36 mg, about 37 mg, about about 15 mg to about 35 mg, about 35 mg to about 55 mg, 38 mg, about 39 mg, about 40 mg , about 41 mg, about 12 about 55 mg to about 75 mg, or about 75 mg to about 95 mg. mg, about 43 mg , about 44 mg, about 45 mg, about 46 mg, In some embodiments, the pharmaceutical composition 10 about 47 mg, about 48 mg, about 49 mg, about 50 mg, about disclosed herein comprises sumatriptan succinate and pro - 55 mg, about 60 mg, about 65 mg , about 70 mg, about 75 methazine hydrochloride . In some embodiments , the mg, about 80 mg , about 85 mg, about 90 mg, about 95 mg, sumatriptan succinate is present at a dose from about 10 mg about 100 mg, about 0 . 5 mg to about 12 . 5 mg, about 12 . 5 mg to about 200 mg, including, but not limited to , about 10 . 0 to about 50 mg, about 50 mg to about 75 mg , about 75 mg mg, about 10 . 5 mg, about 11. 0 mg , about 11 . 5 mg, about 15 to about 100 mg, about 0 .5 mg to about 15 mg, about 15 mg 12 . 0 mg, about 12 . 5 mg, about 13 . 0 mg, about 13 . 5 mg, to about 35 mg, about 35 mg to about 55 mg , about 55 mg about 14 . 0 mg, about 14 . 5 mg, about 15 . 0 mg , about 15 .5 to about 75 mg, or about 75 mg to about 95 mg. mg, about 16 mg, about 16 . 5 mg, about 17 mg, about 17 . 5 In some embodiments , the weight ratio of a first active mg , about 18 mg, about 18 . 5 mg, about 19 mg, about 19 . 5 pharmaceutical ingredient ( e . g ., triptan or a pharmaceuti mg , about 20 mg, about 20 .5 mg, about 21 mg, about 21 . 5 20 cally acceptable salt thereof such as sumatriptan succinate ) mg, about 22 mg, about 22 . 5 mg, about 23 mg, about 23 . 5 to a second active pharmaceutical ingredient ( e . g ., anti mg, about 24 mg, about 24 .5 mg, about 25 mg, about 25 . 5 emetic such as promethazine or a pharmaceutically accept mg, about 26 mg, about 26 . 5 mg, about 27 mg, about 27 . 5 able salt thereof for example promethazine hydrochloride ) is mg, about 28 mg, about 28 . 5 mg, about 29 mg, about 29 . 5 from about 1 : 2 to about 15 : 1 , respectively, for example mg, about 30 mg, about 30 . 5 mg, about 31 mg, about 31 .5 25 about 1: 2 , about 1 :1 , about 2 : 1, about 2. 5 : 1 , about 3 :1 , about mg, about 32 mg, about 32 . 5 mg, about 33 mg, about 33 . 5 4 : 1 , about 5 : 1 , about 6 : 1 , about 7 : 1 , about 8 : 1 , about 9 : 1 , mg, about 34 mg, about 34 . 5 mg, about 35 mg, about 35 .5 about 10 : 1 , about 11 : 1 , about 12 : 1 , about 13 : 1 , about 14 : 1 , mg, about 36 mg, about 36 . 5 mg, about 37 mg, about 37 . 5 or 15 : 1 . In some embodiments , the weight ratio of a first mg , about 38 mg, about 38 . 5 mg, about 39 mg, about 39 . 5 active pharmaceutical ingredient ( e . g ., triptan or a pharma mg, about 40 mg, about 40 .5 mg, about 41 mg, about 41 . 5 30 ceutically acceptable salt thereof such as sumatriptan suc mg, about 42 mg, about 42. 5 mg, about 43 mg, about 43. 5 cinate ) to a second active pharmaceutical ingredient ( e . g ., mg, about 44 mg, about 44 .5 mg, about 45 mg, about 45 . 5 antiemetic such as promethazine or a pharmaceutically mg, about 46 mg, about 46 . 5 mg, about 47 mg, about 47 . 5 acceptable salt thereof for example promethazine hydro mg, about 48 mg, about 48 . 5 mg, about 49 mg, about 49. 5 chloride ) is from about 3 : 2 to about 11 : 1 , from about 3 : 1 to mg, about 50 mg, about 55 mg , about 60 mg, about 65 mg, 35 about 7 :1 , from about 1: 1 to about 5 :1 , from about 9 : 2 to about 70 mg, about 75 mg, about 80 mg, about 85 mg, about about 11 : 2 , from about 4 : 2 to about 6 : 2 , about 5 : 1 , or about 90 mg, about 95 mg , about 100 , about 105 mg , about 110 2 . 5 : 1 . In some embodiments , the weight ratio of a first active mg, about 115 mg, about 120 mg, about 120 . 5 mg, about 121 pharmaceutical ingredient ( e . g . , triptan or a pharmaceuti mg, about 121. 5 mg, about 122 mg, about 122 . 5 mg, about cally acceptable salt thereof such as sumatriptan succinate ) 123 mg, about 123 . 5 mg, about 124 mg, about 124 . 5 mg, 40 to a second active pharmaceutical ingredient ( e . g ., anti about 125 mg, about 125 . 5 mg , about 126 mg , about 126 . 5 emetic such as promethazine or a pharmaceutically accept mg, about 127 mg, about 127 .5 mg, about 128 mg , about able salt thereof for example promethazine hydrochloride ) is 128 .5 mg, about 129 mg , about 129 .5 mg, about 130 mg, about 5 : 1. In some embodiments , the weight ratio of a first about 135 mg, about 140 mg, about 145 mg, about 150 mg, active pharmaceutical ingredient ( e . g . , triptan or a pharma about 155 mg, about 160 mg, about 165 mg, about 170 mg, 45 ceutically acceptable salt thereof such as sumatriptan suc about 175 mg, about 180 mg, about 185 mg, about 190 mg, cinate ) to a second active pharmaceutical ingredient ( e . g . , about 195 mg, about 200 mg, about 25 mg to about 100 mg, antiemetic such as promethazine or a pharmaceutically about 35 mg to about 140 mg, about 70 mg to about 140 mg, acceptable salt thereof for example promethazine hydro about 80 mg to about 135 mg, about 10 mg to about 25 mg, chloride ) is about 2 . 5 : 1 . about 25 mg to about 50 mg, about 50 mg to about 100 mg , 50 In some embodiments , the pharmaceutical composition about 100 mg to about 150 mg, about 150 mg to about 200 described herein comprises from about 150 mg to about 400 mg, about 10 mg to about 35 mg, about 35 mg to about 70 mg of a plurality of first particulates , including , but not mg, about 70 mg to about 105 mg , about 105 mg to about limited to , about 150 mg, about 155 mg , about 160 mg, 140 mg, about 140 mg to about 175 mg, or about 175 mg to about 165 mg , about 170 mg, about 175 mg, about 180 mg, about 200 mg and the promethazine hydrochloride is present 55 about 185 mg, about 190 mg, about 195 mg, about 200 mg, at a dose from about 0 . 5 mg to about 100 mg, including, but about 205 mg, about 210 mg, about 215 mg, about 220 mg, not limited to , from about 0 .5 mg to about 100 mg, including about 225 mg, about 230 mg, about 235 mg, about 240 mg, but not limited to , about 0 . 5 mg, about 1 . 0 mg , about 1 . 5 mg, about 245 mg, about 250 mg, about 260 mg, about 270 mg, about 2 . 0 mg, about 2 . 5 mg, about 3 . 0 mg, about 3 . 5 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 4 . 0 mg, about 4 . 5 mg, about 5 . 0 mg, about 5 . 5 mg, 60 about 320 mg, about 330 mg, about 340 mg , about 350 mg, about 6 . 0 mg, about 6 . 5 mg, about 7 . 0 mg, about 7 . 5 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 8 . 0 mg, about 8 . 5 mg, about 9 . 0 mg, about 9 . 5 mg, or about 400 mg. In some embodiments , the pharmaceutical about 10 . 0 mg, about 10 . 5 mg, about 11 . 0 mg, about 11 . 5 composition described herein comprises from about 150 mg mg, about 12 . 0 mg, about 12 . 5 mg , about 13 mg, about 13 . 5 to about 400 mg of a plurality of first particulates , including , mg, about 14 mg, about 14 . 5 mg, about 15 mg, about 15 . 5 65 but not limited to , about 175 mg to about 300 mg, about 200 mg, about 16 mg, about 16 . 5 mg, about 17 mg, about 17 . 5 mg to about 250 mg, about 200 mg to about 220 mg, about mg, about 18 mg , about 18 . 5 mg , about 19 mg, about 19. 5 150 mg to about 175 mg, about 175 mg to about 200 mg, US 10 , 179 , 109 B2 57 58 about 200 mg to about 225 mg, about 225 mg to about 250 about 40 mg, about 42 . 5 mg, about 45 mg, about 47 .5 mg, mg, about 250 mg to about 275 mg, about 275 mg to about about 50 mg, about 52 .5 mg, about 55 mg, about 57. 5 mg, 300 mg, about 300 mg to about 325 mg, about 325 mg to about 60 mg, about 62 . 5 mg, about 65 mg, about 67 . 5 , about about 350 mg, about 350 mg to about 375 mg, about 375 mg 70 mg, about 72 . 5 mg, about 75 mg, about 77 . 5 mg, about to about 400 mg, about 165 mg to about 195 mg, about 195 5 80 mg, about 82 .5 mg, about 85 mg, about 87 . 5 mg , about mg to about 225 mg, about 225 mg to about 255 mg, about 90 mg, about 92 . 5 mg, about 95 mg, about 97 . 5 mg, about 255 mg to about 285 mg, about 285 mg to about 315 mg, 100 mg, about 102 . 5 mg , about 105 mg, about 107 . 5 mg, about 315 mg, to about 345 mg, or about 345 mg to about about 110 mg, about 112 . 5 mg, about 115 mg, about 117 . 5 375 mg. mg , about 120 mg, about 122 . 5 mg, about 125 mg, about In some embodiments , the pharmaceutical composition 10 127 .5 mg, about 130 mg, about 132. 5 mg, about 135 mg, described herein comprises from about 25 mg to about 300 about 137 . 5 mg, about 140 mg, about 145 mg , about 150 mg , mg of a plurality of second particulates, including, but not about 155 mg, about 160 mg, about 165 mg, about 170 mg, limited to , about 25 mg, about 27 . 5 mg, about 30 mg, about about 175 mg, about 180 mg, about 185 mg, about 190 mg, 32 . 5 mg, about 35 mg, about 37. 5 mg, about 40 mg, about about 195 mg, about 200 mg, about 202 . 5 mg, about 205 mg, 42 . 5 mg, about 45 mg, about 47 . 5 mg, about 50 mg, about 15 about 207 . 5 mg, about 210 mg, about 212 . 5 mg, about 215 52 . 5 mg, about 55 mg, about 57 . 5 mg, about 60 mg, about mg, about 217 . 5 mg, about 220 mg, about 222 . 5 mg, about 62 . 5 mg, about 65 mg, about 67 . 5 , about 70 mg, about 72 . 5 225 mg, about 227 . 5 mg, about 230 mg, about 232 . 5 mg, mg, about 75 mg, about 77 . 5 mg, about 80 mg, about 82 .5 about 235 mg, about 237 .5 mg, about 240 mg, about 245 mg , mg, about 85 mg, about 87 .5 mg, about 90 mg, about 92 . 5 about 250 mg, about 255 mg, about 260 mg, about 265 mg, mg, about 95 mg, about 97 . 5 mg, about 100 mg, about 102 . 5 20 about 270 mg, about 275 mg, about 280 mg, about 285 mg, mg, about 105 mg, about 107 . 5 mg, about 110 mg, about about 290 mg, about 295 mg , or about 300 mg. 112 .5 mg, about 115 mg, about 117 .5 mg, about 120 mg, Dissolution about 122 .5 mg, about 125 mg , about 127 .5 mg, about 130 An example of a method to measure dissolution profiles mg, about 132 . 5 mg , about 135 mg, about 137 . 5 mg, about is provided at Examples 4 and 5 . In some aspects , dissolu 140 mg, about 145 mg, about 150 mg, about 155 mg, about 25 tion rates are measured by a USP Apparatus 2 (Paddle 160 mg, about 165 mg, about 170 mg, about 175 mg, about Apparatus ) at a speed of 50 rpm in a dissolution fluid of 500 180 mg, about 185 mg, about 190 mg, about 195 mg, about ml de -aerated 0 . 1 N HC1 ( i . e . , pH 1 . 1 ) at 37 . 0 + 0 . 5° C . In 200 mg, about 202. 5 mg, about 205 mg, about 207. 5 mg, some instances, dissolution samples are analyzed by HPLC . about 210 mg, about 212 . 5 mg, about 215 mg, about 217 . 5 In some embodiments , dissolution of 100 % of a pharma mg, about 220 mg, about 222 .5 mg, about 225 mg , about 30 ceutically active agent disclosed herein occurs within a 227 . 5 mg, about 230 mg, about 232 . 5 mg, about 235 mg, prescribed time. In some embodiments , a 5HT 11 /12 receptor about 237 . 5 mg, about 240 mg, about 245 mg, about 250 mg, agonist and an antiemetic disclosed herein both have a about 255 mg, about 260 mg, about 265 mg, about 270 mg, dissolution rate of about 60 % or more within 15 minutes , about 275 mg, about 280 mg, about 285 mg, about 290 mg, following contact of the pharmaceutical composition with about 295 mg, or about 300 mg. In some embodiments , the 35 500 mL of a dissolution fluid (0 . 1N HC1, pH 1 . 1 ) at pharmaceutical composition described herein comprises 37 + / - 0 .5º C . as measured by an Apparatus 2 ( Paddle Appa from about 25 mg to about 300 mg of a plurality of second ratus ) rotating at 50 rpm . In some embodiments , a 5HT1B / ID particulates , including but not limited to , about 30 mg to receptor agonist or an antiemetic disclosed herein both have about 150 mg, about 30 mg to about 100 mg, about 40 mg a dissolution rate of about 60 % or more within 15 minutes, to about 100 mg , about 30 mg to about 70 mg, about 25 mg 40 following contact of the pharmaceutical composition with to about 50 mg, about 50 mg to about 75 mg, about 75 mg 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at to about 100 mg, about 100 mg to about 125 mg, about 100 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle Appa mg to about 115 mg, about 110 mg to about 125 mg, about ratus ) rotating at 50 rpm . 110 mg to about 115 mg, about 125 mg to about 150 mg, In some embodiments , a 5HT18 / 1d receptor agonist and an about 150 mg to about 175 mg, about 175 mg to about 200 45 antiemetic disclosed herein both have a dissolution rate of mg , about 40 mg to about 70 mg, about 70 mg to about 100 about 80 % or more within 30 minutes , following contact of mg, about 100 mg to about 130 mg, about 130 mg to about the pharmaceutical composition with 500 mL of a dissolu 160 mg, about 160 mg to about 190 mg, about 150 mg to tion fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured about 250 mg, or about 200 mg to about 250 mg. by an Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In In some embodiments, the pharmaceutical composition 50 some embodiments , a 5HTB/ D receptor agonist or an disclosed herein comprises a plurality of first particulates antiemetic disclosed herein both have a dissolution rate of and a plurality of second particulates. In some embodiments, about 80 % or more within 30 minutes, following contact of the plurality of first particulates is present in an amount that the pharmaceutical composition with 500 mL of a dissolu ranges from about 150 mg to about 400 mg , including , but tion fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured not limited to , about 150 mg, about 155 mg, about 160 mg, 55 by an Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . about 165 mg, about 170 mg, about 175 mg, about 180 mg, In some embodiments, at least about 32 % of the anti about 185 mg, about 190 mg, about 195 mg, about 200 mg, emetic is released within about 5 minutes following contact about 205 mg, about 210 mg, about 215 mg, about 220 mg, of the pharmaceutical composition with 500 mL of a disso about 225 mg, about 230 mg, about 235 mg, about 240 mg, lution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5º C . as measured about 245 mg, about 250 mg, about 260 mg, about 270 mg, 60 by an Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In about 280 mg , about 290 mg, about 300 mg, about 310 mg, some embodiments , at least about 47 % of the antiemetic is about 320 mg, about 330 mg, about 340 mg, about 350 mg, released within about 5 minutes following contact of the about 360 mg, about 370 mg, about 380 mg, about 390 mg, pharmaceutical composition with 500 mL of a dissolution or 400 mg and the plurality of second particulates is present fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5º C . as measured by an in an amount that ranges from about 25 mg to about 300 mg, 65 Apparatus 2 ( Paddle Apparatus ) rotating at 50 rpm . In some including , but not limited to , about 25 mg, about 27 . 5 mg, embodiments, at least about 53 % of the antiemetic is about 30 mg, about 32. 5 mg, about 35 mg, about 37. 5 mg, released within about 10 minutes following contact of the US 10 , 179 , 109 B2 59 pharmaceutical composition with 500 mL of a dissolution In some embodiments , at least about 56 % of the 5HT1B / 1D fluid ( 0 .1N HC1, pH 1. 1) at 37 + / - 0 .5° C . as measured by an receptor agonist is released within about 5 minutes follow Apparatus 2 ( Paddle Apparatus) rotating at 50 rpm . In some ing contact of the pharmaceutical composition with 500 mL embodiments , at least about 69 % of the antiemetic is of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as released within about 10 minutes following contact of the 5 measured by an Apparatus 2 (Paddle Apparatus ) rotating at pharmaceutical composition with 500 mL of a dissolution 50 rpm . In some embodiments , at least about 66 % of the fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an 5HT 16 /10 receptor agonist is released within about 5 minutes Apparatus 2 (Paddle Apparatus) rotating at 50 rpm . In some following contact of the pharmaceutical composition with 500 mL of a dissolution fluid (0 . 1N HCl, pH 1 . 1 ) at embodiments , at least about 63 % of the antiemetic is 10 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa released within about 15 minutes following contact of the ratus ) rotating at 50 rpm . In some embodiments , at least pharmaceutical composition with 500 mL of a dissolution about 73 % of the 5HT1 B / D receptor agonist is released fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an within about 10 minutes following contact of the pharma Apparatus 2 ( Paddle Apparatus ) rotating at 50 rpm . In some ceutical composition with 500 mL of a dissolution fluid embodiments , at least about 78 % of the antiemetic is 15 (0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 . 5º C . as measured by an released within about 15 minutes following contact of the Apparatus 2 (Paddle Apparatus) rotating at 50 rpm . In some pharmaceutical composition with 500 mL of a dissolution embodiments at least about 80 % of the 5HT , receptor fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an agonist is released within about 10 minutes following con Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some tact of the pharmaceutical composition with 500 mL of a embodiments , at least about 71 % of the antiemetic is 20 dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as released within about 20 minutes following contact of the measured by an Apparatus 2 (Paddle Apparatus ) rotating at pharmaceutical composition with 500 mL of a dissolution 50 rpm . In some embodiments, at least about 81 % of the fluid ( 0 .1N HC1, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an 5HTB12 receptor agonist is released within about 15 min Apparatus 2 ( Paddle Apparatus ) rotating at 50 rpm . In some utes following contact of the pharmaceutical composition embodiments , at least about 82 % of the antiemetic is 25 with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at released within about 20 minutes following contact of the 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle Appa pharmaceutical composition with 500 mL of a dissolution ratus ) rotating at 50 rpm . In some embodiments , at least fluid ( 0 .1N HC1, pH 1. 1) at 37 + / - 0 .5° C . as measured by an about 85 % of the 5HT1B /12 receptor agonist is released Apparatus 2 ( Paddle Apparatus ) rotating at 50 rpm . In some within about 15 minutes following contact of the pharma embodiments , at least about 79 % of the antiemetic is 30 ceutical composition with 500 mL of a dissolution fluid released within about 30 minutes following contact of the ( 0 .1N HCI, pH 1 . 1 ) at 37 + / - 0 .5º C . as measured by an pharmaceutical composition with 500 mL of a dissolution Apparatus 2 (Paddle Apparatus) rotating at 50 rpm . In some fluid ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an embodiments , at least about 84 % of the 5HT1B / 1D receptor Apparatus 2 (Paddle Apparatus) rotating at 50 rpm . In some agonist is released within about 20 minutes following con embodiments , at least about 87 % of the antiemetic is 35 tact of the pharmaceutical composition with 500 mL of a released within about 30 minutes following contact of the dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as pharmaceutical composition with 500 mL of a dissolution measured by an Apparatus 2 (Paddle Apparatus ) rotating at fluid ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 .5º C . as measured by an 50 rpm . In some embodiments, at least about 88 % of the Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some 5HT1B/ 10 receptor agonist is released within about 20 min embodiments, at least about 85 % of the antiemetic is 40 utes following contact of the pharmaceutical composition released within about 45 minutes following contact of the with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at pharmaceutical composition with 500 mL of a dissolution 37 + / - 0 .5º C . as measured by an Apparatus 2 (Paddle Appa fluid (0 . 1N HC1, pH 1 . 1) at 37 + / - 0 .5° C . as measured by an ratus ) rotating at 50 rpm . In some embodiments , at least Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some about 87 % of the 5HT1B / 10 receptor agonist is released embodiments , at least about 92 % of the antiemetic is 45 within about 30 minutes following contact of the pharma released within about 45 minutes following contact of the ceutical composition with 500 mL of a dissolution fluid pharmaceutical composition with 500 mL of a dissolution ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an fluid ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some Apparatus 2 ( Paddle Apparatus) rotating at 50 rpm . In some embodiments , at least about 90 % of the 5HT B /12 receptor embodiments , at least about 88 % of the antiemetic is 50 agonist is released within about 30 minutes following con released within about 60 minutes following contact of the tact of the pharmaceutical composition with 500 mL of a pharmaceutical composition with 500 mL of a dissolution dissolution fluid (0 . 1N HC1, pH 1. 1 ) at 37 + / - 0 . 5° C . as fluid (0 . 1N HC1, pH 1 . 1) at 37 + / - 0 .5° C . as measured by an measured by an Apparatus 2 (Paddle Apparatus ) rotating at Apparatus 2 (Paddle Apparatus) rotating at 50 rpm . In some 50 rpm . In some embodiments , at least about 91 % of the embodiments , at least about 94 % of the antiemetic is 55 5HT B receptor agonist is released within about 45 min released within about 60 minutes following contact of the utes following contact of the pharmaceutical composition pharmaceutical composition with 500 mL of a dissolution with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at fluid ( 0 .1N HC1, pH 1. 1) at 37 + / - 0 .5° C . as measured by an 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle Appa Apparatus 2 ( Paddle Apparatus) rotating at 50 rpm . In some ratus ) rotating at 50 rpm . In some embodiments , at least embodiments , at least about 100 % of the antiemetic is 60 about 93 % of the 5HT B / D receptor agonist is released released within about 90 minutes following contact of the within about 45 minutes following contact of the pharma pharmaceutical composition with 500 mL of a dissolution ceutical composition with 500 mL of a dissolution fluid fluid ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an ( 0 . 1N HCI, pH 1 . 1 ) at 37 + / - 0 . 5º C . as measured by an Apparatus 2 (Paddle Apparatus ) rotating at 250 rpm . In some Apparatus 2 (Paddle Apparatus) rotating at 50 rpm . In some cases the antiemetic is promethazine or a pharmaceutically 65 embodiments , at least about 92 % of the 5HTB/ 1 receptor acceptable salt thereof. In some cases the promethazine salt agonist is released within about 60 minutes following con is promethazine chloride . tact of the pharmaceutical composition with 500 mL of a US 10 , 179 , 109 B2 61 dissolution fluid (0 . 1N HC1, pH 1 .1 ) at 37 + / - 0 .5º C . as mL of a dissolution fluid ( 0 . 1N HC1, pH 1. 1) at 37 + / - 0 .5° C . measured by an Apparatus 2 (Paddle Apparatus ) rotating at as measured by an Apparatus 2 (Paddle Apparatus ) rotating 50 rpm . In some embodiments , at least about 94 % of the at 50 rpm . In some embodiments, after storage at 40° C . for 5HT16 /12 receptor agonist is released within about 60 min - 1 month at least about 74 % of the antiemetic is released utes following contact of the pharmaceutical composition 5 within about 30 minutes following contact of the pharma with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at ceutical composition with 500 mL of a dissolution fluid 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - (0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an ratus ) rotating at 50 rpm . In some embodiments , at least Apparatus 2 ( Paddle Apparatus ) rotating at 50 rpm . In some about 97 % of the 5HTB12 receptor agonist is released embodiments , after storage at 40° C . for 1 month at least within about 90 minutes following contact of the pharma- 10 about 84 % of the antiemetic is released within about 30 ceutical composition with 500 mL of a dissolution fluid minutes following contact of the pharmaceutical composi (0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an tion with 500 mL of a dissolution fluid (0 . 1N HC1, pH 1 . 1) Apparatus 2 (Paddle Apparatus ) rotating at 250 rpm . In some at 37 + / - 0 .5º C . as measured by an Apparatus 2 (Paddle embodiments , at least about 98 % of the 5HT1B / receptor Apparatus ) rotating at 50 rpm . In some embodiments , after agonist is released within about 90 minutes following con - 15 storage at 40° C . for 1 month at least about 80 % of the tact of the pharmaceutical composition with 500 mL of a antiemetic is released within about 45 minutes following dissolution fluid ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 .5° C . as contact of the pharmaceutical composition with 500 mL of measured by an Apparatus 2 (Paddle Apparatus ) rotating at a dissolution fluid ( 0 . 1N HCI, PH 1 . 1 ) at 37 + / - 0 . 5° C . as 250 rpm . In some cases the 5HT1B /10 receptor agonist is a measured by an Apparatus 2 (Paddle Apparatus ) rotating at triptan or a pharmaceutically acceptable salt thereof. In some 20 50 rpm . In some embodiments , after storage at 40° C . for 1 cases the triptan is sumatriptan or a pharmaceutically accept - month at least about 89 % of the antiemetic is released within able salt thereof. In some cases the pharmaceutically accept- about 45 minutes following contact of the pharmaceutical able salt of sumatriptan is sumatriptan succinate . composition with 500 mL of a dissolution fluid (0 . 1N HCI, In some embodiments , the dissolution profile is measured pH 1 . 1 ) at 37 + / - 0 .5º C . as measured by an Apparatus 2 after storage at 40° C . for 1 month . In some embodiments , 25 (Paddle Apparatus ) rotating at 50 rpm . In some embodi after storage at 40° C . for 1 month at least about 35 % of the ments , after storage at 40° C . for 1 month at least about 84 % antiemetic is released within about 5 minutes following of the antiemetic is released within about 60 minutes fol contact of the pharmaceutical composition with 500 mL of lowing contact of the pharmaceutical composition with 500 a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as mL of a dissolution fluid ( 0 . 1N HC1, PH 1 . 1 ) at 37 + / - 0 . 5° C . measured by an Apparatus 2 (Paddle Apparatus ) rotating at 30 as measured by an Apparatus 2 (Paddle Apparatus ) rotating 50 rpm . In some embodiments , after storage at 40° C . for 1 at 50 rpm . In some embodiments , after storage at 40° C . for month at least about 43 % of the antiemetic is released within 1 month at least about 88 % of the antiemetic is released about 5 minutes following contact of the pharmaceutical within about 60 minutes following contact of the pharma composition with 500 mL of a dissolution fluid ( 0 . 1N HC1 , ceutical composition with 500 mL of a dissolution fluid pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an Apparatus 2 35 ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an ( Paddle Apparatus ) rotating at 50 rpm . In some embodi- Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some ments, after storage at 40° C . for 1 month at least about 54 % embodiments , after storage at 40° C . for 1 month at least of the antiemetic is released within about 10 minutes fol - about 99 % of the antiemetic is released within about 90 lowing contact of the pharmaceutical composition with 500 minutes following contact of the pharmaceutical composi mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5° C . 40 tion with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) as measured by an Apparatus 2 (Paddle Apparatus ) rotating at 37 + / - 0 . 5° C . as measured by an Apparatus 2 ( Paddle at 50 rpm . In some embodiments , after storage at 40° C . for Apparatus ) rotating at 250 rpm . In some cases the antiemetic 1 month at least about 64 % of the antiemetic is released is promethazine or a pharmaceutically acceptable salt within about 10 minutes following contact of the pharma thereof. In some cases the promethazine salt is promethazine ceutical composition with 500 mL of a dissolution fluid 45 chloride . In some embodiments , after storage at 40° C . for ( 0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an 1 month at least about 47 % of the 5HT3/ 12 receptor agonist Apparatus 2 ( Paddle Apparatus ) rotating at 50 rpm . In some is released within about 5 minutes following contact of the embodiments , after storage at 40° C . for 1 month at least pharmaceutical composition with 500 mL of a dissolution about 63 % of the antiemetic is released within about 15 fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an minutes following contact of the pharmaceutical composi- 50 Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . In some tion with 500 mL of a dissolution fluid (0 . 1N HC1, pH 1 . 1 ) embodiments , after storage at 40° C . for 1 month at least at 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle about 60 % of the 5HTB/ D receptor agonist is released Apparatus ) rotating at 50 rpm . In some embodiments , after within about 5 minutes following contact of the pharmaceu storage at 40° C . for 1 month at least about 73 % of the tical composition with 500 mL of a dissolution fluid (0 . 1N antiemetic is released within about 15 minutes following 55 HCl, pH 1 . 1 ) at 37 + / - 0 . 5º C . as measured by an Apparatus contact of the pharmaceutical composition with 500 mL of 2 ( Paddle Apparatus ) rotating at 50 rpm . In some embodi a dissolution fluid (0 .1N HC1, pH 1 .1 ) at 37 + / - 0 . 5º C . as ments , after storage at 40° C . for 1 month at least about 62 % measured by an Apparatus 2 (Paddle Apparatus ) rotating at of the 5HT 16 /12 receptor agonist is released within about 10 50 rpm . In some embodiments , after storage at 40° C . for 1 minutes following contact of the pharmaceutical composi month at least about 68 % of the antiemetic is released within 60 tion with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) about 20 minutes following contact of the pharmaceutical at 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle composition with 500 mL of a dissolution fluid ( 0 . 1N HCI, Apparatus ) rotating at 50 rpm . In some embodiments, after pH 1. 1) at 37 + / - 0 .5º C . as measured by an Apparatus 2 storage at 40° C . for 1 month at least about 76 % of the ( Paddle Apparatus ) rotating at 50 rpm . In some embodi- 5HT B receptor agonist is released within about 10 min ments, after storage at 40° C . for 1 month at least about 79 % 65 utes following contact of the pharmaceutical composition of the antiemetic is released within about 20 minutes fol- with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at lowing contact of the pharmaceutical composition with 500 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa US 10 , 179 , 109 B2 63 64 ratus ) rotating at 50 rpm . In some embodiments , after storage at 40° C . for 1 month at least about 98 % of the storage at 40° C . for 1 month at least about 69 % of the 5HT B receptor agonist is released within about 90 min 5HT1B / id receptor agonist is released within about 15 min - utes following contact of the pharmaceutical composition utes following contact of the pharmaceutical composition with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at 5 37 + / - 0 .5° C . as measured by an Apparatus 2 (Paddle Appa 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - ratus ) rotating at 250 rpm . In some cases the 5HTB/ 1D ratus ) rotating at 50 rpm . In some embodiments, after receptor agonist is a triptan or a pharmaceutically acceptable storage at 40° C . for 1 month at least about 81 % of the salt thereof. In some cases the triptan is sumatriptan or a 5HTB/ 12 receptor agonist is released within about 15 min pharmaceutically acceptable salt thereof. In some cases the utes following contact of the pharmaceutical composition 10 pharmaceutically acceptable salt of sumatriptan is sumatrip with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at tan succinate . 37 + / - 0 . 5º C . as measured by an Apparatus 2 (Paddle Appa In some cases, the antiemetic disclosed herein dissolves at ratus ) rotating at 50 rpm . In some embodiments , after a slower rate than the 5HT, BI receptor agonist disclosed storage at 40° C . for 1 month at least about 74 % of the herein . In some cases , the antiemetic is characterized by less 5HT , B /12 receptor agonist is released within about 20 min - 15 dissolution than the 5HT , BU receptor agonist after 5 min utes following contact of the pharmaceutical composition utes , after 10 minutes , after 15 minutes, after 20 minutes, or with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at after 30 minutes following contact of the pharmaceutical 37 + / - 0 .5º C . as measured by an Apparatus 2 (Paddle Appa - composition with 500 mL of a dissolution fluid ( 0 . 1N HCI, ratus ) rotating at 50 rpm . In some embodiments , after pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an Apparatus 2 storage at 40° C . for 1 month at least about 85 % of the 20 (Paddle Apparatus ) rotating at 50 rpm . 5HTB/ 12 receptor agonist is released within about 20 min - In some embodiments , dissolution of less than all of the utes following contact of the pharmaceutical composition agent disclosed herein occurs in about 1 minute to about 90 with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at minutes ( e . g . , dissolution of about 45 % , about 50 % , about 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - 55 % , about 60 % , about 65 % , about 70 % , about 75 % , about ratus ) rotating at 50 rpm . In some embodiments , after 25 80 % , about 85 % , about 90 % , about 91 % , about 92 % , about storage at 40° C . for 1 month at least about 80 % of the 93 % , about 94 % , about 95 % , about 96 % , about 97 % , about 5HT 16 / 12 receptor agonist is released within about 30 min 98 % , about 99 % , about 99. 5 % or 99 . 9 % of an agent) . utes following contact of the pharmaceutical composition Stability with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at In some embodiments , the pharmaceutical composition 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - 30 disclosed herein is stable for at least about : 30 days, 60 days , ratus ) rotating at 50 rpm . In some embodiments, after 90 days , 6 months, 1 year, 18 months , 2 years, 3 years , 4 storage at 40° C . for 1 month at least about 88 % of the years , or 5 years , for example about 80 % - 100 % such as 5HT1B / 12 receptor agonist is released within about 30 min - about: 80 % , 90 % , 95 % , or 100 % of each active pharmaceu utes following contact of the pharmaceutical composition tical agent in the pharmaceutical composition is stable , e . g . , with 500 mL of a dissolution fluid (0 .1N HCl, pH 1. 1) at 35 as measured by High Performance Liquid Chromatography 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - (HPLC ) such as the HPLC method in Example 7 . In some ratus ) rotating at 50 rpm . In some embodiments, after embodiments , about 80 % - 100 % ( e .g . , about: 90 % - 100 % or storage at 40° C . for 1 month at least about 84 % of the 95 - 100 % ) of a 5HT1B /1D receptor agonist ( e . g ., triptan 5HT1B / 10 receptor agonist is released within about 45 min - such as sumatriptan ) or a pharmaceutically acceptable salt utes following contact of the pharmaceutical composition 40 thereof ( e . g . , sumatriptan succinate ) in the pharmaceutical with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at composition disclosed herein is stable for at least about: 30 , 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - 60 , 90 , 180 , 360 , 540 , or 720 days, for example greater than ratus ) rotating at 50 rpm . In some embodiments , after 90 days, which can be measured by HPLC such as the storage at 40° C . for 1 month at least about 91 % of the method in Example 7 . In some embodiments , about: 80 % , 5HT B / 1 receptor agonist is released within about 45 min - 45 85 % , 90 % , 95 % , or 100 % ( e . g ., about 95 % of the 5HT, BILD utes following contact of the pharmaceutical composition receptor agonist ( e . g . , triptan such as sumatriptan ) or the with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at pharmaceutically acceptable salt thereof ( e . g ., sumatriptan 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa succinate ) is stable for 30 days or more , which can be ratus ) rotating at 50 rpm . In some embodiments , after measured by HPLC such as the method in Example 7 . In storage at 40° C . for 1 month at least about 86 % of the 50 some embodiments, about 80 % - 100 % ( e . g . , about: 90 % 5HTB/ 12 receptor agonist is released within about 60 min 100 % or 95 - 100 % ) of an antiemetic ( e . g . promethazine or a utes following contact of the pharmaceutical composition pharmaceutically acceptable salt thereof such as prometh with 500 mL of a dissolution fluid (0 . 1N HC1, pH 1. 1 ) at azine hydrochloride ) in the pharmaceutical composition 37 + / - 0 .5º C . as measured by an Apparatus 2 (Paddle Appa - disclosed herein is stable for at least about: 30 , 60 , 90 , 180 , ratus ) rotating at 50 rpm . In some embodiments , after 55 360 , 540 , or 720 days , for example greater than 90 days , storage at 40° C . for 1 month at least about 93 % of the which can be measured by HPLC such as the method in 5HT B / 1 receptor agonist is released within about 60 min - Example 7 . In some embodiments , about: 80 % , 85 % , 90 % , utes following contact of the pharmaceutical composition 95 % , or 100 % ( e . g . , about 100 % ) of the antiemetic ( e . g . with 500 mL of a dissolution fluid ( 0 . 1N HC1, pH 1 . 1 ) at promethazine or a pharmaceutically acceptable salt thereof 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - 60 such as promethazine hydrochloride ) is stable for 30 days or ratus ) rotating at 50 rpm . In some embodiments , afterm ore , which can be measured by HPLC such as the method storage at 40° C . for 1 month at least about 96 % of the in Example 7 . 5HT , B / receptor agonist is released within about 90 min - Methods of Treatment utes following contact of the pharmaceutical composition In some aspects , a method is provided for treating pain , with 500 mL of a dissolution fluid (0 . 1N HC1, pH 1 . 1 ) at 65 comprising administering to a subject in need thereof a 37 + / - 0 . 5° C . as measured by an Apparatus 2 (Paddle Appa - pharmaceutical composition comprising a therapeutically ratus ) rotating at 250 rpm . In some embodiments , after effective amount of each of a 5HT1B / 10 receptor agonist and US 10 , 179 , 109 B2 65 66 an antiemetic disclosed herein . In some embodiments, the surgery or postoperative inflammation . In some embodi 5HTB/ 12 receptor agonist is a triptan . In some embodi ments , a pharmaceutical composition defined herein is given ments, the antiemetic is promethazine or a pharmaceutically at the time of pupil dilation . In some embodiments , the acceptable salt thereof. In some aspects , a method is pro pharmaceutical composition disclosed herein is for use in vided for treating pain , comprising administering to a sub - 5 treatment of a photophobia wherein the treatment is pro ject in need a pharmaceutical composition that includes a phylactic . In instances cases , the pharmaceutical composi plurality of first particulates comprising a therapeutically tion disclosed herein is for use in treatment of a photophobia effective amount of a 5HT B / 2 receptor agonist or a phar - wherein the treatment is preventative . In some cases , pre maceutically acceptable salt thereof; and a plurality of ventative treatment is to decrease migraine frequency . In second particulates comprising a therapeutically effective 10 some embodiments, the pharmaceutical composition dis amount of an antiemetic . In some embodiments , the closed herein is for use in treatment of a photophobia 5HT15 /10 receptor agonist is a triptan . In some embodi- wherein the treatment is preemptive. In some cases, pre ments , the antiemetic is promethazine or a pharmaceutically emptive treatment is used when a photophobia trigger is acceptable salt thereof. time- limited or predictable . In some embodiments , the phar In some aspects , a method is provided for treating pain , 15 maceutical composition disclosed herein is for use in treat comprising administering to a subject in need a pharmaceu - ment of a photophobia wherein the treatment is acute . In tical composition that includes a plurality of particulates some cases, treatment is to stop or prevent progression of a comprising a therapeutically effective amount of a triptan or photophobia . In some cases , acute treatment is initiated a pharmaceutically acceptable salt thereof; and a powder during an attack to relieve pain . In some cases , a pharma comprising a therapeutically effective amount of an anti - 20 ceutical composition disclosed here is used for preventive , emetic . In some aspects, a method is provided for treating acute , and / or preemptive treatment for photophobia . pain , comprising administering to a subject in need a phar- In some embodiments, the pharmaceutical composition maceutical composition that includes a plurality of particu disclosed herein is for use in treatment of a headache lates comprising a therapeutically effective amount of an wherein the treatment is prophylactic . In instances cases , the antiemetic ; and a powder comprising a therapeutically effec - 25 pharmaceutical composition disclosed herein is for use in tive amount of a triptan or a pharmaceutically acceptable salt treatment of a headache wherein the treatment is preventa thereof. In some aspects , a method is provided for treating tive . In some cases, preventative treatment is to decrease pain , comprising administering to a subject in need a phar - migraine frequency . In some embodiments , the pharmaceu maceutical composition that includes a first powder com tical composition disclosed herein is for use in treatment of prising a therapeutically effective amount of an antiemetic ; 30 a headache wherein the treatment is preemptive . In some and a second powder comprising a therapeutically effective cases , preemptive treatment is used when a headache trigger amount of a triptan or a pharmaceutically acceptable salt is time - limited or predictable . In some embodiments, the thereof. pharmaceutical composition disclosed herein is for use in In some embodiments , a plurality of particulates treatment of a headache wherein the treatment is acute . In described herein are encapsulated into discrete units . In 35 some cases , treatment is to stop or prevent progression of a some embodiments , the discrete units are capsules or pack - migraine. In some cases, acute treatment is initiated during ets . In some embodiments , a method is provided for treating an attack to relieve pain . In some cases , a pharmaceutical pain , comprising administering the capsule or the packet composition disclosed here is used for preventive , acute , containing a plurality of particulates as described herein . In and / or preemptive treatment for a headache . some embodiments , a method of treating pain includes 40 In some embodiments , the pharmaceutical composition breaking the capsule or the packet to sprinkle the plurality of disclosed herein is used for treatment of chronic migraine particulates on food or soft foods and swallowed without headache . In some embodiments , the pharmaceutical com chewing. In some embodiments , the plurality of particulates position disclosed herein is for use in treatment of a migraine is administered through an enteral feeding tube. In some headache wherein the treatment is prophylactic . In some embodiments , the pain is associated with a headache , such 45 embodiments , the pharmaceutical composition disclosed as a chronic headache , cluster headache or a migraine herein is for use in treatment of a migraine headache wherein headache . In one embodiment the migraine headache occurs the treatment is of an acute migraine headache . In some with aura . In some embodiments , the migraine headache is embodiments , the pharmaceutical composition disclosed accompanied by symptoms, including , but not limited to herein is for use in treatment of a migraine wherein the vomiting , nausea , photophobia , phonophobia , or osmopho - 50 treatment is of a chronicmigraine headache . In some bia . embodiments , the pharmaceutical composition disclosed In some embodiments , the photophobia is characterized herein is for use in treatment of a migraine headache with an by light sensitivity or light hypersensitivity . In some cases , aura . In some embodiments , the pharmaceutical composi the photophobia is caused by acute iritis or uveitis (inflam - tion disclosed herein is for use in treatment of a migraine mation inside eye ) , burns to the eye , corneal abrasion , 55 headache without an aura . In some embodiments , the phar corneal ulcer, drug side effects , excessive wearing of contact maceutical composition disclosed herein is for use in treat lenses, or wearing badly - fitted contact lenses, eye disease , ment of a cluster headache . In some embodiments , the injury, or infection (such as chalazion , episcleritis , glau pharmaceutical composition disclosed herein is for use in coma) , eye testing when the eyes have been dilated , men treatment of nausea or vomiting. In some embodiments , the ingitis , migraine headache , or recovery from eye surgery . In 60 pharmaceutical composition disclosed herein is for use in some cases , the photophobia is associated with a migraine . treatment of nausea and vomiting. In some embodiments , In some cases, the photophobia is associated with nausea the pharmaceutical composition disclosed herein is for use and vomiting . In some cases, the photophobia is associated in treatment of nausea associated with a headache or vom with nausea or vomiting . iting associated with a headache . In some embodiments, the In some embodiments , a pharmaceutical composition 65 pharmaceutical composition disclosed herein is for use in defined herein is for the reduction of ocular pain , itching, treatment of nausea associated with a headache and vomit burning , and / or stinging , and /or photophobia , following a ing associated with a headache . In some embodiments , the US 10 , 179 , 109 B2 67 68 pharmaceutical composition disclosed herein is for use in dose of a pharmaceutical composition described herein over treatment of nausea associated with a migraine headache ora 24 hour period does not exceed 200 mg. In some embodi vomiting associated with a migraine headache . In some ments, a maximum single dose of a pharmaceutical compo embodiments , the pharmaceutical composition disclosed sition described herein dose does not exceed 50 mg in a herein is for use in treatment of nausea associated with a 5 subject with mild to moderate hepatic impairment . migraine headache and vomiting associated with a migraine In some embodiments , a pharmaceutical composition headache . described herein comprising sumatriptan succinate and pro In some embodiments , the pharmaceutical composition methazine hydrochloride is administered to a subject at disclosed herein ( e . g ., capsule ) does not completely disin - about every 12 to about 24 hours , about every 12 hours , or tegrate in mouth within about 1 , about 2 , about 3 , about 4 , 10 about every 24 hours . In some embodiments , a pharmaceu about 5 , about 6 , about 7 , about 8 , about 9 , about 10 , about tical composition described herein comprising sumatriptan 11 , about 12 , about 13 , about 14 , about 15 , about 16 , about succinate and promethazine hydrochloride is administered 17 , about 18 , about 19 or about 20 minutes . In some to a subject at about every 4 to about every 6 hours. In some embodiments , the pharmaceutical composition disclosed embodiments , a pharmaceutical composition described herein is not a film . In some embodiments , the pharmaceu - 15 herein comprising sumatriptan succinate and promethazine tical composition disclosed herein is not for buccal admin - hydrochloride is administered to a subject at about every 8 istration . In some embodiments , the pharmaceutical com - to about every 12 hours. In some embodiments , a pharma position disclosed herein ( e . g ., capsule ) dissolves in stomach ceutical composition described herein comprising sumatrip or intestine . tan succinate and promethazine hydrochloride is adminis In some embodiments , the subject is a mammal, e . g ., a 20 tered once , twice or three times daily . In some embodiments , human , mouse , rat, guinea pig , dog , cat, horse , cow , pig , or a pharmaceutical composition described herein comprising non -human primate , such as a monkey , chimpanzee or sumatriptan succinate and promethazine hydrochloride is baboon . In some embodiments , the subject is a human . In administered no more than twice daily . In some embodi some embodiments , the subject administered a pharmaceu - ments , a second dose of the pharmaceutical composition tical composition as described herein is about 55 years of 25 disclosed herein comprising sumatriptan succinate and pro age or older , about 60 years of age or older, about 65 years methazine hydrochloride is administered after response to a of age or older , or about 70 years of age or older. In some first dose in a subject. In some embodiments , doses after a embodiments , the subject administered a pharmaceutical first dose are separated by at least 2 hours . In some embodi composition described herein is 18 years of age or older. In ments , the maximum dose of the pharmaceutical composi some embodiments , the subject is between 35 and 45 years 30 tion disclosed herein comprising sumatriptan succinate and of age . In some embodiments , the subject administered a promethazine hydrochloride over a 24 hour period does not pharmaceutical composition described herein has a history exceed 200 mg. In some embodiments , a maximum single of headaches . In some embodiments , the subject adminis - dose of the pharmaceutical composition disclosed herein tered a pharmaceutical composition described herein has a comprising sumatriptan succinate and promethazine hydro history of migraines . 35 chloride does not exceed 50 mg in a subject with mild to In some embodiments , a pharmaceutical composition moderate hepatic impairment. In some embodiments , the described herein is administered to the subject ( e . g . , a frequency of dosing is determined or assessed by a profes patient ) at the time of onset of the migraine headache as s ional assessing the subject, the severity of the condition and needed by the subject ( e . g ., a patient) or as determined and expected duration of therapy . instructed by the physician . In some embodiments , the 40 In some aspects , a method is provided for treating pain subject administered a pharmaceutical composition comprises administering to a subject in need thereof a described herein suffers from adverse effects associated with pharmaceutical composition comprising a therapeutically triptan administration . Examples of adverse effects include effective amount of a triptan ; an antiemetic . In some nausea and / or vomiting, e . g ., associated with a migraine. In embodiments , the pain is a headache . In some embodiments , some embodiments , the pharmaceutical composition 45 the headache is a migraine headache. In some embodiments , described herein reduces or prevents unwanted side effects the headache is a cluster headache . In some embodiments , associated with injectable or tablet triptan therapy , includ - the method is also useful for treating photophobia . In some ing, flushing , sweating , vertigo , fatigue , tingling , drowsi - embodiments , the photophobia is associated with migraine ness , dizziness, dry mouth , heartburn , abdominal pain , headache . In some embodiments , a method for treating abdominal cramps, weakness , feeling of warmth or cold - 50 headache comprises : administering to a subject in need ness , bitter taste from tablets and nasal sprays, and local thereof a pharmaceutical composition comprising a thera burning from injection site . peutically effective amount of sumatriptan or a pharmaceu In some embodiments , a pharmaceutical composition tically acceptable salt thereof; promethazine or a pharma described herein is administered to a subject at about every ceutically acceptable salt thereof. In some embodiments , a 12 to about 24 hours , about every 12 hours , or about every 55 method for treating headache comprises administering to a 24 hours. In some embodiments , a pharmaceutical compo - subject in need thereof a pharmaceutical composition com sition described herein is administered to a subject at about prising : a therapeutically effective amount of sumatriptan or every 8 to about every 12 hours . In some embodiments , a a pharmaceutically acceptable salt thereof; promethazine or pharmaceutical composition described herein is adminis - a pharmaceutically acceptable salt thereof. tered once , twice or three times daily . In some embodiments , 60 Methods of Manufacture a pharmaceutical composition described herein is adminis - In some embodiments , a method is provided for manu tered no more than twice daily . In some embodiments , a facturing a pharmaceutical composition as described herein . second dose of the pharmaceutical composition disclosed In some embodiments , the pharmaceutical composition as herein is administered after response to a first dose in a described herein is prepared by standard techniques and subject. In some embodiments , doses after a first dose of a 65 using standard equipment known to the skilled person . pharmaceutical composition described herein are separated In some embodiments , a plurality of first particulates by at least 2 hours. In some embodiments , the maximum comprising an active pharmaceutical ingredient such as US 10 , 179 ,109 B2 69 70 triptan ( e . g . , sumatriptan or a pharmaceutically acceptable or without a binder and / or excipients , is applied to the inert salt thereof) are prepared by a process method comprising core while applying the dry powder until the desired potency forming small spherical pellets with a narrow size distribu is achieved . When the desired potency has been achieved , tion . In some embodiments , the first particulates comprise a the pellets may be seal coated to improve their strength , and non - pharmaceutically active ingredient selected from the 5 are then dried to the desired moisture content. Any oversized group consisting of microcrystalline cellulose , dicalcium or undersized product is removed by sieving , and the result phosphate , calcium sulfate , talc , an alkali metal stearate , ing pellets are narrow in size distribution . silicon dioxide , calcium carbonate , and any combinations thereof. When the desired particle size has been achieved , In some embodiments , the second particulates obtained the pellets may be seal coated to improve their strength , and 10 are transferred to a vector fluid bed dryer. In some embodi are then dried to the desired moisture content. Any oversized ments , the dryer presets drying parameters such as, but not or undersized product is removed by sieving , and the result limited to , inlet temperature of between 55 -65° C . or 70° C . , ing pellets are narrow in size distribution . In some embodi outlet temperature of between 20 - 30° C . or 30 -40° C ., ments , the first particulates are sifted through a nest of product temperature ofbetween 20 - 45° C . or 21- 42° C . , total screens of size # 40 to # 140 to further determine particle size 1615 time of 45 -75 minutes, fan at 180 - 740 lpm (liters per range . In some embodiments , the plurality of particulates is minute ). In some embodiments , loss on drying ( LOD ) values mixed with a coating material. In one example , the coating following the drying step is between 1. 5 - 3 % . In some is performed by spraying . embodiments , the second particulates are sifted through a In some embodiments , the plurality of second particulates nest of screens of size # 14 to # 20 to further determine comprising an active pharmaceutical ingredient such as an 20 particle size range . In some embodiments , the plurality of antiemetic are prepared by a process method comprising particulates is mixed with a coating material. In one layering an active ingredient onto the outside of an inert example , the coating is performed by spraying . core . In some embodiments , the inert core is a sugar sphere . In some embodiments , the inert core is a microcrystalline EXAMPLES cellulose sphere . 25 In some embodiments , a solution or suspension compris . The following examples are offered by way of illustration ing an antiemetic (e .g ., promethazine or a pharmaceutically and not by way of limitation . acceptable salt thereof ) is layered onto the inert core via spraying . Spraying process include top spray , tangential Example 1 . spray , bottom spray (Wurster process ) or rotor process , 30 depending from which direction the particles are being Preparation of Sumatriptan Particulates sprayed . In some embodiments , the solution or suspension layering is done by using bottom spray (Wurster process ) . In Sumatriptan Succinate Milling some embodiments , the solution or suspension comprising jet mill was set up with guard and covers permanently an antiemetic ( e . g . , promethazine or a pharmaceutically 35 mounted in place and a cover on the feeder inlet. Setting on acceptable salt thereof) further comprises pharmaceutically the powder feeder was adjusted to deliver 500 g /min ( 200 acceptable excipients . In some embodiments , the pharma- g /min ) of powder. Sumatriptan succinate USP ( 500 g ) was ceutically acceptable excipients comprise a disintegrant. In placed in the powder feeder. The air was energized and the some embodiments, the pharmaceutically acceptable excipi air inlet pressure was to 80 psig by using the regulator on the ents comprise hydroxypropyl methylcellulose (HPMC ) . In 40 utility manifold . The grind air valve was approximately set some embodiments , the pharmaceutically acceptable excipi- to 50 psig and the feed air valve was set to 50 psig by using ents comprise low substituted hydroxypropyl methylcellu - hand adjustable valves on the Micronizer table . The powder lose ( L -HPC ) . In some embodiments , the pharmaceutically feed was turned on and the milling process was started . The acceptable excipients comprise talc . In some embodiments , milled sumatriptan succinate was placed in a double lined the antiemetic ( e . g . , promethazine or a pharmaceutically 45 polyethylene bag sealed with a plastic bag tie . acceptable salt thereof ) is mixed with hydroxypropyl meth - Formation of Sumatriptan Pellets (Process Repeated 3 ylcellulose and dissolved in a pharmaceutically acceptable Times ) solvent ( i. e . , water ) followed by addition of low substituted A CPS - 30 insert (with a 45° rotor plate angle , steep baffles hydroxypropylmethylcellulose ( L -HPC ) talc , and any com - at position 1 and 3 , and atomizer set at middle position , binations thereof. In some embodiments , the resulting solu - 50 powder feeder , discharge drum ) was loaded with micronized tion /dispersion is sprayed onto an inert core . In some sumatriptan succinate ( 9 kg ) and microcrystalline cellulose embodiments , the particulates are dried to the desired ( 5 . 25 kg, Avicel PH101 ). The powder feeder was loaded residual moisture content once the desired potency has been with additional microcrystalline cellulose (0 .75 kg , Avicel achieved . In some embodiments , any oversized or under - PH101 ) . The powders were kept away from the rotary sized product is removed by sieving, and the resulting pellets 55 atomizer . Compress the CPS - 30 insert in place. On the are narrow in size distribution . CPS - 30 local panel, the air purge regulator was opened to In some embodiments , the active ingredient layer is 1 . 0 bar ( + 0 . 2 bar ) and the air regulator for the rotary applied by powder layering . In some embodiments , the atomizer was opened until the speed reached and stabilized powder layer comprises only the active ingredient. In some at 5000 rpm ( £300 um ) . The process was switched to embodiments , the powder layer comprises the active ingre - 60 " spraying ” at 500 g /min . The rotor drive was started and dient and pharmaceutically acceptable excipients . In some adjusted to a speed of 280 rpm ( + 20 rpm ) when the process embodiments , the pharmaceutically acceptable excipients air volume reached 14 CFM . The 500 g /min was continued comprise binders, lubricants , inert fillers , and the like . for 3 minutes and was followed by the steps below : Powder layering may be conducted using a wide variety of The spray rate was reduced to 200 g /min ( + 10 g /min ) at processing techniques . In some embodiments , the powder 65 3 minutes ; layering is done by rotary fluidized bed . A pharmaceutically . The rotor speed was increased to 300 rpm after 2 . 5 kg of acceptable liquid , which may be water, organic solvent, with water has been sprayed ; and US 10 , 179 , 109 B2 71 72 The spray rate was reduced to 160 g /min ( - 10 g /min ) after added . The mixture was then mixed for a minimum of 10 2 . 5 kg of water has been sprayed . minutes . The weight of the promethazine solution /dispersion The pellets were collected from the CPS -30 sample port. was recorded . When the wet pellet size has been visually observed to be Preparation of the Top Coating Solution approximately within range of 200 to 400 um , with a target 5 Purified water , US ! , (21 . 69 kg) was weighed in an appro priately sized container . A propeller mixer was started . wet pellet size of approximately 250 um , the powder feeder While mixing , Opadry II Complete film coating system was engaged and the additional microcrystalline cellulose ( 3 . 83 kg , 85F18422 white powder) was slowly added and was applied at 250 g /min ( 20 g /min ). The powder feeder the mixing was continued for about 30 minutes . The weight was stopped when the powder in the powder feeder was 10 of the top coating solution was recorded . depleted . The spraying was also stopped . Spraying of Drug Layer Dispersion /Solution The pellets were tumbled for 2 - 4 minutes and were then A dip tube was secured to the side of the container and a discharged in a discharge vessel. gap was left between the bottom of the dip tube and the Drying of Sumatriptan Pellets bottom of the container. Fluid bed with 18 " Wurster insert The pellets were dried until the temperature reached 52° 15 with HS Collar was preheated for at least 10 minutes . C . using the following settings : The Suglets® Sugar Sphere (25 kg , PF010 710 /850 Suglets ) were placed into the Fluid bed with 18 " Wurster Fan Speed # 3 setting (highest ) insert and spraying the drug layering dispersion / solution was Bypass / Inlet Temperature 60 = 10° C . started using the initial target processing conditions below : Dew Point 10 3° C . 20 Total Air Flow 1500 300 CFM Inlet Temperature 60 = 30° C . Inlet Air Dew Point 10 + 5° C . The residual moisture was checked . The drying process Air Volume 600 - 12000 CFM Spray Rate 100 - 300 + 50 g /min was stopped when the moisture was less than 2 % (if mois Atomization Air Pressure 2 . 5 + 1 . 0 bar ture was more than 2 % the drying process was continued for Product Temperature Range 45 + 10° C . an additional 10 minutes ) . Shake Interval /Duration 30 sec /5 sec The pellets were discharged in a double lined polyethyl ene lined container. Agglomeration was checked using Standard # 18 mesh Particles Size 30 screen ( or as appropriate ). Upon completion of the spraying The size of the particles was assessed using a Ro - Tap® of the drug layering , Purified water, USP , ( 0 . 1 kg ) was added fitted with standard U . S . mesh screen and a pan ( 5 minute to the drug layering solution container and the lines were shake) . purged using the same parameters used above . The drug The discharged material was sieve cut using a U . S . layering solution line and dip tube were removed . Standard # 40 mesh screen and U . S . Standard # 140 mesh 35 Spraying of the Top Coating Solution screen . The drug layering solution container was removed and Blending replaced with the top coat solution container. A new dip tube The sumatriptan succinate pellets (potency 60 % , Sieve was set up and connected to a spray wand . After the pellets Cut 40 / 140 ) were loaded in a V -blender . The pellets were were dried for not less than 1 minute , the top coating blended for 4 minutes . The pellets were then discharged in 40 solution was sprayed using the initial target processing a tared double polyethylene lined container . conditions below : Example 2 . Inlet Temperature 60 = 30° C . Inlet Air Dew Point 10 + 5° C . Preparation of Promethazine Particulates 45 Air Volume 600 - 12000 CFM Atomization Air Pressure 2 . 5 + 1 . 0 bar Preparation of the Drug Layering Solution Product Temperature Range 50 + 10° C . Purified water , USP, (65 kg ) was weighed in an appro Shake Interval /Duration 30 sec / 5 sec priately sized container . A propeller mixer was started28 . 50 Agglomeration was checked using Standard # 14 mesh While mixing, promethazine hydrochloride , USP 38 (9 .38 screen ( or as appropriate ) . Upon completion of the spraying kg ) was added and mixed until a clear solution was obtained . of the top coat layer, Purified water , USP , ( 0 . 1 kg ) was added While mixing the solution , hydroxypropyl methylcellulose to the top coat solution container and the lines were purged ( 2 . 5 kg, Methocel E5 LV Premium ) was slowly added and using the same parameters used above and the pellet were the mixing was continued until a clearclear solutionsolution was obtainedobtained 5555 idried for a minimum of 5 minutes. ( about 30 minutes ) . Final Product Purified water, USP , ( 15 .47 kg ) was weighed in an appro - The finished product was discharged into a tared double priately sized container . A homogenizer was started . While polyethylene lined container. The final product was screened mixing , talc ( 0 . 47 kg , Pharma 400 USP ) was slowly added using Sweco U . S . Standard # 14 mesh and Sweco U . S . and the homogenizing was continued until the talc was 60 Standard # 20 mesh . uniformly dispersed . The homogenizer was replaced with an air mixer . While mixing the talc dispersion with the air Example 3 . mixer , low substituted hydroxypropyl cellulose NF (0 . 94 kg , LH -31 ) was slowly added and the mixing was continued Preparation of a Capsule Formulation until a uniform dispersion was obtained . 65 While mixing the promethazine /hydroxypropyl methyl- Sumatriptan particulates and promethazine particulates cellulose solution , the talc / L - HPC dispersion was slowly were generated as disclosed in Example 1 and Example 2 , US 10 , 179 , 109 B2 73 74 and then encapsulated together in a capsule . A list of TABLE 5 ingredients is provided in Table 1 and Table 2 . Coated Promethazine Particulates TABLE 1 Percent Quantity - Ingredients Uncoated Sumatriptan Particulates 5 ( w / w ) (mg ) Promethazine Hydrochloride 22. 3 50 Percent Quantity Sugar Sphere 59 . 4 133 . 2 Ingredients ( w / w ) (mg ) Hydroxypropyl methylcellulose (HPMC ) 5 . 9 13 . 2 2 . 2 5 60 Low substituted hydroxypropyl cellulose (L - HPC ) Sumatriptan succinate 126 10 Talc 1 . 1 2 . 4 Microcrystalline Cellulose 40 84 Opadry II ( top coat) 9 . 1 20 . 4 Sterile Water for Irrigation , USP qs Total 100 2 10 Total 100 224 . 2 TABLE 2 15 Sumatriptan (potency 60 % , Sieve Cut 40 / 140 ) particu lates ( 210u5 % mg ) and promethazine HC1 (potency 22. 3 % ) Coated Promethazine Particulates coated particulates (224 . 2 : 5 % mg) were encapsulated into Percent Quantity Size 0 capsules (Coni - Snap , White Opaque ). The capsules Ingredients ( w / w ) (mg ) 20 were packaged in opaque HDPE bottles . Formulation of Promethazine Hydrochloride 22. 3 25 capsules comprising sumatriptan and promethazine is as Sugar Sphere 59 . 4 66 . 6 described in Table 6 . Hydroxypropylmethylcellulose ( HPMC ) 5 . 9 6 . 6 Low substituted hydroxypropyl cellulose ( L -HPC ) 2 . 2 2 . 5 Talc 1 . 1 1 . 2 TABLE 6 Opadry II (top coat ) 9. 1 10 . 2 25 Sterile Water for Irrigation , USP Encapsulated Formulation Total 100 112. 1 Ingredient Percent w /w mg/ capsule Sumatriptan particulates 48 . 3 % 210 Sumatriptan (potency 60 % , Sieve Cut 40 / 140 ) particu - 30 Promethazine particulates 51 . 7 % 224 . 2 lates (210 + 5 % mg ) and promethazine HCl ( potency 22. 3 % ) coated particulates ( 112. 1 + 5 % mg) were encapsulated into Size 0 capsules (Coni - Snap , White Opaque ). The capsules Example 5 . were packaged in opaque HDPE bottles . Formulation of capsules comprising sumatriptan and promethazine is as 35 Dissolution Measurements by USP Basket Method described in Table 3 . Dissolution studies are conducted to measure the rates of TABLE 3 dissolution of active ingredients using a USP Apparatus 1 (Basket Apparatus) with a dissolution fluid of 900 ml Encapsulated Formulation de - aerated 0 .01 N HC1 ( i. e ., pH 2 . 0 ) at 37 . 0 + / - 0 .5° C . Ingredient Percent w / w Dissolution samples were analyzed by HPLC . Dissolution medium of 0 . 01N HC1 is prepared by mixing Sumatriptan particulates 65. 2 % 210 Promethazine particulates 34 . 8 % 112 . 1 well approximately 5 ml of concentrated ( 12N ) Hydrochlo ric Acid with 6 L of water . Stock promethazine HCl standard 45 solution is prepared by adding approximately 30 ml of dissolution medium to 14 . 0 mg of dried Promethazine Example 4 . Hydrochloride USP reference standard in a 50 ml volumetric flash , diluted to volume with dissolution media , and mixed Preparation of a Capsule Formulation 50 well . Working Standard Solution is prepared by first mixing well 14 .0 mg of Sumatriptan Succinate USP reference Sumatriptan particulates and promethazine particulates standard with approximately 60 ml of dissolution medium were generated as disclosed in Example 1 and Example 2 , and then pipetting 10 . 0 ml of Promethazine Hydrochloride and then encapsulated together in a capsule . A list of stock solution into the prepared Sumatriptan Succinate solu ingredients is provided in Table 4 and Table 5 . 55 tion . The resulting solution is diluted to volume with disso lution medium and mixed well. Nominal concentration for TABLE 4 Sumatriptan was 0 . 10 mg/ ml (as a free base ) and Prometh azine HCl is 0 .028 mg/ ml in the Sumatriptan Succinate and Uncoated Sumatriptan Particulates Promethazine HC1 Working Standard A and B . The label Percent Quantity 60 claim for Sumatriptan is as a free base and therefore the final Ingredients ( w / w ) (mg ) standard concentration is converted accordingly multiplying by the salt- to - base conversion factor : ( 295 . 40 /413 .49 ) . Sumatriptan succinate 60 126 The dissolution apparatus used is USP Apparatus 1 (Bas Microcrystalline Cellulose 40 84 ket) with a speed of 100 rpm at 37 . 0° C . 0 . 5° C . Dissolution Total 100 210 65 medium ( 900 ml) was Helium sparged for at least 10 minutes. N = 6 samples were tested , one per sinker and per vessel. At each time point of 5 , 15 , 30 , and 45 minutes , a 5 US 10 , 179 , 109 B2 75 76 ml aliquot from each dissolution vessel is filtered through a V = Volume of the sample removed from the vessel at 0 .45 um Nylon membrane syringe filter before HPLC analy the pull point (ml ) sis . LC = Label claim ( 90 mg or 90000 ug ) HPLC conditions: Flow rate : 1. 0 ml/min ; Injection Vol 100 = Conversion to percent ume : 5 uL ; Column Temperature : 40° C . ; Wavelengths: 254 5 Example 6 . nm ; Run Time: 7 minutes ; Mobile Phase A was 0 . 2 % TFA in Water , which was prepared by mixing well 2 .0 ml of trifluoroacetic acid with 1 L of water . Mobile Phase B : 0 . 2 % Dissolution Measurement by USP Paddle Method TFA in Acetonitrile , which was prepared by mixing well 2 . 0 Dissolution studies were conducted to measure the rates ml of trifluoroacetic acid to 1 L ofacetonitrile ; and Gradient 10 of dissolution of active ingredients using a USP Apparatus used was as follows in Table 6 . 2 ( Paddle Apparatus ) with a dissolution fluid of 500 ml de -aerated 0 . 1 N HCl (i . e ., pH 1. 1 ) at 37 . 0 + / - 0 .5° C . TABLE 7 . Dissolution samples were analyzed by HPLC . Dissolution medium of 0 . 1N HCl was prepared by mixing Time (minutes ) % A ( Buffer ) % B ( ACN ) 15 approximately 85 ml of concentrated (12N ) Hydrochloric Initial 90 10 Acid with 10 L of water . Stock promethazine HC1 standard 4 . 0 40 60 solution was prepared by adding approximately 30 ml of 4 . 1 90 10 dissolution medium to 25 . 0 mg of dried Promethazine 7 .0 90 10 Hydrochloride USP reference standard in a 50 ml volumetric 20 flash , diluted to volume with dissolution media , and mixed well . Working Standard Solution is prepared by first mixing Approximate Retention Times for sumatriptan and pro well 25 . 2 mg of Sumatriptan Succinate USP reference methazine are 2 . 8 minutes and 4 . 8 minutes respectively . standard with approximately 60 ml of dissolution medium Calculation . Calculations for percent release are con - and then pipetting 10 . 0 ml of Promethazine Hydrochloride methamulationducted using .the Cafollowing following 1formulas . Percent Release of n stock solution into the prepared Sumatriptan Succinate solu Promethazine (Profile ) : tion . The resulting solution is diluted to volume with disso lution medium and mixed well. Nominal concentration for Sumatriptan succinate was 0 . 252 mg/ ml and Promethazine n - 1 HC1 was 0 .05 mg/ ml . % Released = xCstdstdXd xD std X VA x 100 The dissolution apparatus used is USP Apparatus 2 4. Released- XXVc) + ?TEX ] ( )X 100 » (Paddle Apparatus ) with a speed of 50 rpm at 37 .0° C . £0 .5° C . Dissolution medium (500 ml) was Helium sparged for at least 10 minutes . N = 6 samples were tested . Sample time Where : point of 5 , 10 , 15 , 20 , 30 , 45 , 60 , and 90 minutes ( final time R = Peak area of Promethazine in the sample prepara point at 250 rpm ) . Filters : QLA 10 um in - line full flow 35 porous filter or equivalent; chromafil 1 . 0 um on - line glass tion fiber membrane filter or equivalent. R = Mean peak area of Promethazine in all Working18 Dissolution Procedure Standard A injections The dissolution apparatus was assembled and the paddle C .. = Working Standard A concentration of Promethaz - was positioned so that the distance between its lower edge ine Hydrochloride , adjusted for purity (ug / ml) 40 and the lower inner surface of the vessel is within 25 mm2 mm throughout the test. This step was repeated for each of V Volume of dissolution medium at the pull time (ml ) the six vessels . The speed (50 rpm ) and the temperature R = Peak area of Promethazine obtained from the ( 37 . 0° C . + 0 . 5° C . ) were set. 500 mL of 0 . 1N HCl solution sample preparation at the individual pull pointsnts were placed into each of the six vessels , previously degassed V = Volume of the sample removed from the vessel at us via helium purge, degassed using degasser or other suitable the pull point (ml ) means . The Dissolution medium was equilibrated to set temperature and the temperature of the dissolution medium LC =Label claim 25 mg or 25000 ug ) was checked with a thermometer or thermocouple before 100 = Conversion to percent starting the dissolution . Each of the six ( 6 ) capsules were Percent Release of Sumatriptan (Profile ) : accurately weighed and the weight was recorded . The dis 50U solution test was started . Each capsule was dropped with sinker into vessels noting the station assigned to each recorded capsule weight. The shaft was rotated at 50 rpm . Samples were withdrawn by dissolution autosampler at 5 , % Released = xCut « va )+ i E= 1 XCx Xv ]* ( _ )* 100 10 , 15 , 20 , 30 , 45 , 60 , and 90 minutes into HPLC vials , or 55 were withdraw manually . Filters (QLA 10 um in - line full flow porous filter or equivalent ; chromafil 1 . 0 um on - line Where : glass fiber membrane filter or equivalent) were utilized , R = Peak area of Sumatriptan in the sample preparation discarding at least the first 5 mL of the filtrate , and clear R = Mean peak area of Sumatriptan in all Working filtrate was transferred into HPLC vials . After withdrawing Standard A injections 60 samples at the 60 minute time point, the paddle rotation speed was increased to 250 rpm until the next time point of Csta Working Standard A concentration of Sumatrip 90 minutes . tan , succinate adjusted for purity and conversion to HPLC conditions: Flow rate: 1 . 0 ml/ min ; Injection Vol free base (ug /ml ) ume: 10 uL ; Column Temperature : 40° C . - 2° C .; Wave VFVolume of dissolution medium at the pull time (ml ) 65 lengths: 240 nm : Run Time: 7 minutes : Mobile Phase A was R : = Peak area of Sumatriptan obtained from the sample 0 . 2 % TFA in Water, which was prepared by mixing well 2 . 0 preparation at the individual pull points ml of trifluoroacetic acid with 1 L of water . Mobile Phase B : US 10 , 179 , 109 B2 77 78 0 .2 % TFA in Acetonitrile , which was prepared by mixing Calculation for subsequent sampling time points : well 2 . 0 ml of trifluoroacetic acid to 1 L of acetonitrile ; and Gradient used was as follows in Table 8 . Rn = TABLE 8 Spl x std X (500 mL - (n - 1) ×V) + Rn- 1 X 5 Time (minutes ) % A (Buffer ) % B (ACN ) Asta ^ 500 mL - ( n - 1 - 1 ) V Initial 10 500 mL - in - 2 - 1 }xv + .. . % Rn = 4 . 0 60 Kn- 2 * 500 mL - (n – 2 – 1) ; 4 . 1 10 10 7 . 0 10 Where : Rx = Amount of promethazine HCl or sumatriptan succi Approximate Retention Times for sumatriptan and pro nate released / capsule at the nth time point, in mg methazine are 2 .6 minutes and 4 . 8 minutes respectively . 15To Aspi= Peak area of promethazine HCl or sumatriptan suc Calculation . cinate in the sample solution If a Water dissolution autosampler was utilized , then the Asto - Average peak area of promethazine HCl or Empower Dissolution Software was used to calculate the sumatriptan succinate in all standard 1 bracketing injec profile . Calculation are performed using a validated excel tions spreadsheet . When the sample was performed manually , the 20 Csta Concentration of Promethazine HCl or sumatriptan volume correction was considered for the calculation . The succinate , adjusted for purity (ug /ml ) as follow amount of promethazine HCl and sumatriptan succinate Promethazine HC1 Standard : dissolved at a given time point in the drug product were calculated as follow : Calculation for the first sampling time point: 25 Wstd X 10 mL U std = 50 mL x 100 mLTX Pstd

Aspl Sumatriptan succinate Standard : R1 -= A std x Cstd 500 ml 30 % R = LCf x100 Wstd std = 100 mL- XP std Where : Ri = Amount of promethazine HCl or sumatriptan succi 35 Wsta Weight of promethazine HCl or sumatriptan succi nate released/ capsule for the first sampling point, in mg nate taken from standard , in mg Aspi = Peak area of promethazine HCl or sumatriptan suc Pst + Purity factor of promethazine HCl or sumatriptan cinate in the sample solution succinate standard A = Average peak area of promethazine HCI or 40 n sampling time point ( integer 1 , 2 , 3 , . . . ) sumatriptan succinate in all standard 1 bracketing injec V = Sample volume withdrawn , in mL tions Rn -1 = Amount of promethazine HCl or sumatriptan suc Csta Concentration of Promethazine HCl or sumatriptan cinate released / capsule for the ( n - 1 ) th time point, in mg succinate , adjusted for purity (ug / ml ) as follow R1 - 2 = Amount of promethazine HCl or sumatriptan suc 45 cinate released / capsule for the ( n - 2 )th time point, in mg Promethazine HC1 Standard : % R = % release of promethazine HCl or sumatriptan succinate for the nth time point W std X 10 mL LC = Label claim of the sample ( 25 mg for promethazine std 50 mLx 100V0 mlmL XP 50 HCl or 126 mg for sumatriptan succinate Dissolution measurements for promethazine and sumatriptan pellets measured by USP Apparatus 2 (Paddles ) Sumatriptan succinate Standard : are shown in Table 9 .

Wstd ?? TABLE 9 Cstd = 100 ml x P std 5 10 15 20 30 45 60 90 API min min min min min min min min Wsta = Weight of promethazine HCl or sumatriptan succi Prometh - 95 % - 102 % 102 % 102 % 102 % 102 % 102 % nate taken from standard , in mg 60 azine Pst Purity factor of promethazine HCl or sumatriptan triptanSuma 81 % 89 % 92 % 94 % - succinate standard % R , = % release of promethazine HCl or sumatriptan Dissolution measurements for promethazine and succinate for the first time point 65 sumatriptan ( content of capsule was used without shells ) LC = Label claim of the sample ( 25 mg for promethazine measured by USP Apparatus 2 (Paddles ) are shown in Table HCl or 126 mg for sumatriptan succinate 10 . US 10 , 179 , 109 B2 79 80 TABLE 10 Example 7. 5 10 15 20 30 45 60 90 API min min min min min min min min Impurity Profile (Related Substances) Prometh 85 % 90 % 92 % 94 % 94 % 95 % 96 % 100 % 5 The percentages of related substances were measured using azine Suma 75 % 83 % 87 % 91 % 93 % 96 % 98 % 102 % an HPLC . triptan Stock promethazine HCl selectivity solution was prepared by accurately weighing about 2 mg of EP promethazine for peak identification CRS and transferring into 1 mL of diluent Dissolution measurements for promethazine and 10 ( prepared by mixing 750 mL ofmobile phase A and 250 mL sumatriptan ( in a capsule ) measured by USP Apparatus 2 of acetonitrile ), followed by vortexing to dissolve . Stock (Paddles ) are shown in Table 11 . Small batch . sumatriptan succinate selectivity solution is prepared by TABLE 11 accurately weighing about 2 mg of USP sumatriptan succi 15 nate related impurities RS and transferring into a 1 mL of 5 10 15 20 30 45 60 90 diluent (prepared by mixing 750 mL of mobile phase A and API min min min min min minmin min 250 mL of acetonitrile ), followed by vortexing to dissolve . Prometh - 55 % 78 % 85 % 88 % 92 % 95 % 97 % 102 % Sample Preparation azine Ten capsules were randomly selected and weighed . The Suma 74 % 89 % 94 % 96 % 98 % 100 % 101 % 104 % 20 contents of the ten capsules were emptied into a 500 mL triptan volumetric flask . 300 mL of diluent was added and the mixture was sonicated in an ice bath for 40 minutes or until Dissolution measurements for promethazine and completely disintegrated with intermittent swirling . The sumatriptan (in a capsule ) measured by USP Apparatus 2 temperature was equilibrated to room temperature and more ( Paddle Apparatus ) are shown in Table 12 . Large batch . 25 diluent was added to volume. Promethazine HCl impurity sample solution : stock solu TABLE 12 tion sample was filtered through a 0 .45 um PVDF mem brane , syringe filter or a 0 .45 um PTFE w /GMF membrane , API Time Point Mean Min . Max. % RSD syringe filter discarding the first 5 mL and collecting Sumatriptan 5 min 36 73 9 .4 approximately 20 mL into an appropriate glass container . 10 min 86 6 .6 15 min Fill an HPLC vial with the filtrate 20 min 3 . 8 Sumatriptan succinate impurity sample solution : 10 mL of 30 min ??? 2 .9 filtrate was pipetted into a 100 mL volumetric flask and 45 min 2. 1 60 min 96 1 . 6 diluent was added to volume. 90 min 0 . 3 The retention time (RT ) of sumatriptan in the sumatriptan Promethazine 5 min 27 . 8 succinate selectivity solution is between 5 . 4 and 6 . 6 min 10 min 18 . 2 utes . The RT of the promethazine in the promethazine HCI 15 min 92 13 . 4 selectivity solution is between 44 . 1 and 53 . 9 . The relative 20 min 95 10 . 7 retention times (RRT ) of identified sumatriptan related 30 min 97 8 .0 10 45 min OOPWNNNAAW 99 6 . 1 * impurities and identified promethazine related impurities are 60 min 101 5 . 1 outlined in Table 14 . 90 min 101 105 1 . 4 TABLE 14 Dissolution measurements for promethazine and 45 Approx - Approx sumatriptan ( in a capsule ) measured by USP Apparatus 2 imate imate (Paddle Apparatus ) are shown in Table 13 . Recorded after 1 Peak Name RT (min ) RRT month store at 40° C . Sumatriptan Sumatriptan didesmethyl ( Imp E ) 4 . 8 0 . 80 impurities Sumatriptan Rel. Comp. C 5 . 5 0 .91 TABLE 13 50 Sumatriptan N -Oxide ( Imp D ) 8 . 2 1 . 36 Sumatriptan Rel. Comp . A 19 . 5 3 .24 API Time Point Mean Min . Max . % RSD Sumatriptan 6 . 0 1 . 00 Promethazine Promethazine sulfoxide 21 . 4 0 .44 Sumatriptan 5 min 60 47 21. 3 impurities N - Desmethyl promethazine 46 . 1 0 . 94 10 min 13 . 7 Isopromethazine 50 . 8 1 . 04 15 min 91 10 . 9 55 Phenothiazine 61. 5 1 . 26 20 min 9 . 6 Promethazine 49 . 0 1 .00 30 min 7 .8 45 min 6 . 4 60 min 98 5 . 4 HPLC conditions: Flow rate : 2 . 0 ml/min ; Injection Vol 90 min 100 1 . 1 ume: 15 uL ; Column Temperature: 30° C . 12° C . ; Wave Promethazine 5 min 56 21. 2 . 10 min 13 . 9 60 lengths : 228 nm for sumatriptan succinate related com 15 min 10 . 1 pounds and 252 nm for promethazine HC1 related 20 min 9 . 4 compounds ; Run Time: 73 minutes ; Mobile Phase A was 30 min 8 . 4 0 . 2 % TFA in Water , which was prepared by mixing well 2 . 0 45 min 96 7. 2 60 min 98 6 . 1 ml of trifluoroacetic acid with 1 L of water. Mobile Phase B : 90 min 103 1 .5 65 0 . 2 % TFA in Acetonitrile , which was prepared by mixing well 2 . 0 ml of trifluoroacetic acid to 1 L of acetonitrile ; and Gradient used was as follows in Table 15 . US 10 , 179 , 109 B2 81 82 TABLE 15 Where : Ars: Peak area of Related Substance in the sample Time (minutes ) % A (Buffer ) % B (ACN ) preparation Initial 10 AMain : Peak area of Promethazine or Sumatriptan in 7 .0 sample preparation 51 . 0 69 . 0 ASum Ri: Sum of all related Substances area LOQ in 70 . 0 sample preparation 73 . 0 100 : Conversion to percentage Impurity profile for promethazine and sumatriptan ( in a Approximate Retention Times for sumatriptan and pro - capsule ) stored at 40° C . for 1 month is shown in Table 17 . methazine are 6 minutes and 49 minutes respectively . Calculation . TABLE 17 All known and unknown impurities were calculated via percent area as follow : Related Substances Impurity percentages 15 All sumatriptan related substances combined None Detected All promethazine related substances combined 0 . 2 % RM % Area = R XRRE X100 %

20 Example 9 Where : R = Peak area of related substance in the sample solution Clinical Study for Formulation R , = Sum of peak area of promethazine or sumatriptan and all related substances areas corresponding to respective peak in sample solution A clinical study will be conducted in order to assess the RRF = Relative Response Factor for related substances 25 pharmacokinetics of the sumatriptan / promethazine Formu Impurity profile for promethazine and sumatriptan ( in a lation . In order to obtain controlled results , the study will compare data from subjects treated with the sumatriptan / capsule ) is shown in Table 16 . promethazine Formulation to data obtained from subjects TABLE 16 treated with comparator products . Over the course of treat ment, observations aside from pharmacokinetic analysis are Related Substances ImtImpurity percentages to be considered . Categories for additional findings to be All sumatriptan related substances combined 0 . 1 % considered include , without limitation , safety , patient pre All promethazine related substances combined 0 . 3 % disposition correlations ( genetic or otherwise ), and efficacy findings. The study will be for a single - dose , open - label , 35 randomized , three - period , three- treatment crossover study in Example 8 . which healthy adult subjects receive a single dose of the sumatriptan /promethazine Formulation ( 90 mg sumatriptan Stability Study succinate /50 mg promethazine HCl capsule ) in one period , 40 a separate single dose of IMITREX® ( sumatriptan succi The formulation was examined for its stability after one nate ) tablet 100 mg in one period , and a separate single dose month at 40° C . Calculations Assay - Percent Label Claim : of promethazine HCl tablet 50 mg in one period , under fasted conditions . More specifically, subjects will receive each of the treatments listed below in randomized fashion - D % LC = A sample cox - X 100 45 during the three treatment periods: ASTDsample x CSTD X ICXNC * Treatment A : Test Formulation sumatriptan succinate /promethazine HCl Where: 90 mg/ 50 mg capsule Asample = Peak area of Promethazine or Sumatriptan in Dose = 1x90 mg/ 50 mg capsule sample preparation 50 Treatment B : Comparator Product Ast = Average peak area of Promethazine or Sumatriptan IMITREX® ( sumatriptan succinate ) tablet , 100 mg in all Standard A injections Dose = 1x100 mg tablet CSTD = Concentration of Promethazine hydrochloride and GlaxoSmithKline Sumatriptan Standard A (ug / ml ) , including purity and Treatment C : Comparator Product conversion to free base (Sumatriptan only ) 55 Promethazine HCl tablet , 50 mg Nr = Number of capsules used Dose = 1x50 mg tablet LC =Label Claim : 90 mg (Sumatriptan ) or 25 mg (Pro Zydus Pharmaceuticals methazine Hydrochloride ) Treatment C may alternatively be administered in a single D = Dilution Factor dose of multiple tablets , totaling 50 mg, e . g. , 4x12 .5 mg or 100 = Conversion to percentage 60 2x25 mg. % Area for Related Substances : Each drug administration will be separated by a washout period of at least 7 days . Each dose will be orally admin istered along with approximately 240 ml ( 8 fl . oz . ) of room ARI temperature water following a 10 -hour overnight fast. After % Area = x 100 = A Main XA Sum RS 65 dosing, no food will be allowed until 4 hours postdose . Except for the 240 ml of room temperature water provided with the dose , no water consumption will be allowed for 1 US 10 , 179 , 109 B2 83 84 hour prior through 1 hour after dose . Meals will be the same cokinetic analysis , although the subject' s data will be and scheduled at approximately the same times relative to retained in the concentration - time listing of the report . If the dose for each study period . pre -dose concentration is less than 5 % of the respective During each study period , 4 ml blood samples will be Cmax , the subject' s data will be used in the pharmacokinetic obtained prior to each dosing and following each dose at 5 analysismaxs without adjustment; however, an analysis will also selected times through 48 hours postdose . Plasma pharma - be provided excluding the specific analyte . Any exclusion cokinetic samples will be analyzed for sumatriptan and based on pre - dose concentrations will be documented in the promethazine using validated analyticalmethods . Appropri- pharmacokinetic report . ate pharmacokinetic parameters will be calculated for each If a subject experiences emesis during the study , the formulation using non - compartmental methods . In addition , 10 subject' s data will be reviewed to assess the potential impact blood and urine will be collected for clinical laboratory of the emesis episode on the pharmacokinetic parameters . testing at screening and at the end of the study . The subject' s data will not be considered evaluable for Each subject dosed in this study will receive an assigned pharmacokinetic analysis if emesis occurs within 2 times the treatment sequence based on a randomization schedule median Tmor , for a given analyte and treatment. In this case , prepared by the clinical site . Subjects will be randomized to 15 the concentration for the subject for the specific analyte will receive either Treatment A , Treatment B , or Treatment C be excluded from the pharmacokinetic analysis , although the during the first study period . After a minimum washout of 7 subject' s data will be retained in the concentration - time days , each subject will cross over to receive an alternate listing of the report. If emesis occurs after 2 times the treatment. After another minimum washout of 7 days , sub - median Tmax , the subject' s data will be used in the phar jects will cross over to receive the final treatment. At the 20 macokinetic analysis . Any exclusion based on episodes of completion of the study , each subject will have received a emesis will be documented in the pharmacokinetic report . single dose of Treatment A , a single dose of Treatment B , Concentration - time data and pharmacokinetic parameters and a single dose of Treatment C . will be summarized by treatment and analyte using descrip Pharmacokinetic Analysis : tive statistics ( n , mean , SD , CV % , minimum , median , and Plasma samples will be analyzed for sumatriptan and 25 maximum ) . All evaluable subjects completing at least one promethazine using validated assays . The samples from all study period will be included in the pharmacokinetic analy evaluable subjects completing at least one study period will sis . Pharmacokinetic calculations will be performed using be analyzed . Pharmacokinetic parameters for sumatriptan appropriate software , e . g . PhoenixTM WinNonlin® (Version and promethazine will be calculated using non - compartmen - 6 . 3 or higher, Pharsight Corporation ) and /or SAS® ( Version tal analysis with 10 % adjustment for the 10 mg difference in 30 9 . 3 or higher, SAS Institute Inc. ) . the doses of sumatriptan . The following pharmacokinetic Statistical Analysis : parameters will be determined . Comparison of the log -transformed pharmacokinetic Concentration - time data that are below the limit of quan - parameters Cmor , AUCost, and AUC ;nf for sumatriptan and tification (BLQ ) will be treated as zero in the data summa promethazine across treatments will be performed using an rization and descriptive statistics . In the pharmacokinetic 35 analysis of variance ( ANOVA ) model and the two one - sided analysis , BLQ concentrations will be treated as zero from t- tests procedure . Partial AUCs [ AUC (0 - 0 . 25 ), AUC (0 - 0. 5 ), time- zero up to the time at which the first quantifiable AUC (0 - 0 . 75) , AUC (0 - 1. 0 ) , AUC (0 - 1 . 5 ) , AUC (0 - 2 . 0 ) , AUC0- 3 . 0) , concentration was observed ; embedded and / or terminal and AUC0 - 40 ] for sumatriptan and promethazine will be BLQ concentrations will be treated as “ missing. ” Actual included in the analysis for comparisons of early systemic sample times will be used in the calculation of pharmacoki- 40 exposure across treatments. The ANOVA model will include netic parameters . The following pharmacokinetic param - factors for sequence , subject within sequence, treatment, and eters will be determined : period . The ratios of the geometric means ( test to reference ) The maximum plasma concentration (Cmor ) and time to and 90 % confidence intervals will be reported . Cmax ( Tmar) will be taken directly from the data . The The Tmax values for sumatriptan and promethazine will be elimination rate constant, az , will be calculated as the 45 compared across treatments using the Wilcoxon signed rank negative of the slope of the terminal log - linear segment of test. The median and range of Tmor values for each treatment the plasma concentration - time curve ; the range of data to be will be reported with a p - value for assessing potential used will be determined by visual inspection of a semi- differences between treatments for a given analyte . A sig logarithmic plot of concentration vs . time . Elimination half- nificant difference will be defined a priori as p < 0 . 05 . life ( TV ) will be calculated according to the following 50 Two alternative analyses of Tmor for promethazine are equation : 11/ 2 = 0 .693 / z . also planned . To utilize the intrasubject sensitivity of the Area under the curve to the final sample with a concen study ' s crossover design , the time to maximum concentra tration greater than the limit of quantitation (LOQ ) , (AU tion of promethazine will be compared within individual Ciast) , will be calculated using the linear trapezoidal method subjects using paired t- tests to determine the number and and extrapolated to infinity using : AUCing= AUCjast Ciastaz 55 percentage of subjects for whom the Tmax ( Test )< Tmar where Cjast is the final concentration LOQ . In addition , the (Comparator ), and a p - value will be provided . Non - trans following partial AUCs will be calculated for promethazine formed promethazine TmaxMA will also be compared across and sumatriptan : AUC (0 -0 . 25 ), AUC (0 - 0 .5 ) , AUC (0 -0 . 75 ), treatments using an ANOVA model with factors for AUC (0 -1 . 0 ), AUC (0 - 1. 5 ) , AUC (0 -2 . 0 ), AÚC( 0 -3 . 0) , and sequence , subject within sequence, and treatment period ; the AUC (0 - 4. 0 ). In this crossover study, if a quantifiable pre - dose 60 ratios of the LS means ( test to reference ), 90 % confidence concentration is observed , the subject' s data will be intervals and p -value will be reported . reviewed to assess the magnitude of the pre - dose concen Statistical analyses will be performed using appropriate tration and potential impact on the pharmacokinetic param software , e . g . PhoenixTM WinNonlin® (Version 6 . 3 or eters . If the pre- dose concentration is greater than 5 % of the higher , Pharsight Corporation ) and / or SAS® ( Version 9 . 3 or respective Cmax ( in the study period in which the pre- dose 65 higher , SAS Institute Inc. ) . concentration is observed ) , the concentration for the subject While particular embodiments described herein have been for the specific analyte will be excluded from the pharma shown and described herein , such embodiments are pro US 10 , 179 , 109 B2 85 86 vided by way of example only . Numerous variations, 11 . The pharmaceutical composition of claim 10 , wherein changes, and substitutions will now occur to those skilled in the pharmaceutically acceptable salt of sumatriptan is the art without departing from the invention . It should be sumatriptan succinate. understood that various alternatives to the embodiments of 12 . The pharmaceutical composition of claim 1 , wherein the invention described herein may be employed in practic - 5 the antiemetic comprises promethazine or a pharmaceuti ing the invention . It is intended that the following claims cally acceptable salt thereof. define the scope of the invention and that methods and 13 . The pharmaceutical composition of claim 12 , wherein structures within the scope of these claims and their equiva the pharmaceutically acceptable salt of promethazine is lents be covered thereby . promethazine hydrochloride . 14 . The pharmaceutical composition of claim 1 , wherein What is claimed is : a ratio by weight of the 5HT3/ 12 receptor agonist to the 1 . A pharmaceutical composition comprising : antiemetic is from about 1 : 2 to about 15 : 1 , from about 3 : 2 a plurality of first particulates, wherein each first particu - to about 11 : 1 , from about 3 : 1 to about 7 : 1 , from about 1 : 1 late comprises : a 5HT , receptor agonist wherein : 15 to about 5 : 1 , from about 9 : 2 to about 11 : 2 , from about 4 : 2 (a ) each first particulate has an average diameter of less to about 6 : 2 , or about 5 : 1 or about 2 . 5 : 1 . than about 500 um ; or ( b ) each first particulate com - 15 . A capsule comprising a pharmaceutical composition prises from about 55 % to about 65 % of the 5HT1B / 1D comprising: receptor agonist ( w / w ) ; and a plurality of first particulates , wherein each first particu a plurality of second particulates, wherein each second 20 late comprises: a 5HT1B / 1d receptor agonist wherein : particulate comprises: ( a ) each first particulate has an average diameter of less ( i ) a core ; and than about 500 um ; or ( b ) each first particulate com ( ii ) a layer enclosing the core , wherein said layer prises from about 55 % to about 65 % of the 5HTBILD comprises an antiemetic , and receptor agonist ( w / w ) ; and wherein the pharmaceutical composition is in a solid oral 25 a plurality of second particulates , wherein each second dosage form . particulate comprises : 2 . The pharmaceutical composition of claim 1 , wherein (i ) a core ; and each first particulate further comprises a pharmaceutically ( ii ) a layer enclosing the core, wherein said layer acceptable excipient that is a non - pharmaceutically active comprises an antiemetic , and ingredient that comprises at least one of microcrystalline 30 wherein the pharmaceutical composition is in a solid oral cellulose , dicalcium phosphate , calcium sulfate , talc , an dosage form . alkali metal stearate , silicon dioxide , or calcium carbonate . 16 . The capsule of claim 15 , wherein the 5HT, BD 3 . The pharmaceutical composition of claim 2 , wherein receptor agonist comprises a triptan or a pharmaceutically each first particulate comprises about 60 % of the 5HT1B / 1D acceptable salt thereof; and wherein the triptan or its phar receptor agonist ( w / w ) and about 40 % of the non -pharma - 35 maceutically acceptable salt comprises sumatriptan , ceutically active ingredient . almotriptan , frovatriptan , eletriptan , rizatriptan , naratriptan , 4 . The pharmaceutical composition of claim 1 , wherein or a pharmaceutically acceptable salt thereof . each first particulate has an average diameter of between 17 . The capsule of claim 15 , wherein the antiemetic about 100 um and about 500 um . comprises promethazine , ondansetron , aprepitant, dronabi 5 . The pharmaceutical composition of claim 1 , wherein 40 nol, perphenazine , palonosetron , domperidone , prochlo the core in each second particulate comprises a sugar sphere . rperazine, chlorpromazine , trimethobenzamide , granisetron , 6 . The pharmaceutical composition of claim 1 , wherein hydroxyzine , acetylleucine monoethanolamine , alizapride, the layer enclosing the core in each second particulate azasetron , benzquinamide , bietanautine , bromopride , bucl comprises one or more pharmaceutically acceptable excipi- izine , clebopride , cyclizine , dimenhydrinate , diphenidol, ents ; and wherein the one or more pharmaceutically accept - 45 dolasetron , meclizine , methallatal, metopimazine , nabilone, able excipients is hydroxypropyl methylcellulose (HPMC ) , oxyperndyl , pipamazine, scopolamine, sulpiride , tetrahydro low -substituted hydroxypropyl cellulose ( L -HPC ) , or talc . cannabinol, thiethylperazine , thioproperazine , tropisetron , 7 . The pharmaceutical composition of claim 1 , wherein droperidol, haloperidol, metoclopramide , diphenhydramine , each second particulate comprises from about 10 % to about cannabinoid , midazolam , lorazepam , hyoscine , dexametha 40 % of the antiemetic ( w / w ) and from about 50 % to about 50 sone , emetrol, propofol, or a pharmaceutically acceptable 70 % of a core ( w / w ) . salt thereof. 8 . The pharmaceutical composition of claim 1 , wherein 18 . The capsule of claim 15 , wherein at least about 32 % each first particulate further comprises a first coating or of the antiemetic and at least about 56 % of the 5HT, BD wherein each second particulate further comprises a second receptor agonist are released within about 5 minutes follow coating ; and wherein the first coating or the second coating 55 ing contact of the capsule with 500 mL of a dissolution fluid comprises : polyvinyl alcohol, cellulose acetate phthalate , (0 . 1N HCl, pH 1 . 1 ) at 37 + / - 0 . 5º C . as measured by an polyvinyl acetate phthalate , methacrylic acid copolymer, Apparatus 2 ( Paddle Apparatus) rotating at 50 rpm . cellulose acetate trimellitate , hydroxypropyl methylcellu 19 . The capsule of claim 15 , wherein at least about 63 % lose phthalate, hydroxypropyl methylcellulose , hydroxypro - of the antiemetic and at least about 81 % of the 5HT1B / 1D pyl methyl cellulose acetate succinate , shellac , sodium alg - 60 receptor agonist are released within about 15 minutes fol inate , zein , or any combination thereof. lowing contact of the capsule with 500 mL of a dissolution 9 . The pharmaceutical composition of claim 1 , wherein fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an the 5HT1B /1D receptor agonist comprises a triptan or a Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . pharmaceutically acceptable salt thereof. 20 . The capsule of claim 15 , wherein at least about 79 % 10 . The pharmaceutical composition of claim 9 , wherein 65 of the antiemetic and at least about 87 % of the 5HT1B / ID the triptan or its pharmaceutically acceptable salt comprises receptor agonist are released within about 30 minutes fol sumatriptan or a pharmaceutically acceptable salt thereof. lowing contact of the capsule with 500 mL of a dissolution US 10 , 179 , 109 B2 87 88 fluid ( 0 . 1N HC1, pH 1 . 1 ) at 37 + / - 0 . 5° C . as measured by an wherein the plurality of second particulates comprises : Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . ( i ) about 25 mg of the promethazine hydrochloride ; 21. The capsule of claim 15 , wherein at least about 88 % ( ii ) about 66 .6 mg of the sugar sphere ; (iii ) about 6 . 6 mg of the hydroxypropyl methylcellulose of the antiemetic and at least about 92 % of the 5HT1B /10 (HPMC ) ; receptor agonist are released within about 60 minutes fol- 5 ( iv ) about 1 . 2 mg of the talc ; lowing contact of the capsule with 500 mL of a dissolution ( v ) about 2 .5 mg of the low - substituted hydroxypropyl fluid (0 .1N HC1, pH 1. 1 ) at 37 +/ - 0 .5° C . as measured by an cellulose ( L -HPC ) ; and Apparatus 2 (Paddle Apparatus) rotating at 50 rpm . ( vi) about 10 . 2 mg of the coating . 22. The capsule of claim 15 , wherein a dissolution profile 25 . The capsule of claim 23 , of the capsule when stored at 40° C . for one month is : 10 wherein the plurality of first particulates comprises : at least about 47 % of the 5HT1B / 10 receptor agonist is ( i ) about 126 mg of the sumatriptan succinate ; and released within about 5 minutes , or at least about 69 % ( ii ) about 84 mg of the microcrystalline cellulose , wherein of the 5HTB1D receptor agonist is released within each first particulate has an average diameter of less than about 500 um ; and about 15 minutes , or at least about 80 % of the 5HT1B/ 1D 15 wherein the plurality of second particulates comprises: receptor agonist is released within about 30 minutes, or ( i ) about 50 mg of the promethazine hydrochloride ; at least about 86 % of the 5HT16 /10 receptor agonist is ( ii ) about 133 .2 mg of the sugar sphere ; released within about 60 minutes following contact of ( iii ) about 13. 2 mg of the hydroxypropyl methylcellu the capsule with 500 mL of a dissolution fluid ( 0 . 1N lose (HPMC ) ; HCI, pH 1 . 1 ) at 37 + / - 0 .5º C . as measured by an 20 (iv ) about 2 . 4 mg of the talc ; Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm ; and ( v ) about 5 mg of the low - substituted hydroxypropyl at least about 35 % of the antiemetic is released within cellulose ( L -HPC ) ; and about 5 minutes , or at least about 63 % of the antiemetic (vi ) about 20 . 4 mg of the coating . is released within about 15 minutes, or at least about 26 . A method of treating a headache in a subject in need 74 % of the antiemetic agonist is released within about 25 thereof, comprising administering to the subject a pharma 30 minutes , or at least about 84 % of the antiemetic is ceutical composition comprising: released within about 60 minutes following contact of a plurality of first particulates , wherein each first particu the capsule with 500 mL of a dissolution fluid ( 0 . 1N late comprises : a 5HT1B / 12 receptor agonist wherein : HC1, pH 1 . 1 ) at 37 + / - 0 .5° C . as measured by an ( a ) each first particulate has an average diameter of less Apparatus 2 (Paddle Apparatus ) rotating at 50 rpm . 30 than about 500 um ; or ( b ) each first particulate com 23 . A capsule comprising a pharmaceutical composition prises from about 55 % to about 65 % of the 5HT, BD comprising : receptor agonist ( w /w ); and a plurality of first particulates , wherein each first particu a plurality of second particulates, wherein each second late comprises: particulate comprises : (i ) a core ; and (i ) about 100 mg to about 140 mg of sumatriptan 35 ( ii ) a layer enclosing the core , wherein said layer succinate ; and comprises an antiemetic . (ii ) about 50 mg to about 150 mg of microcrystalline 27 . The method of claim 26 , wherein the pharmaceutical a pluralitycellulose of ; secondand particulates , wherein each second composition is in the form of a capsule . particulate comprises: 40 28 . The pharmaceutical composition of claim 11 , wherein ( i) about 10 mg to about 60 mg of promethazinein the sumatriptan succinate is present in an amount of from hydrochloride ; about 100 mg to about 140 mg. ( ii ) about 30 mg to about 150 mg of a sugar spherehore ;: 29 . The pharmaceutical composition of claim 13, wherein ( iii ) about 2 . 5 mg to about 15 mg of hydroxypropyl the promethazine hydrochloride is present in an amount methylcellulose (HPMC ) ; 45 from about 10 mg to about 60 mg. ( iv ) about 0 . 5 mg to about 10 mg of talc ; 30 . The method of claim 26 , wherein the antiemetic ( v ) about 0 . 5 mg to about 10 mg of low - substituted comprises promethazine or a pharmaceutically acceptable hydroxypropyl cellulose ( L -HPC ) ; and salt thereof. ( vi) about 5 mg to about 30 mg of a coating , wherein 31. The method of claim 30, wherein the pharmaceuti the promethazine hydrochloride, the HPMC , thehetot talc , 50 cacally acceptable salt of promethazine is promethazine hydro and the L -HPC are present in a layer enclosing the chloride . sugar sphere , and 32 . The method of claim 26 , wherein the 5HT BAD wherein the pharmaceutical composition is in a solid oral receptor agonist comprises a triptan or a pharmaceutically dosage form . acceptable salt thereof. 24 . The capsule of claim 23 , 55 33 . The method of claim 32 , wherein the triptan or its wherein the plurality of first particulates comprises : pharmaceutically acceptable salt comprises sumatriptan or a (i ) about 126 mg of the sumatriptan succinate ; and pharmaceutically acceptable salt thereof. ( ii ) about 84 mg of the microcrystalline cellulose , wherein 34 . The method of claim 33, wherein the pharmaceuti each first particulate has an average diameter of less cally acceptable salt of sumatriptan is sumatriptan succinate . than about 500 um ; and * * * * *