DK202070049A1 - Pharmaceutical composition for modified release of methotrexate - Google Patents

Pharmaceutical composition for modified release of methotrexate Download PDF

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DK202070049A1
DK202070049A1 DKPA202070049A DKPA202070049A DK202070049A1 DK 202070049 A1 DK202070049 A1 DK 202070049A1 DK PA202070049 A DKPA202070049 A DK PA202070049A DK PA202070049 A DKPA202070049 A DK PA202070049A DK 202070049 A1 DK202070049 A1 DK 202070049A1
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phthalate
cellulose
pharmaceutical composition
methotrexate
cellulose acetate
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DKPA202070049A
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Dervishi Majona
Bar-Shalom Daniel
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Ros Therapeutics Aps
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed herein is a pharmaceutical composition for modified release of methotrexate, wherein the pharmaceutical composition comprises methotrexate or a pharmaceutically acceptable salt thereof integrated in a matrix comprising an enteric-resistant agent and, optionally, a hydrophilic matrix forming agent. The pharmaceutical composition is provided with a dual pharmacokinetic profile releasing methotrexate at a predetermined rate at the pH prevailing in the small intestine to ensure bioavailability during passage, while minimizing the release of methotrexate at the pH prevailing in the stomach.

Description

DK 2020 70049 A1
TITLE Fharmaceutical composition for modified release of methotrexate
TECHNICAL FIELD The disclosure relates to a pharmaceutical preparation comprising methotrexate, in particular a solid preparation, comprising methotrexate as the active Ingredient. The pharmaceutical composition provides a pharmacokinetic profile relsasing methotrsxats at & predetermined rate at ths pH prevailing in the small intestine to ensure bicavaillabiliny during passage, whlle minimizing the release of methotrexate at the pH prevailing in the stomach.
BACKGROUND Rheumatoid Arthritis (RA) is a common chronic autoimmune disease that mainly involves the joints and is the most common iv diagnosed inflammatory arthritis. Rheumatoid Arthritis is characterized by synovial inflammation, Lhyperølasja, cartilage and bone destruction which develop into long-term damages as deformation and stiffness, leading to disability in one patient out of three, Rheumatold Arthritis usually arises in individuals aged between 353 and SP however; onset during childhood 1s not excluded. Rheumatoid 28 Arthritis affects 1% of the population. Women are affected 2 to 2 times more often than men. There are different therapies that aim to minimise pain and swelling, prevent deformities, bone erosion and control arter & eur gt manifestatiors Tynde day snr i do en Sd age ed FAE 3 SVSLERIC MANLIGSTALTIOLS., ANTITNSOMaTLO QXgs nave & naetoaragaeneons ser of mernhanisms of sotior The most commonly CREE LET DAY 3 SNES SOL OU MEDOMLANLSME OX fotadn. OG MOSE COFMOT Ly 3 i Te oe er & - + 3 + i + Nee > — ed an J — pp gel ar mf REM MA i ds EO AYSTP RE nab ares ris sed aru US aT CRY LY Sood GE vre LISA V 3LS N COMSVLETGLCSA 3 : w £3 Moa YLE . - FRY Raed St z ~ $ forde ee Tory Naver øer TY gate es FACET TS eg Å Set 3 stred A) re På gen ty åt EN ae ANTI INT alan omy LUTUGS PINAL IIS FOLLOWS DDV 11S8SaSe 2 Mrsed 3 ad ww Fen 4 we ler oy ap en of 3 tr Lu way re Ed SNA ID I oh 2 MoQiiyving antirneumatic br US LNMANKE) . Men tt da ey dr rexate was or Iain 3 TY a eve Terri føre fy ow resbtbment Oo Fr Fanart GE AE une WARD SAL SL ETT LE Y LAY LAR ESS LiL LL LEN ES. NEL. 0% ro + Fo. ot : EN SRDS Y AS 3 folio solo anslome with the mim of inhibitino cancer as sa follc acid analogve with the sim of linniblting During ang vovrimidins synthesis Cre Tres 39 im TOLK Vu sive gs FOLAL 4.250) ER EAN LLL LL sa CWE LD a ALAR XR AOF Aw TT ER A a = 3 . . + . + eg La Cy + i cones dr år endt pean ae on Et at sy Tener bo in gx vs ef ende J Vm po: enge for LU methotraxala Was shown Lo De an effective Lharapy or Wea deme ed ve bat do og MS FF Fvyorn dt ay MOMS Te oY pe Tre on eb MÅ DT OOS HRHDEUMA3 TGI: 3 i YS 113 Faronrnt mhavrmaoa tour al ve 3 ha DO Rheumatoid arthritis, Different pharmacological mechanisma of . - . . . : . . . . rode 3 mt rey de en eng or + ba mr Tr h ØK I åmeresett 3 em dene? beat == fade acllon of metholrekate have haan investigates out 7 ta dats + . 6 . . . - . + 0 . ou \ 2 Hor mee oe SOFT ae XD RA snowy an To wes eno b vå on be ag BY ETA a ke BOR 23) EN YN RY 5 AY EN An ITEP LN, 1Ll1f9O8o06VLYO ANd CLINICAL Gala Support hs auendsine FR . oo foe . . - 3 : > 8 mel ag Boel mv bee do © nerne myst: cn Tr yy de borer tr i, Mera vad STL L- ANT LAGE QTY KDE AE E I: BE 1 iif Lreatment (RN + uma al 3 rthri +Fia mya] an sut ANGOIMS AT tha meat remmen id MADUKMa OC AYTNYINIS CYal and SUND L3NGDOUS are LO MOST. SDOTMGT routes of administration vPelie Redd is vausl lv mrecers bod LORIE NT 1 GRAAL E ER 3 RL SL EO LP XMS EA SR ENA AA LESS LEGE I EY KAL VEF EL LAGE ca a LN an Å . z \ a Nx . oe alone with rsnthntræsgatm miven Phe antimefanbnldite nnture of ALONG WILD WMELNOLKFeRKATE Given CDE ANTIVMSLADOLILES NMATLFE of nat Pot rave ato arr 5 ae mr i 1 xr soimin eraradd 3 Så DL tb ye MOTNOTFeR3tEe, and AT 48 asud lly acmlnistlered Ain days GEDer Jon ase NEW moethot raver es doer Syn 4 > der we sn de 2 Mes i 2 en en LOAD the MSEtLNOTTrSKETS BCAULIVLLSVTAVLOD. FOLYLC ACLÆ anya Lament ab don hnreøvents the sleve: Lorre reb mg ro vells < SR AAAS RSL KITE LL DASE HAT ER 41 SET LA VAD LE Ena 150 fd oh Rr od Los berm evnen TS 3 me yim 3m Tam md Sp åre Eyam ede mm = rå SOTMOTMa LAN IES, INSSWMI a, OREATIC AVSIUNCTLOFRS AM ery Foe vit nede 3 rem PRES affects BY ets st or tre yy TT A 2 Sd 355 DANLFOINTLSST LTG Fras SLESULE, NOWAOAVS DECT3uSe of 108 DTT pea ey Soret nisl o anforyv error FT a SY Tour nr
CLEAR ALLMAN SLY LLL LAR SNA RW RIEL mn Pr HESSEN Sr Ser envenomed dr den wen mde ements oS 14 es gt ed Cy Ap ee Am A ae methotrexate is one of the most commonly used treatments fox 3 Brhevms todd Ayi hylet o Ee pe Fie Fr er Obama t ri rå 23 KMNSUMal0Io MYLAYLEAS. BOY Cne Lraanmann DE MAOMa3 LOG D gen de den nn I een de dn ren dr ge png eye ns Bb ie energised mm TY 2 ere Tee Te or AYLDYALLS, metholtrexabte zL8 CHUTE KLA. LY awd lanls Er] Tae A he INT AR NTR Tm mr: les hb PSR or a ee oy Top oh meets 3 ren om? 3 fj 7 > << IDCKFGRMISCULAaE ATC QURCUTADSGUS AECL LONE, ATI WIR 33 Sonnet ahem em jo gin <2øk ey 3 3 evant I. > rer i mb ata LanuneGistle fejsase a8 LIDILOS OL LADLETS. => Umm Ya rn SN tt EN Ge form, de my se ee ey eo Sn ET A AS + i vy OS Re om a a 1 = 3U vojute Sarrler {DLL CTFSNSPMYELeFS seal CO play & anual yale fon ovmarhiatyavatrs seat ion am int r irer eam Ao ven + By gam + be ATT BYSLINMST LG KALLE SUSONEL ET Aly QAR LILIA SO. ADIT LN, wine
DK 2020 70049 A1 3 Froton-Coupled Folate Transporter (PCFT/ SLC46AL) and the Reduced Folate Carrler 1 (RFCIL/SLCi9Al1) have been extensively studisd. PCFT is specific for the absorption of dietary folate such as oxidized folate, 3-methyl tetrahydrofolate iB-metyl 3 THEY B8-formyE tetrahvdrofolate (S5-formyvl THE), other folate derivates and methotrexate given its analogus structure. POET is a proton symportey and the energy for the inward transport of methotrexate is provided by the proton gradisnt across the cell membrane. PCST is mainly expressed in the apical brush border of enterocytes in the prozimal small intestines.
KEC1 iz the other transporter of SLO family that seems to be involved in methotrexate absorption, REC1 js an organic folate antiporter. The driving force for the transport mechanism is 13 the adenine nucisotide gradient. EFCL 1s expressed on the apical hrush border of the small and large intestine and its contribution to the folate absorption seems to be greater in the distal portion of the small intestine.
Methotrexate inhibits the DMA synthesis and proliferation and exerts this effect also on normal cells leading to a number of side effects. Side effects seem to be the major cause of the discontinuation of the methotrexate therapy rather than its lack of efficacy. Gastrointestinal discrders are the major side effects followed hy hepatic dysregulations, pneumonitis, hematologic disorder, infections, nephroboxicity, dermatitis eto, Gastrointestinal side effects are experienced by 20-70% of patients during the first 1-2 years of therapy, Nausea, vomiting, diarrhoea, abdominal upset, and anorezla ave the a 4 rost common side affects ang sesm to be dose devpendent fre 3 most common side effects and seem to ge goss de Fa AUEDT. LYAL mi 2 : = on : mf 3 2 z 3 ncministration of methotrexste at higher dose levels leads tg KARLRILSVYALLOKH OL MØELNOTKFOAXKHLD SÅ Ox U Dey Jose avails Le ad S TU % + Do _ = 33 x FT - 3 - 2 3 5 1 Små mf oe rr dS mr me Tome bee im Hime MD PMR TUN SYG ON votre 1 TEMP er + MI Lan EIDL LGR SD aAlarrhosa. FNng MESCNEMIDSKMS Invelivend seem LO bx fe be es on de ON de men ~~ Ch a iv et py ga de og de de on Ee då en, intestiral be the innibition ob the segmentation of tne intestinal a - ve om de le Noa ” mee YT < Fr 3 Ney i 0 de 2 ge WHET ON o a by anne -—, 3 Ye v SPY oP bi Yd HAr men? ] 5 Fur ey by of bod Aor YYRI A rt bud ar ~ Lv + Po 2 epities ium USLIS Ly inhibitirng LINA SVYVNYIMnEBSEIS ant LOG 1 . . F \ : Ly . FEV - fn Tanga de SE Se o£ yy Så aen STE Fr ie deo fd os gere vrd 41 Thus ANOTFTSNIDG ar And DAMAGE Co ne MLOIYO VILLIG AMU; 2 ; ; + : oo . 5 \ - : gastrointestinal side affects afher oral dosing are the most JASLIFOLNVSSTANGI SLUAS «Isls AFL LEY oral QoBAing ALS LAS MGST . a 0 . x… Fr ox es 4 4 » 4. + COMMON and seen bo be dose-denendent and related to the direct common and seen to le loss-Gependent and related to the cdlrecot Fe fo 0 0 x. , El SX YO " y= the mn ge ft Rn res ae ) 4— + mn me ~ Sr Ta sxyuocsnre of the gastrointestinal tracv to msthotrazats. 3 j: + 1 Mima A mbawemnstiresst mafarnt Licstion WOPDO7040987 AD 2 + he he DD TAYKNS 3 mate BYNFY Io 3 2% svn ENOVYANMGGMILIODBUT AO in Th PO INTSEFNAC LONMSI D&TENT SPPLICALLORN ML GUF yd AK, in The TURIN of meas Lahorstories Tri hs + international JERE OF LNDAK 1 OL8LOTFISE IRI. na LE LYLETDALLDNG Tan Td en eN ke oe må + i oa OM OA eger OR MITT mn ~- mo ey HR an en, dae - an Does em Hs 9 4 erb i 8 sg bå ener såe en I i + + 3 rent She Stort my beat don ALi oation dats of åd RADII OF ins SDALENT, 3AVEILCATLaT isen I ama Sha rma eet rn 7 comoosivlens for Lumediste and/or FAG ST ATEFKUD Ia AASE LAR LR Mr BRAT LT LER RNIN AELSKUNDLE DE LED CRLERA FO MV s… controllsd release of absorption window active sgents such as 13 COTY LR FOLSGSRSE OL SØODONDLIOR WINDOW ACLIVS agents Bush 38 met dart egn nr = forbear be rr einige ene ~} rå S od, en ev i ey tg in men od or ge merhorrexate, «Nigh are usualiy aDsorbheo in the atomash ang for ams i Ynbmaub3rg
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XY YRÆMUD TIN KFNS RK 3 v 3 me eed geni ~ RS. | dog my em read 2 NG i em ene Cam dear fey ee It is an object to provide a pharmacevutiloal Composition for every een YE oes A wan jog Så ae SN f mebthøob rav? ae tyve i mM > Fin CONT TOL Le] VS LEAD Ou DØCTMNOTFENSTE, WIE In LÆS - Lo 5 CL , - . : = cymes rer YoY rend møammøst Dom SNMMYAYYTU Y GEN Så med Feet rae a ny sy fe BNSTIMA&COLULLOAL COMGOSILLLGT DODYILSES MOLCLKLOTTSNALE OX & onasrmasceutical iy saocaptabhls salt thereat intagratac mn fr ONAYMACSUTLCA ly KCOSEDLEDLE SALE NAK EGOE lnvaegratsd in SE mat rl oe sora riaian an antavioerastaotant asant and amt tøonal lur ALFER LKO LA LOWE SLi fl WADE I LID LDL DAI gen i ANd, DODLAGODSÅLÅ Yor i Yn pnd dT 3 sr aye sd kr Ee ard Pty Se ve a VG BOMILIC MATFAK Irwin SUS. . ? Så 3 i i I A) hyre hoot < SV Ra Fryar a aay § fervent ha it 18 LIR NDYDOTDEeSIS ny TINE Dragan Invaniols that rarharrevats da mainly asabeansrhaeg in the small ivtactire hut methotrexate is mainly absorbed in the small intestine, but The abenrrntinn tg linhlø tøm satruration lrinetiørs Da tnrstinvn 108 AaDSOFLUION 138 ilaftle TO SATUFATLON KIMNSTIOS. D&ATUFSTIOM Bod ryan Åen san Fr tackled buxg spreading Fhe Lye vøloste KIMEBLILCS Le Si nae LaATK Led LY SRA ng wile CTL Loidadse throughout the small Intestine over a osritain period of time arth aah Lol owned Ld silane nite aval oa me AVE LL ORANGE LN EES Lod RHINE This would result in ar imorovæed and seællable blolggrigål år NÅ SALAD WILL LAU A Ae KA dd LIOR ANS MODNE LEA LSLLADJLE D1OLO SÅ RIE avajlahbilitYv that would jicdeallv sonal the bloavajilabilitv of MOLE DALY LOA i, awa LEE AES EL EO RELÆ EL FAE DLOAVAlLLIDLILLE Y VA -x Sit EN SRdR ENGEN PRT NOE FNS sed ETI AT Al SM? Ne ud lm 1 aetna SN + met bys meget und 3 SUODCUTAaNneGUuUS QF LA KAMANDGOLAE Waly C2B8E OT FMÆLNOTLTFERSLEØ. ae se : ae made as en de [CRT SF SNC Are Cl ay be © oy en de geen od Cn ed be pn ag ST ov dels ? io ed åren aed fo hj erb Få ry + mast intet mag s io tt i 100 Yrtant LO ALGAALODET LITA SASCLYEOIARVEBSTIDAL 3108 nn oy IA en nen rn uw på tm Frem, | 5 Cm gr + - | h "mt tr mdt a TS ) af facta aoay n be Sogo Monaoarngdapt SrmvaadinTg the mathotravyato SU SLICE Socem LO DE MOSS gg 5 25080. SOYGAMID Woon MEU NOT Iga LS rs dsmes — Sd ARS fis — orga i intestine would result 3 ry en LIOLIDAaST a long Cire SR LL INTSSCTANS WIAD LA rosin in LWT ' : . : : . 5 ve dt dut Ét en rt A gh ney Shs ey ok YO SN RE ant DEY INTIAL SMÅ RREN MI Aten FYPFLEDYY ÉT OM ÉN OPNTMÆNPSGE EN ØB Ren, metholfexate ooncentratjion in any given segment as oppossa TO din Derr el hom wel SNE FÅ Er YE Le rr sols et ve > Ia TTY ye ren nd ow the lmnmadiate release dozags forms where the upper part of tha Intesting 13 exrmosed to the whole dose Fxennosugyra of tha UI LS LÆNGES 15 AE E KAMEDLA 300 UNIS VIiDNI OS OLED NER + Ko RALF IE ES i [EER small jintestine to lower oonocentrations of methotrezste would a SIAL lL INCSSTING CO LOWaD CONCSNTYFATLONS OR MSELNOULCESKHSTE WOULD HE: sv For End oo Fed Ti enon ro aT ub sy result in reduced gastrointestinal side effects. er I. FY. - oe - 20 reg år per a ow “ | So en om mm : - - er THEN \ LAP mt en TAPE GES or og a=] [ITI TY ah ova TENT FE AS methotlrexate HWEFOGUUCLS LE BEL AHCmINLSTtration RLY muret Tomis Ten or omer) os te ml mame Tysøuiiiøtom ome Your Frem pgtn oer SR Yen ed AVELLSDLE a5 LUGNILATS KE LOSNE VTDOILUCLSE ond Yo there 18 a need I Arem elem rE doer OD Te a AF md wel mm Fe RY ope ser Wb om &e sett ed Tamme bor SU CO GEVSLOD a odd fied veleasse dosags form that would Lead to
DK 2020 70049 A1 & fm $ 23 min dT Em imorovement vesultins Se enhanced Sl +mi ma DLUAVa&XLACDLINLEV IDCGLOVeSment YOSUIVIDG i SMMAnEA TLIDLOAL efficacy and tolerability. ft ois thought that targeting the release of the dosages of 3 methotrexate mainly to and along the small intestine in a gradual manner, where the active transport of methotrexate sesms Lo be greater, will lead to better blosvallability, slmilaxv to intramuscular and subcutansous methotrexats, avolding the acute exposnre of the gastrointestinal munosa fo 18 methotrexate of a conventional relsase form thus reduocing the side effects. hy es oa an en 3 LEN need end Phen en ene S nn t a op eg uds i Styret Fy woo I on Fea = ri vag dng Dorsdoing and oOTner oOonDJeclLS8s ars adhiavad DY LIME LØRLUYS of the independent olalma, Further irolementation forms ave 1% apparent from the dependent claims, the description and the figures.
According to a first aspent, thers is provided a pharmaceutical compns3itior in which tha release of methotrexate measured at pi £,8 is at least 10% by weight per hour, such as st least 15% by welght per hour, such as at least 20% hy weight per hour, In a possible implementation form of the first aspsct the 2 we Yaa 1 unga ker yaw st gr yer Ql Tre i af ml 5 2 3 <a St HOS rt = oY x Is! NF 3 rejisaze OL ReLKLOTrekale Wea SUTFAC AL DHX &.6 18 at MOST SU XY weight per hour, such as 40% by selght per hour, and suitably at most 30% bur weight per hour Al MOSE SV OY WELANE PDEX Lux.
To 2 rngsimle Sranslement mb 1 evn From 5 + 5 ga I Foret RODNET + +h ge 18 Aa PASEIDIS I1WMPLementarlløon form Or Ehe LYST aspect the release of methotrexats measured at pk 6,8 is 10-50 % bv å mede wns wn PRG ae ean on ene EAN 3 v aiøht oer hour - 3 as 3 met rr vi a sn ya Sa ADO 3 ur ENT ED tT OY ne HOLM NE FICNAE 4 EON KE doa al 5 LV We 1 Vi ii Der TAY 5 AN sulttablv 20-30% bor weigh Ter hour SULTADLY JLU-3Us OF Waign DEF aout.
- Cy : . Lo På P" . oor Le … og yet bd em — Some carreras doa te 4 end anaes ÉT IN FPL gere de mp degn de IN en fn 3 DOFSIDLS I1MOLEMENTATIONn Form GE ne First KEDETU Le ga wor de EN | mob rd groymri åen FM, DS HLN bey … de en E] 3 ” å om mM nr vre Sl ev dr de 2 relsase of metholrexale measured abt pH 1.8 is ZU& b Vo WLG 3 , + na Fede $ > . 3 od vagter by fede 4 eves] emer an myyahoo RR der fend medy ie føder da ee avy OT SN ane “wi og per hour or less, such as 13% by weight per hour or less, and way dob 3 Yo Vay 1 ES hy > td 3 af b mee riv sv OT grov ey NI TA AX TARP + NE OY WAILERS PIAA A MO: [Sei Jr + - 504 : + \ " ei Le - . . 1 i pr en gr — or Sæt - oy + 3 Zoom ser oo, ES 4 BE = ege, ty, + in a possipls jinpmplementatlon form of tne first as LECT LAS & i i 70 en I on qo MO ££ omar oar ve wats moasy ened alt mH & & Four SME ew os > Fhv aa V AABS nL Madi AR .LEG SIE ABLULEL aL Fr. Kr. OG + NG ME WL, or mors over 3 hours auch sag ADE hy weiliaht oar more ower 3 SE SKE ED Sr LES VDR I KN lSA. ES mT AG GY werd alin An SALT ES LA WT mi; : 0 MAE : “ : + Bere SY YP EY Sx en be ae FOG beer amy hE Se tment ETT ON Yo de et aen - 5 + hm ir OUTS, SUCH AS FUE OV WSLONL OF Mors LOVEr 3) NOUKS., and SULLA Y Fr OS LY 3 SM Byer het 3 sr id PME rive ees moren CT rygere SLE Dy wS31QAL OK more øver J Dours. FN - 504 : + » i" on a . , 1 te Tam os Pros ite Farry sae er FE Em er ml 2 met Mig en ae 13 In a possible implementation form of the first aspect the + 2 (coy : . e . . . , , x 5 intro) arrede d 3 3 es nd om £m nd er pry + 3 ml sett gå ru pyaroeshiiie matrix EOYMNG agent 13 selscref trom
3... oN ce rear If < Cx > « > ormen t rd ert bars Tomes ile fe Fer arm bard sed ei aren} DE poavaeLayLane Ride PERO) fpojivethylene JAW Tal (FL , hvdrogzgvethvicellulose coarborvmethvivcellulose Dmolvathyviøne ALIN QAVE UY ALL IEL ENDE Lead SASOA MH I ST WE NEDE LATE EET MULL LY eee + 1 2 yo CENT eT PEP] + 2 orm , og Yao ay) 3 meer) meen — FOYMESØOTAR men i es de 4 od ey de 5 ere MEE mvøersen bog re a ae ALVvCOT OLACFVLATS ([FEGDA) , Gelatin, GELACLANOFEGUS OORALYMSE - s : . v3 is + 2 a 3 Fyn birysavit sn Sme slå de ey ay id rd Fred Worse Rs YY TYAS Dored ben gs < Q AVALULOTFAGC Soria ¥ TCNLLOSAMN, Få MAE DR ¥RiL 2 BAY SLO LARUE eT Ge Hovlmethy ma ] "Torm rød 4 3 Re mener i om torn rist må ar bY a SGYQTOXYRIopyimginlviogl Lllagsse, SOLU aACL VILE, Sd MIKLUKLES fg ne LINBYGDE., SE NE A Ten RT yea de > res pee a Tey In & possible implementation form of the first aspect the “Yo renen 3 om : 3 % + - de de Va form tt deg ie 2, : SN + + Fl Le SEY EY 28 fra 1 eae oo yy rekyt nt hen vay vr fot berg io gnvvk fS sr dorian 3 ig Fa eny F mon 23 gonlecular wolght of the va Vvielnyvlene OX 18 rom J Ue Q9 Fa. SSN MY våd bre gs wars ev Te ney TOT MLS dee 3 GMO MOS LI Sop MUD, VV KHELTOME SUL au SE KAF AR LI åg MANU IVES md Some ment mrad ft min Rem 1 EO. MOL Rom SEITE OSYSESY så m de em lås YE roe or oh 3 by FoF es ea ; f mv Toe i HH im 320) Tano DAA ROM, MO BLLT SO 1 vo EKOom LDU, NER TO DU, DUG daltons.
Tri =] FYE EL sl oe Tray | ems tak 1 on From 5 +R I + vat Sy ryen gt ir Sme 1H Aa DOSHIDLIS 1I1MDPLlSMmMESNntacllon FØrm OT LOG 19909 aspect une 2 fn av Cee es YS nt STE Ty ze am lama Så 40 rr, h 2 rel SØ SER BVP VEY 1 SU ENCerlcTLes1StTANnT agent X5 SBLODLØG LCLCOM MVOAFONY DEORDVI rn te me wT … AT 3 - - os der en er mer - - - form 3 øm a ame amd - - Ne he ment byer sem dT ix i evra meet sd TA modes es I VV SS doen INFO DI mi nent metre: oat EN em MELDYI CELLULOSE 3CSLCaLS sSUuUOCInale I» ERAS fr AXES STTVISLE yt > - | 3 oa ros 2 x at Weel EE TREE Aen A | rE en th mom it de en evs 2 Yd en 22 ng e mo aq mt her ALKYL acryviates conelymers, methacrylie acid Aang Støt 2 2 : or + z KAMYSF I DT TYE EN ART IT YT I YATES Wan ThLirmry inte UTEN ATI IT ACYYLATE COLOLVYMEE AMON LG mathagryiabe DUAPDLIYMGEI, ff 5 a N . 4 + + + 2 FR x må 3 bers} methsorvlate rim rvs fore yes om dem ede Fras 3 AWA NC LEY 4 methaorvlate OLED 1 VM YE y BLE ACW LATS Mt TV mes td ACN LA en FINE NATED Y i" ut af io t es? met i, BOT om t ce Øie i US ES MAL 3FGRI FOG Lod pile a FEE asd na LÆGE unis Lae 3 GR BLY 5 3 mi Yar ram scetate nhthalate sellulocse oy py dg e en ay oy de 2 Cellulose ATETATE PALNAL STD, veljlulose acetate szu0vinate, må 34 3 ; ced Ya 4 1 : x re ør Pax] me An øm ENS og de a ged gen 3 de md a Sh 3 ONE APS NA SNS ent Tea SNE nellulcse ACSTATE, trimeiliitavte, NYDYOHMDYOPDYL vellulnsge nd a \ 2 x « FO +... vo z . + ely ely sn ) SNS em hor TENANT VST cra Levee do eve mbhyt den oben Maret ye RE SMEDAaLATE, AVOGYONDEORVI BULNDVÅCELLUÅODES ODONTDAaLAVE, DVAr ORY Å + Ca EE ay “ s - 4 um VES TY Yd nt nerd an fru i smut go db i, Va bo hg vokgvethyvlgel Faa toe mene BLOODY WET OY L CSLLULLOBSSE påthalate, BYGYORVELDVICSILINLOSE nhthalate methwvigelinliose shthalste mt grer domes Sd nt piri dat, HELLY LGR Low KISPV SEE ammo, E OLVVIDVI ACSLALS = +. a + : + . . \ 5 it . 0 0. i øm toby a ) gt em TREY ELAM rl øvet mig rs ges yi shh bia tom t es men jo? ex Ses + 1 SMUDaLATE, BOLVVIDVIGCSSLCale DYGRKOUST BPILUMaLalE, CSLLULGSE he. ma. + 2 2 4 5.4.0 1 i atm mhthalatres cellulose æthaær ="hvthalabes unit rim SL DSU IATLSS TOLLULOSE RL NEY phthalates, Sodium
490.09 . + + : z + 48 : + ME I far d meg Somat ag byt hy mt mtr mr må a da om} a+ COLLEGE, STDLATE DRUMS Fats, atarch AOL DAVNS late, Ph 3 as 3 2 dgb gt 2 Yeu pg be wy aes in & en en 1 1 lø SEN moret en wep ty lo en tr dte CSLUULOSE ACSTATLD DULVYVrale, CELLULOSE ace lats MALSA&TLD; omllulnsase ssetabte tbrinliitat im mal liso acm abe MØD ona te CDBILULADSE ACETATE LEFIMSILIALLATE, TO LLULODRAS ACSLATE PYDVDLONATE, ae : + vy - + . + i stvrens maleio nå ef 0 då erat art nhthalate covDolvmer oe x pam do st Frets malelrc aB0OQ1Gd ray. DALMNS31ace copolymer, STLVKSne mn i oo ac i : Sui grer i mx i a3cetate md h = 1 ai OMI, Tees mht lon SKEER ALE 2 Ås AM LN j= EMO LEE TANGEN LR L.A NE SALE LJ SØE LSE LET he EU + ya YE 7 IIIT LRA 5 > 5.0 5 0% + a + er ; ir : SY ed wd ie ced på mon 3 mt rr ey tid ed sarbomvmethvlethylselluløose KITLIDIAC ACLO, MOLS ALFJINGKLE, DALDGAVEBELIVLELAVLCELIVLOUSDE, co=vcolvmerized methscrviie søidimetharrvlir mo må met dyr LAAT RL WIRES Rå KS HUD Lately a ase STI Ma THAT TYLILd She A WIL ALY - br pm, arr er Sen er pn ONE Der AOA SS SS Jo Ten an en en AE BOAVSKS, GO MINDOUFPSS UNETVEOE, - pa : + - i" on . . . Tm = oe, | en 3 i ey do em Em ng HE dm i aeg i FE am ie in sa possipls implementation form of the first as CECT Toe snteric polymer is HNOMCOAS comorising 4-7028 hv weloht aunecingd SNTLArLe DOL Ye FF OLE DBYUNMLASD CC OWES riging 4-0 0 Voel One BAN eg Hr. . on gen Sd F: + va : ~ 3 0 » PIGE A TORE fe pray 5 amt rl SEY TT SS Ren a aa 77 SET) GYOUFPS at Hi g=- Lhd O Vows gil aoetyy JOUR; ZU AK B-<UVS LW Je Å sket maa åer i eer erry moaned FE Ima team erm meen tour 1 orouns vn wd WELORE SUCCINVI JUauRd 3nd ET” 13 DY Walidht acetyl JLOUPDS, and oe So 2.5. 5 eri a 20.004 : + + oa era 03 60 28 ein ake i gå ] Fo ] Go cs Lr Uren eT Eh avast ris t mer IY EE A oe od Så mtr Tren inf 0 YVUICADIS lå LS DY W&LONT SUCDLNYL Qrouns and 4-9% by weight smetul orme
OLE MA ALND Tri + mrsuett) ao Imm lamentation Foyer mt + F zoom i Sry sy ih hoon STs ROBSIOLE IMPLEMSATALIOR norm GE Une LIS Qld LOS von bod pn Yee fetes Gb mord ort fre ØE Gt vd a sven ecb sm og Bus rem i 3 ratio Detlesen The entlarilC-resistlant agent and a nyQrophii iio 2 ES Son rå SN øv & Se VMS. DELE 3 A On £0 - 2 Re non Ww SYP Tag EY To mM GROEN myterbs aoe 1 … = ed Ty aU MATFAIK KOYXMLFGY gent LS 3-2 iFo-al, SU ch as 10-40:90-80, and suitably 158-352: 85-65 SULCLAGIY Lav 3BIGODTDD.
DK 2020 70049 A1 in a possible implementation form of the first aspect, the amount of methotrexate 1s 10 to 30 mo.
a In a possible implementation form of the first aspect the pharmaceutical composition is ocoverad hy an enteric goating selected from hydroxy propyl methyl cellulose acstatle sucoinate (HPMCAS), mixed scrylate-alkyl acrylate copolymers, mathacsrvyiio acid ang ethvl acrvlats conelvmer arumnon io methacrylie acid and ethyl acrylate copoelymer, ammonio sethacrylate copolymer, æaminvalkvli methacrylate copolymer, ethyl acrylate wmethyl methacrylate copolymer, åbutyvlated methacrylate copolymer, oailuloge acetate phthalate, vellulsse acetate sucninabte, cellulose avetate, trimellilats, hvdroorovvi cellulose phthalate, hvæåroxøorogvl ethovloeliulogse SEVILLA DRY LL I I DIS AHL KE 2 0, SXVLIE LIR LEDTE YD LJIDVY LUK ET Laas 1% phthalate, hydroxyl propyl methyl cellulose phthalste, hydraxvethyvivellulose phthalate, methvicellulose phthalate, polyvinyl acetats phthalate; polyvinviacetate hydroger phthalate, cellulose ester phthalates, cellulose ether oønthalates, sodium oellalose, acetate phthalate, stavoh acid phthalate, cellulose acetate butyrate, cellulose acebats malsats, ocesjlujose acetates trimellitats, celiuloss aostate - - om a … + + - " - oe ie - eg 3 $3 on — % | + he 1 - Rm tm, vore . 7 propionate, styrene malein acid dibutyl phthalate copolymsr, styrene malels acld polyvinyl acetate phthalate copolynes, zhalliag, alginic acid, metal alginste, 235 carboxymethylethylocellulgse, co-polymerizegd methavrylie avld/wmethacrylio acid methyl esters, ov mixtures thereof., According to ea second aspect, the invention comprises a method Tricity th stene oF HANE RANA EAN LET bp; NE hd Ae
DK 2020 70049 A1 sm
AA mixing powders of methotrexate or a pharmaceutically acceptable salt thersof, an enteric-reslstant agent, and, cptionally, a hydrophilile matrix forming agent, and compressing to a pharmaceutical oomposition. 3 Recording to a third aspect, the invention comprises a method comprising the steps of mixing powders of wmethotrexats or & pharmaceutically acosptable salt, enteric-resistant sgent, and, optionally, a hydrophilic matrix forming avent, providing the mixtures in a dis, compacting the mixture using & Vacuum, heating the mixture to a temperatures at least partly melting the powders, and 18 cooling for solidification of the mixture. In a possible implementation form of the second and/or the third sspect the invention, the mixture ccomprises binders, fillers diluents, lubricantes, disintegrants and/or glidanta.
fn a fourth aspect of the present invention, the invention relates to the phavmaceutical composition dizolessd above for use in a method for modified release of methotrexate, wherein the pharvmaceutical comgosition comprises metholrexate OC a > , Li 3 Co he es 0 os pharmaceutically acceptable salt thersof integrated in a matrix comprising an entevico-resistant agent and, optionally, a hydrophilic matrix forming agent. Ta <en moret be Sym Eni vei 3 1 Fyr Sms vort Ære mme + Bom inese and Quer Aa3ODSCTLS wii he apparent from and the embodiment is) described below,
+
FTAA NT YP ENT CSNY SNEDTTTDES VEY TIL CT RIN RIITOT SVR TTA CTY RY hry FANTTTDE mu WN TRIN RY
DETAILED DISCLOSURN OF LONI LNVEJN I LAN ome fe Ym ome Be om ae my In 0 mr destin Tar Moral? Fri Sho Poem on Seman de oR NELNOTFEKRLE WAS QOFIILDSLAV aavaiopsed or The CFØATMSNI oF cancer because it inhibited purine and ovrimidins svnthesis CANCEL DDLAUSS LT LINHLDLESOG DUTIES and PDYYAMLOLAGS SYDLDSGSLS. i dy : Therefore ¢ i en methuotrezste se veer im vie mate Fo srt bed edn LILLE ALE Wha MOETLNOUTFAKSLE 18 sen in So FED RATILER LL LAL on STEL EL LEE zo We Ye py en God mmortr Paes mam eed oy be Pe sd 5% sven sre en sed men TY ey ae ee AE 2 Cheraoyv It may be assoojlated with unwanted ocejil necrosis uf 035 —- . + : . . ; øde ad fS SÅ vad ded SNS Af ØR FRU keg ge mm Så PE ENE SÅN SN RA ENES mene Å amore 4 4 SN 4 om OM nor Ege With G8KE. InNnE AM OY LIB OTreaskent 1I1NnveEnclon LE no i 2 % 3. 0% ‘ " : . gradually deliver methotrexate during the passage of the amall MEL CAME LER SE VO ANT A VL HER LIS LA TRL AAA LASS SEED Se Bye ATET Wn LHe Dias Lb co Lo ir a i . : : N : i - intesting wh ib z regarded a the main absorption oart of SILD LL r WILOS LE regarded as "ME MALM SVSGDYDLLOKH art OU - EE de en + vo im 4 4 lad oa md ze meen the gastrointestinal tragt. To obtaln this am 10 jeg 1mportant io blot Pha matrise of Tha Ohavmarcertiral comment tion So afÅåoet or A LEN CAS MATKAN OF TAS ONATDMACSUTLTAL CTOMPASLILONn LE a4usted om ion de mm lse - Sr mu yt ~F t ha Fan Ee en d t rå og 30 Oat DMLY 3 HMALODOE varet DE Me TELDOTLeKATE 18 »3 5 AF een 3 em … a) 3 p - - ie len tr Ta + - Ne ry | - ah AE om fram li onsn od im hg mt somme af = fyr Ol uherenas th aissolvegd/rsilegsed in the stomach at a low DH, woereas the ØS SAN Sv Sens om 25 Nm de er En 2 endu a pet rene ad Senay on a rn es if de 2 tin es VT x remainingd nari Gu the DNa8FWMaCSUuL Load COMBOS TET LET LCD EL IO Re re mwnrien lt ur Fi gemt armed Stem tomo assed dit ed mee Join er 2 Priest en SMoOu La se gradually disasolvsd/raisaasd during the 5 oul s… massages time in the small intestine from the stomach owlorus do nassafe TAME In tne small IDNTESTIND LEOM hg SLOMACN pyiorus mt it mswmrisnal ts +hese farmire it 3 an Te rt luge 2 pod Corb en bee UNTIL aYrival TO the Tarminal Ligum. in OLAF words, when he “ravrmarcrantioal somrmoai tion reachos the Snlonpm on) 2 miner DSATRACELNTLLOGT COMDUSLLLUN Yaaonag he daddanum Only a Winey natt Of the møethotrøxaste would have been releszed dissolved DALE OK Che MeTNOLrexale would Daves Dean VDLORSOO/ILSEDOLVEG, LIPS 9 ES IN UN wy t gt he lm FNS SY ER UN SNS an de de deg am ) Tote ay dt 4 vy pN rd ey aby WMOEFSAS, ALTESK TAS D&SSRQE OF TAS shall LnTasiing, when ne - 2 et 3 ft - Lo. ow . + WTAE eer ST od GNIDE TT rå wenn hy bh SE aI yn mani vr DSARACESUTL LOS TORMODDSLLLOF FO&TNTE LOS Saul; LRE ennui + 2 i 6 . - : aAfmrarnit mes mat boom 2TH STONY ahi Ee SF mat hat raw ars f TTY += a amount or æt Least sas manoy amount of methortreæxate from ths an Fam mA, fS DD A ena 3 ere ei e Fer oe he men Tem ome peed Fen er seen på onarmsCeulical COMDOSLYLIOR SHOULO De TO L8BARSO/TYeLlSaset. i i Tie py Nw ra YT ey ee a Tee en gr Sd EA 1 PLN ØE oy bh a EEE amy RY Pe 3 iE DES ant Ans nTors nave dave loaned 3 LEAR KEMACSULLIS 3 PISA OY i bo 3 eam Fa de 13 mits +e ven nam ligaen i tion mo FK] KAL STER DNF SL GL ÆRE LIR Es Joa ED LA AAR LL EDDIE FOA LID LA) and LI 33 : 3 : 3.3 it … : : 3 » x Ly megen de Jen oe de ape pay even de soen de de rr: ae Er pe pe pe a OL SS on Sr bo ae on doe enw oy ene be rd: e mernol reale an lle ac ps voococurring an hs STOMmaen Wo LG % 3 - 3 et 3 | 3 Fad % 5 vo + - &- - På vy mt deert res eve ER. ALLOWIMG dra dual relssse SÆALSEGLULLOM OK DMOCLMOTLFØKSTS AT a on ed rvergs br nant ra 1 aby tore ENTEN ge SE tha ama i inbtøut Sorg he GLE TO NE&UTYAaL, WNLOD OGOGEFE 159 Ung minal i 1DTESTIDE., IDE ODMATTMACEeUVT CR 3 CUERVO 5 3 mr CEST TY Sg ES vem wooden Sy ment rd vse ate RILA LIRA Ladd CQIMpQE LL 100 SOM I SES LOSICER ME TROL IRxXAaTE 3 i er nen ES REY me Å PN... Nes om don de es de msi, — mad red ae mynd 3 3 mn de An me 2 alfer i => mært um Sera natant acent ST a hvårcohilie: patria 3U ALSO SP SHKLSKFLICOTKFSSISLADT agent amd a NVOKGODRTLLC matrix TYPE yo vig AHltÆær NTR VEN YY YER SY EY FDNOVÆEnNnr ann Ero ATER Th ~ forming agent. Thug, ths present invention raiatas TO &
< Ems 25 aman ev an tg de 3 ed 3 SENET en 2 bd eee Moan vr ti or sp OSSE SR aa pene de ony ar bm dw en womb en ey pharmaceutical composition having alfferent sustainad reiease at Varios BW owvgloan with & first sustained release profiles at various oR values eo WITH & KIKS t suatalined release DXDT LAE mdt 3 ft Nm Ea pny tt 3 kt 3 vrd re em ee med at ac id Fa oes.
TION på i LO PH 3, Sd 3 ZOCONØ SUSTALNED es Sage orn File logs tø noanvt ral så 3 fFrm vt fS fr mit 3 FSILSASS COFOTLLS L088 TO neutral DM, 1.8. Dan DA 3 CO pH +. za Nee a Phy på STG wegen marae i 53 yen rem Yen oy og rt urt 3 7 oy oon på i: 2 LDUS, ME Lips SUSLALDST KOLEBASE BLOYLILE al KULD pH + ' WER EE 3 + re «+ : An WY A E a wha. ~ Ba] OM ae Pe AS IO, TIN EN PS SAR SE SY Af St 3 34 OS rn ge Ae NE BSUYUDETANTLAL IV IANMLOLUS tre VOLERASE/KLI BSOLUTLCOD GE 3 . . 2 oy : : x vr met et org ay ben whereas he serond sustained release vrofile FSOELDOTYSKATVE, Whereas LMS Salona SUBDTALNST valeage UYroOfiie + + em 4 + . + , . around nmnævntrat mp raelsages methntreavate at a modsrats rate ALOUDMNGI Denna DE LFØELSA3SSS MELTMOTFØKSTS ST FIL MORSFATE rate.
Fe TER os fo en Heer RY pan on of sen Se PÅ 2% ur sy GEN Ten er; ten SES elesyir dit grid åg Cater bE ae Lows eave 44 ne way MACFAMNT ; AS Used NSFELN, daudled LVS WELLTVENOWI meaning in the pharmaceutical arts that 1a Somalis matæsvrinsl WEE an 1 ng 29 LAS DNSIMSCSULL1COAL ILL, nal 18, At SOLUF MACLDSYLSÅ LE enge de en ae å så ende — as og em es 2 vo ped de 3 3 io t. 4 FT OS mf mv vee Fører 3 om + or, Snit nm EN 3 ToT 5 sr ENTER TY 0 af an Snlerio-reststant a JRNT ANC 3 NYVWIFODNMNILIC matrix formi nd eres tt h Sven vist Miss dt EN gen dt grp op an dg) Dvd ene ge de es tå beer Te ATENT, NEV LT MELDOLKSKHMATLS LKLESGratac LODSYSLN ine TY judy ry ep ty ev Som peri en 3 + 5 så, BF po, oT Yn gt ES ar pe A Doren ag ES me $a syn ea een en 1 SLY, a ++ > FN ER: 3 Fayed oY yæ Mel LH SULLACSA LSS LL sn LA LITER SE ESKE LIVEN AON + ag : wa + 3 8 Fr + . 0 La toi 1 St a Er ET = 2 NE TTI ae Ty 1 gr A pms tt syr fe ex dom er ie i SYUILADIY 2 30010 AOSage LOFM orally ingested (8.0.2. 3 Lapis, . en er 3 2 a ho 3 ver. på i gen ar de den ven dr ze gn hr oe, FR enn ye pnd A man om en ende Yt se ps. - Does merry Pen ge nr mg + gå 3 CAPSUlE, DArCLI1CDLESCTeS, SLO.),., When thes TSYMm DSLCNDOCLTSHZatLe is used in the oresent description and olatma it includes the AS LATER LY LIAS RL AN ET LE L.
AVE NS dL J COROT Af Aarau AK SR SÆRT EIE LAN Fresno ar 38 ge TT se TNM UD SED 1 Timmy] mor EST mb Im a 1 Bo Cyd > only 1 EN SIRE AVL AB WELL db DLaLHaCeLL 10. SOVSPLSDL8 SALT.
DUEL LANMLS . oo 3 . . + . a + 4 + mn a Ae Sy sr 1g de 5 ee én en Tok rr oy åen de Brn relent ae SN ed dg 2 ho onarmsceutlocal sadts Inoilude the mong or disodium ss well as i Ee TAT Pree fF ed amen be ey oY RSD amb a. f wry avn Ey oy by ono my Pen LOG IRQno or dipotlassium salts of metholrexate.
WYOTIN ER SAT NAN SY CT FOER IM 3 dre h vr Fuga tier men 3 MESNTRYRR SND OT åt GR SAY SATE YT Yor a OKI in some embogdimerntae rf LIE UVNn3KM8a0CESLICAL I SIE GITLOD oo Gps YLER3 . Lo + \ : + : Ly FE an anterio-resistant agent that odo nob substantially swell al entaeXid-rasiatant agai, CMalT AO MOL SUDSTANDTLALÅ Yo DW i en - 3 2. 3 - ” 2 dn . hi] 3 TU 3 TT Ym, - Fa.
STE eR meldug t i even ge vied PoE yo øm EJ 3 I 7 Ty en 22 STUSODUS S3SOLLLLONS around npealrda 1 Cid yp Lei, DM fe Lhe NES gevir ga wo] ree goa oct my 3 rr t mar fer over ove tered ammeter OS evr FOTO a SENTRIIT-TREILI STANT ASM mav os sSgian Led amon Wood Large KARTE oT ENE må Som en Ted yey Tyased gris ae mens eg tese mest Ta ener Qu LDOMGOUMNGS ADL ONELING FUVOLE HM BDYLOKY MEL avd TDSLLAULOSE amt nt en Sri Rå åt en FIDIDMÆSS RON solvrinvl 3 reder i lecithir ATW ATE IoC inans PHPMIUASY 4 BOLVVITY & ALCON, LELAND, real Til mao ethers: bent øer ure nys 3 rat il vm ved vey va ras CR liniosg SURE BYGKFOXYRYODY CE LAI LR, AYQYQEVRIQDLYL + > 9 3 N Gov Ca 5 + ? x dt Fer sm 3 3 30 3 PAS Em eat dag øen fol Rb en Te ment ku) Mire venom trea Mr io ethvicellulosSe, QUAY AL CDGBLLIULOSR, MmEBVMVIDVOTOK VEL > Fy må tos) rene volvriosvlovrrolidene red + me yi pv me feer 3 2 FE i ed : FRYS ERNE er i i ris SYN Yo 790 i Fat SR matr ZU COLLULGSE, DOLYVIDVIDVYKOLIGONE, SOX UI CRYLDGNY MELDY mellrlose zanthan hyvdraxvpronvimathvicelinloss {HRM CEA LAR AeotliL Dodi AMAL LAS YR LOGY LAR LA YL GRRL ad Lh I EL I
- io 40 nå ama) mew Nand on non Yo Er) S an meg] oy ke en ger oY i. : de ba + 3 nen AY werd seemed men pre d RO SAS ey a ony srvrre oa te — Pirie Ive as veer event dn eg ør Hege db em ren 4 PÅ MINEO adrvViate--RirkyL ACKYIALE TODOLYBETNS, MSTMACFYLLC ACA 2 2 + 3. + 2 os + +. oY avfbsl nøvulabe non nn ammo io mæabthaovvligte canal wma ang LD Y A SUL VILE, LO r UR We I ; AMMONLO MELNACTVLIRATD oO ce UL VE ner ; . + 2 . . \ . i so x hved rs? br? methsorvlate RE rvs åt aresså me — me ir SW NCA LEY L methaorvlate DOTED LYING I y SUNY SYN ABTS Mt TV even de dn ar" rate Arend rere Yr i uty Yom ten methacr om te mere ig mer MAL 3FGRI FOG Cape EERE A KIA VOER LAR SMED LEDE rv ia le Le GR LYRIS ro må dr ram scetate nhthalate sellulocse acetæte fre ry ye 2 Cellulose ATETATE PALNAL STD, CSLLIULOSES acetals SUOILNBLE, % 344) : ig FU ge 4 : 4 sa to sg ang åd 4x 3 pm er PR og SS cam se I Få de AN SR rå SPY SNP sø Ve Se CESLLULGSE acetate 7 trims iiitats 5 NWYATG zE Y op VI DELLUIOSE ønthalste hoydrexorgogyvl atbuløn?icløgue ohvhagl ate hyedroax Mil did NB Ls AVAL ING ED YE SAMY Ama AE MLS.
RCA LE LAKE p SIMNKER LAA EL 3 + 3 so 5 x i + is gr 3 s 3 - mens i undt boned men i times mhthnlt ate rel YT NRE] yy may yp mat hr? MED MOL HELI 1 Få CHE LLELOER OUTS LRT, FEMRIL OD X Wa RAL & LAVE HINTL IL YL +34) - - ; en eed Tus pe m= et Mom TY ae : rr rr Fax Y oo - + gm ew nd mm dn herre pw oan Tr re, de hr rr Fm Peg i mær, mm - 3 ie, cellulose anetate syuocinste, hvorozvethviloelluiose phthalates z ! Y 3 3 2 30 ergata) ever) Tar evo yh hy al ate TOE AEN TIL Sevan be nh hs 1 ate fS BIER MEY Am LA ASS Re 181 2 LO BORA VOV AE YO HO LL MOLI Ld Ly volilsvinvissretates Mri roman vhthalate sveliuinsse ania DOAVVINYISCS TATE nYUFOGEen DNYMAaLATS, CTESALULONE LELTL sey 5 Yaw . a i » 4 0% vin + ei ey ga mt Ted reg at har miata) alee midi strå mt Tand me ET MALACSE, CELLUICOSS STOF DATLDnAL3TSE, SOM LUM CSLLULOSE, oe . = . bit . . 3.0 ‘od yee day de sm — 0 BA SU Eve Toa gyde rå ge oh gr så mn der eb oy 1 ste øm i Voel syre somt ste ACSLATS PMMTLNAL STS, STALIN alia PNYNS&L ALS, CELLULOSE ATSTALE bit bruge ftp met Yo one [ra maleate felluloer rende at hi at øm? lilje Vor ate ri nate sen] Tay oes arab ato DULVYYATLE Load dna aloe tan KRALCOATØ, Fr KV AE RS I LASSE OLE AL + : + : +. ho . , 0 IA fFrimellitate møl iniose AaCstatle Drøm tonate St Vrørs malet Ao Må SELEN I SA LM Le ar EA LS AVS SB Er SSU EN at L.A KPL AFREJS WEES LED VE AT IRS Silo.
OT EA en od 23 rt ert shthalate im Cerra 2 ds ran SATT Én må sd A HL AKUT PpPRniUnailatt COTO LVS SLs mail SOLE 3 sy . st N CN \ <n ss 5 rr voalvejinvi aceatats ohthalable coopnDelvier sabhallar alføgintøe mør DBIVVIMDYL SCOTaTE PNTMALATE COD: AVLET, SKMOBLIAO, a GK nic AC, matas! alringste and agaiavin METAL ALTINALTB APO TELALITI. 3 Mys redo esser Peres wees dn by xp ven EY aT ene scetats succinste FLITA RO Redroxy propyl methvi cellulose acetate succinate |[(HPMCAS) may be used in various grades az the enterio-resistant agent say NE oil 212 Var Ol alles as Lie DLL LLOTLMSLS LDL suelo.
Rg: Tha nos i sontant ju generally in the ra TE pe 1 Fa + PRUs, The ACBLYIL CORCDeRT IS GeNneraliv 2% ong andes LD, Tne : arm 3 vredt sent dm are, AD fre, GE & dn, ret hor] vendt eat ba SS: i ar rom AS ry TRE bi mer) Prier > SUCCLAVL CVOMRLEOQT LE from 4% to 25% s LIQ MELAMGAVYL COMLSMEE LE mn SPS em PLS maaned mer bared amen ae trv ema rd Temp de ede dr Se LER mm ToT Eye ear 2 mr Sn ai OV he RPE YON NE LAIN ETS NY yd TR byw bey TR CKORM JU CO CM, and he OYAKFONVYDKODYE 0 content 3153 DE TO L1D%. fn an embodiment of the invention ha nocetvi ønrtent ia md 311 CRIA ARLEN RTL Lb LA.
AXE LLMETLER I LANE LARRE DALE LN A RLUSTEE RTE EL + <n + - = me - 2 5 … + 2 2 - regimer vt 3 doge buen i syer TO DS Er : avl era Tevnbsloo byg: To ryg GQGEMNSTaLLY INBAOW 22, 53 ut i AS hb 200 dL a 3 Anc LE lara ly DELO0W DE eo So Sd emne «1 A en a rer ane oy 10] ra = fø: Fe Se 19 ek, = GE and the sucolinwl content is generall Vo ADOVE, OK, SUCN as Se. goer oe ev noe med me nm aner em en Tg ER y er eN Lt > ier mg? ne iside mt Få cra ey nevirey TAD Howave rr Ey HUE, SUCH AF LUE SION AS 128, SVUCDN Jove laa.
NOWSVEY, LEVE? acetvi content is generally above 3% and zuitably above 4% aTerLyl conlent 18 generally above 3% and FZULLADLIY above ÆT, > » rat oo må Ye REMCAS re ye øn & avaliable ener DuPont => 3U aA DUI FDB Frage IX AVALIARDLD from JAUTOTNT 38 > ET ie ST TI TARAS RA vw UFO Eh A hem , c Was eben Yee - 3 Som Er Ed rey TTR HPS FYR sb dag 299 5 mid srades include ALELNGSOUYU HFNCAS FLO.
ALEX SULTADIE grades LISE Ue
% A i ie sed SO EY RLYITNRASSUD CI ho ac tm ad Mog ne en ea TT YI OTANS OI KD tg TI CIR SN J as Affincsel'F HPMCAS Slo and ATflnosoi%" HFMLARN 1285. HPMCAS 18 Suen mn Fo mmm over i Tow & IA mai sner mf mg P das Rn En ae gu fond a en Nt ed SEALE OK TCONMTFOLLENG TOS Toisas oF DMECLOTKFOXNALD IN anil md på re 3 bom 11 vm rtm rod bhanlt ner? oe meQia ÆALlvEøn Tz On od SVENN DSMnaVLDOY.
Te: ærme Ear eed Trey sg ie ok PEE Sp vent evn TT eh rE ea SRT SNEG Sen ITE Gh es RA 2 Ir some SMOOMITMESNTS., The DRAarmaceutical QOMPUOSLTLLOD COMPYrIses få VT tren GAS on wate ad ae Boer SP wm PYSN GÅ Ge de ss saves 3 0 ÅRS SN SAA SS SNIGE eN a vol y meric Matix CKOYMING agent TNMNat Can Sweail In STLSALUS 2 + i - - - i i ir pr 8 rr æ et - ey deb dans sygstittet nent rs ay fy €£ wk ? + i" ry: YT SOLUTIONS KÅR VSYISTEL Deltas Lat ES Kr Et i + FE ÅER SOME . . Å . , Cy % . + J arin nm wa hvdrevhilie meld sr om Sa) Evt en EE ye SOU INmENTE Lhe LVATDCDEL LI DAVIS I 18 selected “Yan 5 a h an sd x. s 3 4 + + £ + vr rr rå signe syr på Vo ref sr vred bis . as dom ere re ry re t.
ROLY CE ÆSKE OKLOS., MOVOKOK y æt LY CLLULGSES, CA hor VEL Lhwi- 30 gs Tar) ede Sey Ase h vraag lys ol AT acyl abe FITTS even agt +. 4 CELLOS, POLVSLDV LORS QAVCOL ALBOKVLATE [FD(2LDA: + OJ9iladaU Li, SYR i om i Yp DENTIN PUI TY OS FT a FO da gg Torr vena Så mer mR ebm qd me gr Ty Tm XL Rm mrk pm GJELRLIN FLUPLA COHOG1 VS, MVaLnronile SCO, OMLTOSNAKM, AVQEOEV rrr lea il mer hvdroxvnoropvimethyvinselliulngse arie 3 1 sm FRU VIIL DDS, RYOKFOKYDEKODYIMSLOVA OST JUL OER; SL UT even i om 5 gs and covpolvmer: heveof Ye rave — est inessd Spee en ed se Er Aaryiate, AM copolyners thereof. in some embodiments3, the vrede end dT Ser men Term år pra SS ei re et tm 3 FN ne mgs er 3 3 ae de es ro, AVArGENI ILT DOlfyhaerlc MATFIK malertal 18 OVOSEIQIDKEG. iv + ed Yor … 323 z £ ei x : mt 40 . ] . + io mi dag ge SEAT TROY ri Xi + FOA mu Ta Trem rE i do 3 + ÅR NE på wep Sr do other embodiments, the first nVYVGErcehniile CGOlymerlo matrix rem ban and må 4a TAPE cranes linked manarial IS none QIoasslilinssd.
Uh, r + I To vd er vh 3% munde ne Feer 3 revy oy FYE nt 5» or on eds ay =o When the h VAro@rh ld La må trix forming agent az selected as oolvoxvethyliana oxide (DEO) the moleocular wos d mh is MIL WA VD LIS VA DE UAE AED TEGNE LAL AALS Lan WIN 18 ” ER: Sand mp d & om, oe > h > THEY ee bs røn io på Yo NEN ES Arm 3 i GENSFAaLLV SUYULEFLOLSRL Lor LOE ride LO Qe SYOLLG.
AF genaral Lae + z Le er . , : + . . hed smil? ar rom deriva mE vha vee Tour fat sr i mme ear 3 mis % Se rr ee SEV mojsouvular welght ol The polyisiayviens oxlae) is more than DØ MAN ie 3 de ren a evne me . ot YE SM aw I a > Mn 3 + sm me x se + bro yt Yi SOM Tyrus Eb nr en afg LE DBLLTOTNE such an more VOAr AAT ESS Dallons, BIG < GE a “ ALS ANS on - > arr d oyna myte + ha ~ TaN ANS Den Vt een Rowever & even] eves vr SULTADLY MOKE Lian 420, VVE Jaliaas., FOWRVQU,; Lhe DO YTSE sam mb mt re TIES vrd TT wend mæiversm i 3 22 Sretensr el SL OTYSYSY DVN Tia le many walight OL the FES will not normalti yvoexlesd 3.000, DUE Dal ons, 5 enn nå oe + SAS Nan Yao 7 rem : 3 - UD, MY i 2 ark ev 2 any ng Tim i + mere rey Sv PO MUND I vied og ed alii Cha dg AAAS pA Ld LD3ALVLOME p sun sy og WASNT g ASAIN, SUN Re) 3 MM, MU Thay de eyes mel ani boomin rr aad 3 3 erb ema emgiemed SOT FIFO mae eed i, VOL, DLO LDaltong, and sualtadly WLÅL MOT sxoosaen SUD, 9800 much es KM MAT Tia Vo eo ho) Sah oA h Te DEY da averse 3) ma) mm FT pm pre, Muy yr ey ag OLV, Ul VaLCOns.
A suitaplis FRO LS availlagds form Cura i, Than dr ge Se deme - Lor J on ga re UY cc yo re MM DLL SE 3 ; i.
Nutrition & BOV Ii ana Ts € Dy 1 Foye DE Die Si Mt Other maid nitte ILT ELE dl & MLOSDI DARCES, ER Y DKG EET ERE LATER suitable . [I . FE So 3 3 SE: ig Rio MP a 3 eR spa ør x vrid I fg & De) ede rdr ki — RDL S fed se TH STEED Tem mre inst SMODYNIIDENVE include P DLIYOH NL FOLVONI WDR Loaguiant, > red SOM BODY.
DM 1 3 wy 1 . EY terse th eee pon : Cs 3.9 x + år rear MM SDI. 2 mr Re Fey fb WER LS TY 2 Hr No = WEY 0 RW 5S EN ZU FOLVOX Wore dhl, ahd FOLVFORNTF AON- SUS.
Fi LE 3 Wadsley USA est ya gevir ir mis rs reat BY em gå Fenris I om oY ery gr rp = cen rh be ven ed SROLPIaNT LT phnaiiadali LOCAL KOTMUIALIONS and 218 ans iosvad i5 Aa ceva dd yde Yes ge Se Elen edd meen borte dean ie es med tese £ ony go Cd es suitanle for in the dissolution rates regquirsg for nis vant on LAOWRNT AON. Ts hbn eng em be 2 or Soi . & ded s . FRE GRATIOT Dd Te ent abn enge er ds Ley “ay SREY ene SS mee + oy of fed an SORT AS et ÅEN LIPS Ty = $ en LVEn LIE in an STMOODALMTMENT Of 1831 AG ALANINE, HMPCAS 18 2 EUSA LLY vusead as an enlerto ating agent, in COLE 1Invenktorn å de da gta Se SE NE NE KS eN gr ÅS an pay he Tag SN SA ved de h MEN, Vis it is used as a matrix-formi: 1 GV mor Lode ther with PEC. SBV = 3 v J Ct os ou > Ls sr . 5 . 2 . Arfiiret irer bo rn ner ai yo different dissolutjion rates can AGTLUSTANG LNS Dovel KAaTAOSe GIECLSKFSAL GLSSOLUTLOD Yates oan - 2 + . : | i > + om hun TI i KME PN DE 1 me 3 op, ma t Fun Kr nr abo k sg nyt eT jo Sd IM SD TD EM 3 = DE BCDLEVEGO, result ing 1 MESTOOCFEKALlE MInGg KSITAass0 ln contro Vis a manner em Eka arate aries vem nment CEA ræv, METRE a CATIA EOF ENA EN 4.8) LEJER EN RIDER. BIEN RL DIE SL LER MEML AMS 3 i huvdroobhobjle and of devendenot behavior ang the hvareshilioiiv + 1 AY RYORBNOSAO and i so GReSDENAKENT BSLaVLOE and TAS NVara ED DLLIOLU Y nm FEOQ the nraevaisnt mhechan i sm of drug YRIaa as TARY ha LA LIN LSE LAU VER LEDER D HID A.L 30LES ADELE ad RRA IE RSD SELE A St ga . . 4 sok 1 or . ar 0 . Fl ECan dm 3 + mg må od em rd 4 fen I : + om EY 5 Gå diffusion in the actolc environment (pl 21 fo pH S) and Sif fyreior and eromion at oH val: os close ta neutral ok af 7 AXE In VEF SUSER HR DE LA LANL RA. EAST VOLS LL Lf rail RATT LAL : Lm
FE mn I
LG hn ay mam de oe or en ln nn even sr Ånd mma År om Pr År mont A Åbne dem or The ratio between the enterio-resistant agent and the matriz- = : NE mx Cw ‘ , ; alt. 2 son Å Trp mcd Trot PLAS EI ETT bo 9 oo ven i RATE IO OMU SNE TES ag] WITHIN wide ranges LØOrmin Gå AYGO DD ALT DOLVMOK 03 D DS Varied HITDAN wigs ranges, Tæven jo lor + og tå between the enter remme oan Pt smart Sy eo b LSVal11V, SAME KAL10O Delwsean Che enlsario-redisnany agent, Such as HOMCAS moede ene ped oem ånd RÅ er PAN de ge ore SEN RANE wn oy ENS EN de vids woes as NYMCAN,., and a hvoarcøniile matrise- forming sogent, sSucn as ” UNE 2. E rn Og me em vd ~~ a 5 A ey ron om ao rede om æn SM nn 3 DE » RRA on 5 0 ciel no D…Lå0.-3t?L80 atter SS Rd Vend Mr SM TET < Q PEO y AE DOU TEI-SU, BUCH AS T-AL2QFLOUDB, BUSH AS Lu-asii nue FL, ee ewe pa ey i} fa. qn Nee Lore a om EG SEE. £0 and suitasblv 18-35: ir such as l158-38:88-62 r AVU SULTSDLY L139730100T700. » 35050 ‘ . fo . 3 Ym Seicl it dom Ne vent het rows ta mrgreen tomb meh nga yy t am AT AGT TLOT Lu DER LDNLIGKREVE, SNnVLEKLOTVLKESLESTLTANT agent ANA rarironki lig matrix Formigne DCA the mrassant
OY QUGRTELLLC MATIAS LETTING DOLL VISE COE ULSSTYRI oe 4 os 2 4.3 h © I. . : pE EN: erne, 3 4 3 rig er ræantair møl em er om ig 23 DONSTMaCSUuULLCAL LOTMDOUSLULOD Hay OOMTALN BEQIDIENS, La. mh armacoetioal Ty ncemnentabl? hævn jivea srt TIE Ey use Sl se gr Da fMaveuT 101 AaACCVCDT&DLS, LO8CLI VE SUDSTANTES USS af E 3, =, ema vd mv Tove the mim v mea eat Xen io ag rede $ vren So dt gb 1 Dem formå +, Så a TALKCLSK LOK LAS PNAFMACSNELACDSLAV AOLIVE ingrasdalaedt (SP) ATA Torres lt oaredgn et vt insheermor:i e bos vrd ent et merit 3 mv Ai md ontamrnnt Laden SNL LINENS, Linders, SORTING, ALE raniis, Fay go a) ol 9 1 remy boa FY oa res YRS Fi il ku Tr t SI FT Yen sl: Aa sd FILLEBES, ULLVUSITS LLIAVOLS, i STE, TUDLOULS GLIOHUILS, På GEN TS GEN YS ØR OIL SLENYY SS eN hadede lene Om Pro Bo Toga bus © me made rs we en NFA Å tr au KLSLDEeLALDG agents, Watiing agents, Lunyidan ta , DEBBSLVATLYES, mt -. E -. + . - 3. rå + a 2 - Fr 3 + Pen io sømmer ob <a z rd RIE END SA YVetA YU a Tha CYR ONT ren SS ESS YO gavi $ wt ur 1 1 SOFDSNIS AMK SWESLENESISE. LL SGL NE ROLLE LS; WIE server nn Fate ea mig = er + sa pi es i syn mode DE nenengd AT: KACTLOXKE [ARE RSE] and Tie ix Fry iouiar MoE ar acminjistrationp and the nature of the dosage form ACMRAMNLSVNGTLLOSK and LIE nara OR LAT DØORBLTS ors. Fyuarylss øf SY rs and AN Yer ea ms f fle ENE eh Sd er TE i SEN ri ILMERIST ll EL A. 2.3 LEDT s wd LI LAS 2 ARTIT ESS SK Liles MLTR REET wed BIE Bvme lide før money) vrdi vam scarbonsate laotoze merit yen 3 LUC Lugs, LO BKSNDLE. Sodium DAKDOMale, LATOR, BOG LUT 1 : s 9.0 1 . Sd NO 3 “ + gen du AR anon By a de a ang od Tr lant me Y Tua Yo ey a Fyens wa wry, boy pn ke TY Von ae Wn an any AN Øm ae SN FUDSODNMAL 8 ANG pian. CSLÅIULCBE (ure DLAaNnt FIILAT 3 » A Tange OT i i 3 3 ! + verøtuble fats an 5 st la maner h S Lise ot i mv oagr tr even om Ie ir savmnil ge VELLIDT 4aL ASLE Gado Hi Y IÆED I FNS RA fi Aan GANG RÅ all DSE RO REEL AS ER + Orher eæxsesmuties of fillers of the oresent invention inoluds MALL PRE SM LS GL LFALLEKLSI GOI LIS AV resent lIinvent Lon 1LNDLUDE + Cas i 5 3 : 3 SEP AD ER reba re ey Ee aa 3 for 3 ox Sri el ory ed Te ENT SR SE oar a I mm en SUSTOISE, TLUCCOSS, KHMANDMNALOL, SOFDLLOL, and MAGNE SLUM stearate. + 1 Tr mmm 3 = ES eg va Tom Ee » + md -)3 3 NE = Ea me en Ty KT? n + Ds any is — rani at vy RTE Maintamranta of Fu TTS ey LESMBLIEE OL Jranuiigiing and gisinueglants oF Choe DESSERT . . . 5 ; » … 05 so >. . iontrgant imm 3 rute lias Fnr af mær ans mm ler eo Am msn in rer invention inolude corn staroh and alginic asig, orossiinken > . a rs aN | 5 … i x FRØS sr FANE TNE YE ESS DOS SÅ ery en Søs Nr Shh oy gm db evt rev Tay dt RNA prea ti gr TON ah he on få ØSOLYVLIVEI DVYKOALGORES, BOOGLUM STALOMN VTLVIOiaAle OF CXOSBLINKSO sodlur carbokvmethvl celluløoss Fører os mn ey veges TY pean en SCALUN CaTnOoRymETR Yy. cellulose jorosæacarmet LOSS) io i + 1 e + : 2 | ; : Los » ; i memes I EN Få ha im er — ey to A pa. en + RTE i oe år arie RLEAHDIGSS GT DINGING agents of the present invention includs J st : - : ana , oe af areh nøeælafir ASA a vellulgse cellulose devrjwatives atarah, J@iatill, adaclia, TOLLULUSE, VELLULOVSE ACYLVALLVOS, mme =- methvisellulose wt eee erat at 33 rn cellulose ri [UTD as METRICS LAURE, MLCEKEOCEVSVa LINE CELLILCOSE AL , 2 4 om LL. - rs INS SE KEYS I SNYD mt dd reven Er 4 oben a Sean en pe Ans AVIYOXK FOD TORY.L CSLIULOBDÉE, BULVFLNYLDVYYVOGL LOAORNE TUCYKOED 5 red embed øre rl sr Tom ett em me mnt mV eersbeend me TÅ Teen wand {den 1 a0 DGAVELAVÅENE GIYODOL, 1a3actosd, OF TVUGAL ALCONOLS Lx NYLITOL, Smhi mi ans ms led Pad SOLOLTGEL ANC MALTLIDOL. Tae meme i os ne gr Ty abe på rn vide er ban ras Or eN år 2 rede me åt gad he Porn gt tir So Er urt 3 me Fy Gis 3 EY YNDER mM ONS I 9 NS EN Laahiplay GE LUDCLTANDLS OX the present inventjion include . ; : . . 3 3: + FS In wd AI SO ØS tm Se frede SÅ ee eed På mm fm Toe MATES LUN SUERTE, BL SaFlLD SL AMG VIC.
ES md Lamia OX suitable OXYZL COMPOSLELONS DE the present . Å : , a x > | + . x » a imran tion Thc inde tablatee Sami ie rørene ger Fyn orm inventlon inciude tLabDblets, capsuisa, Llryoches, iorenges, OX årene OF 3 (2 RY FLANUILES. > “eth = ean em 1 ett Æt re Sow on at åt ere 3 x k øn rr eT 3 35 Dres en 1 ro Fe HET i ca h ti FYLTENYA TU GE YA TYING Ni Tr CNN ET Fr tt EO YY SEN 3U Ing tadlets oF Loe AFVORL LOE Ay SE PLOUG 18 Aon with conventionally so0liegd methods Tr ener ombud mant ++ WLED CONVeNnCLLoOnaLIvV 83pD91LEG MSTAOGS. IN ane eSHDOGCIMENnT LOE s 7 if ML Le : 03 : % . : : s pnd 4 enor i dipect compression and LARLSTS arg DCLOÆRSAQ NV ZODVEDTLLONAaL ALFSODE DOMOTrSe 381% ana : + + 3 30 3 mt 3 3 % + I im esthor omiunmdtimonte + h Co Fal Tan om PC TY Yudit mad er semana rot 3 ee 1 in other embodiments the tlaDbDlets are LYOGCUCDSB Sy CTOMRVLRLIGDA hbn YU Formino t wont ones Se h me mu Teatro tnsn Intech ion LIS TTR DOIN Td SELLA ALTARS SWC ad HUS LL DUT EB KOLT AN EDEL JARJSLULDE re > , , N : . ] ro Try ev Sd ree mag lamme rr SNO OPNLF OM PMA IGEN Sena They Arex Å SATA OFRING ol ye TIE en THY LOU CTA LSNOIaK Ing ar OY FSU COMRTISSSLEN ÆOLALNT. ne Qa cove dx den er ng ET en ge pes ev 3 vane Me ære Ve Hr ge Y ert vt er Ne Ah RE ST ren 1 ge met Feed cer raed ie vie = i I yp FILFUR NUUK SOA YY HOR dey nen Yet ve 2 helnoG VOT ODroGGauTring Taniels DyY vadunum Compras sion molding : + 5 Dive 1 Fl + \ 0 . Se iron iar SA lang Fh TEN RY + sowders into a die SEY LAY NS MDLUGES TILLING The MIKTUYVE of Dowdasrs )IKTO a ALE, apoivain i ud £ I ” - i od i 2 3 i. LEAT SUEY LIN Blan va PRE SIT a ev TY Fre Der rae Nød sk eN rem I 3 SLY OY EANTEAVE ner VAL s LAS LEDVY CDOMDaCL ANG CMS DOWOISF 48 WELL 88 DFSVENTILDG Tatum i? ad oat om vous i tir Sa Er t Pr åg ENE 2 LANG LES, KADLA HIRATA 32535 SCNLEVSO LV aualtlilg ie daw GI ht ml ate or ir lar toe] His haat ny raat it oo EN A Faved mr mT HOL DIAatle OY S1mMilaly TOOL. AS Ngan ingdg CZASUITE IN A Tuslon of 3 2 30 felses Ea endt 4 gå os to create a Treen eds ey Y mme 3 t Totem emt 3 ws + hg a+ LID RSS LOL DLR RK ML AL om SELANIGNLE EN TID RD LIE MIG le ON RAND FE NILEN LE LL Yr i 535 5x : 5 am i ao 35 . 5 . = : FIT ER YN RD SIR I gig amt ol xr TS SR 97 TY Pha 9am Tx MUS, KE OY OM mn Uni MY die is cooled ra PLOGLV CO SOLI dify the sam 2 le. More information mes be Seite - er frre may be found at meltoren.oom/fveom. xx xx MmMabs late me avez les mn rf + ho renter t 3 onmwranb im ma h S UDOOATLE ma FAD LELS OF CaDSUIGS OL Lhe PTESANTt ILNVENL LOK May Je QUDnCOAaLGR ger rr; bear heri mb i ørene Ob in dt 3 prøves must Ae avy or øe«oaled By Known Leanmidues. oud VODALILDOSs may asiay
5. fo . 1 1 . , 2 Lo Lo + HES Fi eN mh ovat i omr msi ig 2 dm ge »t rim J. i Frem Qt ME meet 3 min 3 Lo giganbtegration and thus, absorption an the gastrointestinal + am en pm + met fra mv NT mm amenTE a På - tt må me ad mi 3 men NTFS - ens eres at LYACE Aangq/or mav provide a SUSCLAlnea aAGLIOKR over a Longer ~ mee am sed Re sen am de -3 3 ay på Be he Ae, Je = way en own op ne the 3 peg 1 io rr io % DKF ØU Tr mt ambien ree he YA FIE orn I COIR t ir ea Dr period, In an embodiment the pharmaceutical composition 1s an - ve dn ey nes me gave ay oh av 3 CR I +, ps EN, Set AN Tog ” må gen, dr År » - hjem, ad 43 vs pr Er ddr em an dt ey ser, en Fr grå ds do rn . oo Ved vy BY hid Eat Sig reg + ho enleri0 cooateså tablet or osolet. In arother enmtoniment the msn cl Ma ITE form a a A Caran To In An oth so vitet Thame + H Sy 1 risa 1 8a30e LOCYM 18 A Ja BASIE GLÆD é Ads drain fa — ÆDASKDGROE RIEDEL DL EDER ial 20 dosages form is an ontario goatee ecapvsils or enter Fe event ari ob WS a3Q8 Ln LS fl BILLE LO Ua iad SSR ULD OG SS LLETE LE Le LL SEE år de, To, Ar T Do øn dr ln em, ae FLUE, ov rd gn ey ye > in a fon dr a EI eve 1 YS ve ow ETP vn ex a Be Pagdiaet,. In another embodiment ths oharmmaceuntilocal © COIS A Lon om am aramid devas 3 ment hor mb eed pen pn Cc 2173 må on en 2 18 a unlt ooze. in another embodlment Lng unit dogs 1d a ur i rire i tabl at scanlaet ry smuk 3 og J or Fy mr ene fr gm RY fr Hingig Leider ll, caplet SX CAaApSilig valle EAN af ARSEPL AR I LÅ er og ir my Sr rt En Sr dy sst 3 Pe Wma No mir ne Ar res FA ISS Ps rise gå FERLELANT BGOMAT. IA ØSNLSKFADO-FSSIELANnT AGENT may DS INOSSN LOA PY Fe vy am gm fo 5 + fm - iy rs a be -2 fm f Pe ge sm Ye eg = i Mme mm Me RDS AT AMT amme = MÆMIT OT SID Se WYATT Fs ? Ea oad GAWDNG The @nualicrTagisiant 3SJENT I MeNnLTLONneaGg saoove LOE Tha Eraser dt 3 raps en EE been rang dr nå we TOTTAT ANN ST TAE MALY1LKX,
RETER DOESORTETTON OF TRE DRAWINGS MEAIB DRholUR IPT LUN US IX DEAW LRG Ten lam ml Treen riey sled eat inst 2 re, mt bus weer penne tb ll wee Toy ena ae In the following detailed portion of the present disclosure, a SE en m cnet mar ba an Try emsnt at dons vw i Ing the ASDECLE, aMmhodimeonts and inpiementhatilons WILL he
& im Semi ainesd in mere derail with fafoerenre tr the eam SXLAINEd Ln FOFS detalii witn vefsrenges VG Ene SKAMDIE omhngdimønts shown ir: tho æavwnmnloe and the Scrawincs ir: why dey oe OMDOUIDMENTE SNOWN AN TRE DKXAML LEX and Los drawings, IN wnidnd os i 3 " . i FE a. 2 a 0 $e Soa an PÅ å mee me oon BR dd er få 3 sens "89 dt § eae hanen ST es sy Se MS AI ? > OF eN er Fig. 1 is a diagram of the dissolution profile av pd i.
Far z Få wenn br er SSG KN Tore de mb Fendt ge fmen Toy mir “~ Cpr yy dt wy ery en 2 GLIFSØCEL COMDKSSSLON TADILSTS (WALL) Maving 8 CcCoOncentratlløon of methotfoerate of 15 ma and 28 mo METNOTFEXATLS OX 13 MI ang «0 hg. er ~ 3 43 0. ss. 2 2. 3 ae . em 5 er 09 00 må ee ? ia § diacram of the dissolution vrofile at of 1 > mor £ du. 2 AS ou I La Li ram DEL COME QLSSOLUCLOD BLEE I s SI HELL.
A For På gem er eee PT ØR EN SA SAA + ede FO SIENA 4 Ed ASE TI SÅ SATTE? OS eare Ed SM oe F HSIrsCctl COMDFESBSl1ONn CAD 1eTS Cc op TLBIND VANLOUS BYDSDOELLORS OF sm 3 bie 3 …. . LE f IEA a. i TETNE RNR at i sen i ere Bens? envres ene So PÅ 2 FODE) ri SS DRMMA 4 1 SOLYFSTIODVLSNS OXKLGS [Få fa io MYUMLÆAÆDS ES mo ekunnser AT asrnm mt he dinsolution nvofile st nH 4.8 Fiog, 3 shows a diagryam of the dissolution Drofile at PE 0.8 fr = & 3 o + . i TN fmen : . Kl øn ONS pe on et SØN MAGE WA IE SN OPLYS ean I Yom boa fyn myren AY fy te NY VEY RE Ce GE €9 3 SN for direct compresslon tablets (DOT) and vacuum compression Tri rit oe br mit PFYIFNRÆD MULAGLING L8D SLS Vy). ' ru i Pic & shows 2 disaoram of the dissolution orofile for tablete SAG. % SW s a ALA Gam GL The QLSSBOLETLOM LSA da ER RAR RER RA ED LOSS en per SN - ITUNES LOC mn - SR IM - FE ØR bs eg 3 3 og i ør - PR ve 3a en, iv ner 3 Yee OA MERGER TD a MS: ed Tw TE we eet ore ro 3 vr ET NEN SA SSP NaAaTLICT a H FMOAS PEG of 20:80 oroducec by dålrevt LUKDYESSLOD ed om ØD ur ETAL pn m1 mo ae mV AT pe ge Me So, 4 mea) om 7 YE a or I 3 3 Fe - HOY NYRE SVEDE FIE SR EN NO SATT Tey iX ver = HM im > => ) Ty + xl mo and vacuum compression molding sat an initial på of pH 2.2 fox dey er, 2 gende — MT ren ay sen på . + nd my an png ay ed de I Og tne Tirst J Mours and then ananved to p H &.E. +
FE 2 = lta mm YE Dre YA SAS > h a Mm met. men Ta F my de my gt oo CLT. 5 EAMNOUWS 3 OQLYECTAF OY The ULBSSOLUCTLOD DKLOFLie8 oy TaADLISYLS having a HPMOAS:PEO af 30-70 srodjned bv direct compression having a HPMCAS:PEU of 3402: /0 praghioeo DY O1r8ect COD FERBSIOM 2 . wax Ce " - . rn and vacovuurn comnression molding at an initial of of of 1.2 for ANCL vwVacuwunm com BLDSSLEOMN MOLS a vr an initial © AR DA MIE La LOE go i, a FE ud “= PSR) TY Rd rd + em sn.
I or en eo im, om EJ oo Tk ROE NAST 4 MOLES and Than TNnangqgelQ LO or VD. 3% md oe ~ + ze ei sr aan PPE - a= te, £ shows a diagram of the dissolution orofile for tablets Fig. & shows a diagram of the dissolution profile for tablets med ger LT UMÆALNUD ET a TION OST DDS.
DEN er. k of SP eee, An er, mr RAN em AL alone = LT TRE Te NG - I DS NT sene Ny ev . SY IER RST 3 FR having a HPMCAS:PSEO o£ 0:30 produced by direct compression avis vrais DA COMDTe SE EON ma Hah iy AL an som i + i ul ak af rr H NG f nor NE VD be ldnddny he LAA 3 REST OLLI IRR SILAS LEE RL RRL Lal LaLa KATE MER kt ove + NÅ. tie LI gm ger de TA Fønss mp eed i Free ens rn sd fr py a 2 0 the first 2 hours and then onanged Lo DM Dada = 3U
Te 7 shows a diacram of the disaolution orofile for tabletes Fig. 7 shows & diagram of the diszalution provtiise For tablets ! 5 I pi. ! : : oe Mg HO » : mead ermel br Si sti rere em ad AM GS (410% and & TMG MM Gt 2 PFOULDS OY aALlCFØGCT gongrassion AT LFLU EEG SFA N AL SIE Ko fr 6 4 Er o er “ : ra 1 i 4 + - - Goma ou om vil ~ 37 1 > £ æn fr den Be æt mi [SN «Anst ame I ey ero md TAT Lal VH On I= HOLLY [oy the Dist Z MUDUYNS AUD Then oghansasd fri orn SK ; ~~ ØS LÅN oon Vet. 2 Fi rt 2D brmvger om SÅR asy am of ob hi a Mjeagonlution omrmofilee F nr tablet eo TA.
OG ALU OG La fj A GÅRD Uk LIE KRAV GF OSL LIE I ONE LDL LAE RAE RA RL AE LER Fire S Sme VI ADNMÆED P.S? MY Fr: Ske TT mened y - I > > 3 3 > me, ” on fon ja kor YO MSN on UI oO 1 or ihe PI Fri? Y ren i Fort mmm? mn Mm = i Mr having a HPMORZ PEC of 24:70 grocucsd by direct coompressLomM 5 4 . . : Cu Corea si + SAM LIT TR ATI MASS Dim Sram nal Rose Tat os Ser Eos WITCH and withoul magnesium stearate and &:resil at an initial a PE YI NT a oo I SSL sneg de TY ween pone maamed 5 her cele ay pron — de LY i eg ei NE j m Sen en si øn FS met 7 ene we PS Do hrenen eds Dørene fees vv 4 1 KAM APL Ep da nay ie Load RL ow MOUSE Anis LISE: Uiia NY åd La wn a8. 8 mom NO Fr mn io gm aA CA LEE nam an annen 78 Mowery om] ey Mes ym al o 42 HE TR T8448 andl Mei 0ods MPa lat mye, mt Zen Er LAAs Lda Tahblete of § mm diamebary about 3 run hejloht and FOO mo woicht Faia GL 8 mm OILABELSE sf ROUT > nun De MOSE. aiid LING m i ANEDE ES ES 2 %. 5 3 rt ~~ ? FTES A 3 TT LEY vm ma va Feed i Av TU æørseb rese eet grå SM fru veri meena EY DESPDareNi Bolly DW Dyxect LOUD LOSS LOFT LA HD WEE TULA Serre Aa EY mr lej cis TN FRICTREN Terri arioans ware Seve lovant fo 3 LOMRYSS8100 SKX3IGLDNG VILDE PETrMAL AT IONE WELLES OSVe LGD LOY af tablet containing 16.44 mo of Methobrøekgate Disodium |DS=MTX) SA tablet containing 16,44 mg of Metholrerave Disodium iDS-MTX) see ww 3 re 7 vr ne - a - + -. STRATA Tho r, a ne - i ~ ” art vy yomen de de zo cor ds di SOE SP ON Pr FRIT Disodium salt Was øoauivasent vo AS MI ma thotrexate MTX]. Disodium salt was + : 2 . Ht 95 4 ede PRS EDT FS Å kr vi 3 fm errant ae Røn bandrd 3 3 Far onosen given LUE Jraaner SOLIUDLLILTY.
Ma foret na Tao Tag TI some TORS HMS8LOLTLALS LG LA.
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Magnesium stearate iMgSt)i and Asrosii 204 - em ed wy 3 " —- 2 ~~ Ym = 3 ku I dee nn rom oe hs we 3 TS Få en 3 TE Per letrutlor sove? jo mg? uw the Faoulty af Health and Medioinel Wala KLIVSLV SUPRDÅLILSC CD ne radii ly GL AAL and Mailings IX em Å Tr Tynset mand AF Dharma GLEN CSS, UEDAFSTLÆSNI OX FRATLIALY =
DK 2020 70049 A1 Direct lComnression ASE ERE.
LURID ES AE Direct compression tablets {DUT) were prepared with a singls- rs RH 35 LOY bletsa | : Bræt g ingls punch tableting machine {Perkin Elmer - Hydraulic press, Germany) using a dis and s punch of $ nm diameter. 3 Affinigol™ AS 716 G was in granule from, therefore it was initlally sleved using a sleve with meshes of w= 0,5 mm and ge 0.32 rev, D&E-MYX was mixed with other excipients as AS 716 and PEO N-80 in diffarent ratios, Ll % ww of MqSt, and 0.5% of Asresil 300 as shown in vable 1. The ingredients were thoroughly mixed with a mortar and a psstle using the geometrical dilution principles.
Two hundred mg of the physical mixbures where welghted and compressed in the single-punch tableting machine appliving a force I¥L0Y N, MOTs (AZ Tig: PRU 13 W-80, 30:70) were also prepared by appliving a force of 14144 8 to evaluates the impact in the dissolution proefils of different forces applied in the manufacturing proness.
Vacuum Compression Molding The instrument used was MeltFrep VOM Technology (i(MeltFreg GmbH, SOITL8S, Austris) and the VOM insert used was VOM 8 mm disc tool, US-ATK was thoroughly mixed with AS 716 snd FEO N-80 in different ratios wlth a mortar and s pesstls using the gqeometrical dilutløn ørinciple.
An amount of 200 mg of the selected fovmulation was loaded in the VOM 8mm disc tool (lined wlth Polytetraflucrethvlens, PTFE) and vacuum was ER YET Y eed 3 Tr mr 1 gr ror MAD A + + Fr grå NET 33 gå 3 SIT a mygind Fr 2 aia 3 gx HM OL ra LER I ba A LL iik MAW DL mil AEE KFAR DEER formation, The VOM Bmm-disc tool was placed on the prehaated hotplate at 120°C for 10 minutes.
The VION was placed on a
3 3 F 5 ~ on - Ye æ o Senere 3 … - 3 2 ~ aa a second plats vere the sample was ongGlæd at room temperature for 7? minutes, Both heating and cooling step were run under vacuum conditions. Eventually, the PYFE foils were peeled off + — TY ~ 23 3 + < - va må : ~~ må from the sample resulting in defined gecmetries., HAS TI6 SURO — OS-NEX AS VIS PRG K-80 NySe lerwsia® 0 0
FE NO fe fe) de fe _ __....._.____________ ROT with glidant and Iunheicsnt : rioSt:80 — fi8g.4 — f38,8 — 343,7 i: hi 0 ET 1 Sm 0 AE a UT ey St 1 0 Sm EE EEE EE ak gb BOTs sand WOMTS : RR RT yn seme bere re be ER nn - eee eee eee eee ness eee eee eee]
I Table 1: Formulations of direct DOTa with lubriscant and AE] {uv we le 3 0 UFSMED rn ed NEVE % Me Ta NY eam " gqiidant fFI, FI, F3) and VOMTa and 0CTs without lubricant ox gildant (F4, FS, FE. Note: in every tablet the amount of DS- - - å e Seit I Yee AM » ~~ A a ne ES NS i gore ae SN ervey MTX {zalbt}l is eguivalent fo 15 mg of methotrexate {acid form}.
+ Tr FS a hy 2 Tas . Rr Po + In-vikfgra Drissofgytlon tests Purified MIilliQ water was uzed for the preparation of the 33 nn Ca CR. JO Qi me. NE, on x Ao Sn a cr met åd mm media, For the preliminary dissolution testa, for the acidic PS TY mn i OR = ten gå Te + 3 + EF om, 5 re 2 » de >ym 5 - media 31 Di N was used whils the huffar stage was a phoaaphats 18 buffer solution pil 68.8, In the delayed relsase dissclubion = FO rp an bck Qj + NA Ze 3 3 mr el ro NS FO, oS > ~~ TEN test (Kur, Fh. 2th Edition} the acid stage consisted of 750 nt ~ TENT aD 3 v - Få + as AE ~ = - ~ any - mi OF HCL 0.1 N and the buffer stage was achieved by ths medie —~ NM Y deg 3 er aed 3 ber I - Adon ood VE: rå an ny + addition of 258 aL of frisodium phosphates dodscahvdrate STE TEN m bed 3 - åg uni ~ on ~ Ae AT Aye 3 Æ ege md 3 2 = yo FISFODR) 2.2 M. Standards where prepared both for medias 1 and Z0 media 2 using DES-MUK. er > m 5 x o ne 2, 73 700% EI ur ET EX YDLI måne om & em Every media was prepared with purifisd water, Millitt obtained with sa reslistange of 13.3 Ohm using UV Ultra Clear surifying
= arter & gary [SG szvaterns Derma war The ai alm maeddis wan enn zen yA LER Leia SR LAND Herman Fo» AARED — CERA SL SAR Re ANAL — VESA LÅS CE ON SKOLE hv Z20~min ultrasonication using a Branson B3S1i10 Ultrasonic AN PTL ER KAR VOR ER DATES LA SE LANGE BURE AN fed ISR LLG LE AO WL ER ASE LA mn : a + . z DOM SRT rr 2 + de 3 i ey AR wr Te yr dem ae TON IT Synger led de ay Sgt sg 3 cisaner (model numer BooiUMY, United = tates Fo ro Må aor Ti der ead a pena rae berr høste li mes ll sb od AVS SYNPLS py big TT 2 Dissolution testy were run Dy means dissolution apparatus IIT fev mdon Vet fås ent Vs n 3 + va OBE Ars & Et Å ES, ed Aden ontt es 5 EA: VALE LL LTL.
VOL IA VIN FOR I MTL RED Limi LIE FED -, . …S -. vy 1 ie en ed Så in ee ee 3 - : > 3 4. 3 ræve x Hyver bie vom SE +23 1 EN | TIP rr + ADDAL3LUS, UTTL Lad Savas; Caled WoL LI SY WES ra ty Eee tm SPs yy sema BM fm dar LP RTR ) Mm ex SP8e2LYOPpnNODLOMSTET 1VArlLaADMLo SYV FÅR United SBLATES) » LOG … Noes —-- me ! end re . . ad ed or FE 27% 3 ris ar mn T41 … i ran at en ] > vy å mom on 3 ne TES SÅ ge HAISFKOLUTILON apn AFALTUSE Nas VAFSKLIS ang sadn one is js FOVLOSO + SE 5 Fiber smtils nr uith am sofie path Tønsth sf BR mm — PP + 1 SE a LLOSF ØVLLC DLODE willy an GR LIT LETH engl GL 3 mm. toe snectrovuhotoemeter and the li en ak rs ATER RIT a dE €D fn by spectrophotometer and the dissolution aspparstus were both + \ ~ cert raw ams + ; . i ~ - Fron dt ges 3 OG al 3 7 æg Fig mn TINS Fi musiker dens TA ge ge, 3 mm mæ x oft ge CONEY LL o Yoo TY WEIR VLSSOLUILLOD Anil an inn HOLTWarsa fsvrersion 501.0, 10960 The softwars Seneratoes ur mubormat tet iVSLÆLDOE om de Ms LN LIE BULL LW UR dunes adil CALA LC FSRTE LE fr . a 1 0 + 2 so 2. 2 2 5 3 3 FEY i here the + of rust øivnmænlverd je ocxlioniaraed ang owes aly UE Where Ene 3 oO £ dr Wind Ua Soave Lo wali nll Arild Wi OST a. . . te et de ØS SÅ ES id Correia.
Following analvals of D2-MTX svectra in both medias nH 1.2 DALAL AW ANN — ER ARVE EL yaaa Ll LETUMLA SPDSUTLFS 21% DOTS Medias (Re) å nå ED VT ena 3h - . oe rm ot a £m 3 3 1 - am 8.81 3 Tim ans Gå næ lave cohoszsen fo tha absorbanos and 6,8), 307 nm and 104 væ were chosen for the absorbance aen a oS pe ay Fem am rer anv od nn A an en wa ed yw em IN ES gan EN de vre ] or XX IN FAG, ] e readings for acid and buffer media resnecotivelv.
No sample was withdraws from the media in anv dizsolution test oliven MM HR Wd Lh a WL AE REE HEEL GL LiL GES Y VEL SE SE or ds Bd he ABER he LSD Nn DR uk FONG SE - 3 - — + ~ IE I wr 5 Fa Ap - . . Pm mm ede rma mal mn & rr Le de tre me FI Fyn To rey oe that sach VENS OF ATILIÆNT VAL LAN VK FS V-SS8Y1853 TU, | nok a - i my - - 3 - - - 3 Fe + i, apr He on - Br - - on ben amy 3 rere ly der Then oy op oy be ri e SYNE ert oo bo bod em EV sp VISUM IT ION ADDATAaTUNS 18 SVDDI180 Wish OpLid Fiber BPEODBYS, T, £73 ge re NE QA ay p AY ew oo em TE FOX er, åer A en Ny + THE & - Ty CY i mært NOR Ty mo YY Eh oT ITTY nT gr + TI NYY LEY Sv HR ew Sn we A flrst preliminary aissedutlion Test was run on BUTS of DS ES AT få vahlets loader så gi — TNEDLAMEØS mevii di wren E gaa de 0 Ge TE re rn SD MTX fS vablets loaded with DE-MTX equivalent to 15% mo of ; ; mg de dn er de er pir i & - 3 7 0 de mdt ende ard de RE reva deen deme de dee THE ei re vet be den er Be ope ge Sy ; nT egt oy 4 er ea army ony 6 om, ri en meilholremwaute and 3 tlablets with the øouivalent to £5 my of me bund mr mm ori sed OA wd mr FM RO TE MM: me Sheen me ) 2? emer ew Sood ena Ar retholtrekxate) and AFfLfiniso£f 8 AB Tio © as Che onlv 2X0 BLEN t 3 amr mæ ÉT A Here 4-0 on + mo mo 3 ar Fe, boxer men dok 3 A ws prå 3 få 4 co CONELYK nan 853 fin 5 LPOQYILY FOLD LD an ATLET SATIRE Sarkrhed TT The fd gaa lat dor bead woos TUT ow 200 ml + RD 1 SLYLFORMENEE .. fe QAO iUTiIon VeRT wal FUD 15 FVU mL OL SÅ 2M Fu HE RA ge gm ao 2 = Ur SE en ja Ter ing pe CEE Ch TE EY YY We Ed - ZU Weld By QW TTF SU. &… LOE 25 MOUKSK.
FANS Yadoands wnaeye mer Farman hør the juin mrnbes ato oa RA SF DUT ver Tha lawl Per oTmed OF TLS 1IN-SLE0 DFODSS atl a A OX 3d DO.
ANE LIST eo møn ie $ a hev spå be ge yer 4am oe ren d ma AE ey £ ar ro + os gr Tob An A TEL IN AEN 5 + > FN Et AO RONIN + SEN TORN AE: io + re IA ? i mer FSB WAS MAGE afLler arn 2InNnKILDALVGE SS BOA JE RAR Lou EL fan FOY SUV man Jas Der formed WAS Dericimaed. x et NAR Yd red er om oe Ho nyde 2 Fr eigenen TE TITY FN Go AEN EY ATO TNR ES TTY YX ro Påå rere late Dem = eb fe, n tr + PAS pr &+ 3 A SAGONG preliminaryv 1380)iutilon test was run on 3 DCTs with 0 - FO TN ST SIOE AT SE TY ge rå GE FOTO ET - RO VG EO FORMS, NY 2 2 ? SF Blab og 7 a FE med y > = < TZ 4 YY Wa 2 a An fFLOFTFEÅ, edu LALLG OL Jul iu anda 3 ALS A AD Jans rdlr ow CHET mere mt RIYA dea may Yoo mm de hae infivence of different HO owartio of 3D0U:50 to evaluat: the infiuvenns of differant . & 5 ne ie ~~ Se en fr re pe SY {ye ed åd svie Grå dt i - vo aac lution ert å 3 en iy eet åen add EE ag FAXE FAO LAE GLBBCLUTLON MARA LAT aid SOLO oo ve, 3 » FR : : i SUN - SE DYDER NR FTE pe VO År MR en SÅN OD em dt ein + og i No? ya 3 2, GMO ml + $y 1 Anvironmentn. 10g OALSSOLUT LON TEST Wad Duy 1219 SUS mL GE HLL få 0 at DM eemen — Of ay Dom Ee — st der ey wa att Tey soba va Wal By av TEM 3 if. LL LOE 5 HOUSE. Ei reais WELT Eoe on o 0 Cy . i. ; . + em Am at ~ i eee Ternen ber dig å vred 3 fr 95 wna bNes ir SP oo 9 BOT ven mme tant + UI serrormead øv Tone 1n-sSL0U3 Ronse AT & A GE SUF ny. ihe LAST TERAing WAR Male after an infinity amin af 150 rom for S30 wir FEAGLING WAS Male ariel an 2INKAINILLY Spin OL 100 FE LOL SV Mil på as verformed WAS DSYLOTASU. D AA om ere Tan 4 ar be, en de = RTE . = i; es dn ert eg Fy St rer ~ FE TI FO ry å Giassolution test was run in phosphate Duffer på 8.8, The “ Sr [I . ann 6 + " <x . en - " ir Imm Tre Sm fed rama amar ÅSE mai med 3 nm Ad ORE eee €e 13 GHISSOLULLOCS LØST Was Mun In 3 0 1 mL OF DEAQLA SAL 9V KOM Tor of 3 rn SÅ . a. ~~. his mer 3 Pa 3 I Ee - + 3 3 i The reading uwhors ma norma Forf hm Trea 3 mother st og
3. She readings where performed DY the In-Situ prohes at oa A oF 30g rn The last ves oi TS WAS Ma de n3frør an j n f Sri bar oars TO £ a GAR ils AMEND LR LRA 32 35 — FREE OP RAED SE AL LD 3, RE) rth nla LY Sp AE 1 Rf mim af TEN ran WB Mer From SU MIN AT Lol rpm WAS PENCE OYMed. 3 TNE ener taste d me tet Tena Plet mirreari ove Foon ry øn del fåes ne re DV 5 a ame TT mr togt a+ tor FÅER II RIGA SNE em PN BOSS SN SR TY DF I ON SÅ PPS a Ty GEN I ry EN f OR Dissolution test for delavecd-relisase solid doa ve TOKLME (FA. Huy Ark Wey 8 omy — Mærhr & AnyYmaratiua TY {rand i gi was HUE. HLA RCL LON MALI My KLDSFaATLDS bl LDS W33 øihrger + Tnvsatioaatras Tha raløonus vv i + le m?o + AT Føl + FF ayant CNOSSFR TO INVERT ILOAaTS Ins TF&ISASES OLGOLILG DL ne UALLLESTFSMU Yervermi:i nt od evra FER mg veste ide red ae 9 4 EN SO et ror re coed ei mb en = rå LOKIMULARL ions. ne MELNOG CDONSLSTEG DL Af 40d STAHOO ana oa bas FF op bm re Tara mir si3 eared ard So mr + oe opf Lr e iii 2 an de nd gen FOG ene ra Sy LUITel SLAGS. LVEKY GLESOLULLOK LSST WAS Main in QVYLPLLOSTSS “Yo ED on om 3 £0 er År mm) - aA - - … he F - ET 4-3. Få 3 em rå, 3 gere a - + en rn abe pE Sea grin ed rina 1m Ed ert frøen of smn mb møs eT tres ed cere dad 3 era er 0 for sach formuilation. The flrst stage of the dissolution test rr HA ST enge TR eng drer Se FEDE maT YY SO å ed mrened — Pix IN was vun for Z hours in 780 ml. oof HOL 8.1 M followed by a erne Så de ore syd SX AE oT — Sm da ned A ar Aabo er n år Zeng BLANT WET SUE ni aX CEA 3oUIum phoestnana så og … + Creed re de POY TREN ON vy “3 We = 6 -. mx mh rn 3 - J - fr re 3- … Å eg +" Aeerdornbxrivn tg fYGIEKDLUN i IWS ware mrirtenrri ir Forde + St LY tk LIAR IAIN AL ad KO LOE gL, SM ware guoed Ln order TO DY Lng the An dn ED 08) raa + ig der då er eae æn er der ra fa em eng ee - egn de mp de TY TO 4 4. mr Ty Er] TOTS To EN TKD TRÆER TET EA OIL 0 Q0owW > I LY NI Enw et POTD 9.9. FOY TOO WODLE Rroadess TODO TEMmpeuersalure was san od t i - Qa . a 20 re 1 B Ye ae od Py met dd ey Sey ond OGS A een tri Ta = + EØS sewn su af KU. C and the rotation speed of the padoles at SU rpm. The reagdings where performed by the in-smitu ønrobes st minute SNE LORGIDGS WAEFE DSKLOKMEG OF CLOE 1OD-8KlU PYOMSS 30 KMAUNGTE od
ON x + M + £, 5 mn I aye od gl eger od de der em, rs oy 42 er sn ae - mx THEY 3 fo FN ri AN av Fi are therenpftør Nye XE SES Ds 20, 15; SU SO, 45 and oll, and Chereaftear, every JU Minutes until the final rondirno FARS TvarFormec at Fh after tha 7 LATE LG Le AFL PARSER EINE WAS sa rLOre Aan i fa FE LIS i ? fo ger . a om 2 ye . yo. . mann am SEA LY Rar DF Mm of TEI prin Soe i wad ow Ty 2 vr i > MHOUFS, AN INLAFLTV SDID OL 4356 CCM LOL Sø MID WAS BVDPLLED LO i J 1 i 3 9 So hs vas = . . på overse the rmomm)iaete mi canintion of the MAøngmnre Frys aAnsure Une COMDILETS DLESSOLVVIOPR OU LAGE Qosads LOTTE. 2 FR mg Ju Tan Re apn an pn aa RK an AM Ar pa ay an TROL manulagTuring SEG N-B80 showed to he a fyr EY revrå vise orienterende pwned ep TMD i aed BY OM Øv ct Wa ane bo NEM + TOMMER Ed me FY Sn YEA MANE EN ay Veen mer ? Te > ås gt FEG N-20 showed to be a frse-flowir T FOWISE and LOE ALS mae Farm lat dor AV TIE. DMT ONE. GDS sat irs DDO sis me rear TE AW Iormuiation AS f18:PECG N-BO ratio 20:80 did not x SOULE any © ory . EE . Cm mo 0.0 de = CL - ri 3 På py + . Vader dn or A Li TT TE v små em ? Teturen om Sir st st GILIGANT CE 1UDKFLCANT. HOW&Ver, On YS1LCA MIXCTNFOS OL GLSALGE pe FE 3 om som Ye TRÆETS Blew ce gr 2 rr en Dored br den om sn 0 eg i ad am ge + 0 ed . i Sy Ti ge OVS Bin 3 å rs med ve Tu vor ; 3 Selen Sew by > an AU AS TLL PREG N-80 ratio pagulreg Lhe use of giidant such as Rhmyvnstli 30D fØ SE wiwl riven The Soar fFlowabilitwv conferrægd ASYOEIL SVU AU IE WS Wy govern ng oY LLOWAODLLLITUF CORLSYYSA » : : . er Aaa . 3 : se a Ro meant re mor te mt 3 og TY A Try more tr "md sm ad ede io rå 2 YoLAGOE AZINE AMOUPDLSE OL ABD FLID. AN Order TO KSALCE LYLCELLOD Levere sa Taglar mart ma Meds SORE hg Ava d was ino iudad ir bes LATTE, 3 AUDBLLIASNT, &3% goal DA am TE WW VAD fAOLUGEG 19 LOE Formulstinorn AFL DSE SE. Lhe io i oo : or ed - : vr i + £3 a A aren 5 9 TMS GS SS pes DYST a FUF ES FAE GP EN Lovie ey a [a med og så eg re ir LILST DYSLIHINATY BALLS PISDAareg Where TIK OLIGSDNÅ nar < . . . ; + \ . : fn . 3 & 2 lubricarnt ware used a Taveriory was whistle nu praoanal oo lonr LUST ICANT Wala used, a JAVDKLLOJ WAS VLELDLE AS grauaal Colour Tmt mre Firnstddoamn ob avh ine Tren they rt? 00 F mn Sam med me boners Ar h am dre intensification starting fram the surface in contact with the mg, pe US k Ye: FÅ dan gren ge de SR RØN HA EY wt ØS SN Den ove my ex een Fo So rå de lower punch, The different lavers were irnvreasinglt VV oOVLELDIE : . - 9 ene ” , 5 2 i for incrøssine AS TIS: PED N-D: nt dyn urt Phnom ou TØ CiEST < Q LOE LICY GAS UV FAO YE, Gi ATL, ared the K; WERE EVE + 8 e EE 4 a ro. mo TS 2 + SE SET? Str Sen Ar og dn ] he OP LY FE? ny + i Ro F% og == - mo my boa mors evident for Daolel porevarec wWltUD Ah Si AS ths oni y i . 9 he es fe : \ : + + 2 Lo , BROIDLØNG., All tablets nad a TOCULAY OVLi1NnOEl1Ocal aha De. TX reen vt en de rr on be SE the sinole-mnmunch tablæetbting Hytte > hr FYE rå am i ST OTe od Yin Cr rey Lm et tablæfttrig MHOWSVOE, LAS WOUD-DUl PUNONGS OX Lie KLAQTLE-DUDOF LaDLSTLNG mars ne or tir i + hx se Foarrmat ir sf a ST Eevee ane mu thin Mr ma ine seg so Ene Karmat Lon Gr a Jroovws and very ENID goges 5 fed i emnrd vre bE es nl Frysk de ES ar ÆT 33 bo mdr gs de Fo] TA Dent eet i mer 2% fer? , En rt 4 oF Boab 3 + 3 33 SUE oy 2 i 3 0 faliowing the perjmeatler of the tablet, ALL IXITS8, LD LUGLDOG Foe FY ee ened any sree bog vie £ SEE TE or TET 0 N s h Cady a Ce ad Chose prodiuoes OY appliving Lola Qf A EU WN Sided GOT ven ed a A eg cd vr a ne I Sr nT En SS fp ie er bey a J Sri avid med MOODANLIGSE SCYVSMOTNM, seemed to be robust snough and not Fed abla fed 2 LAA msdn = DL AA ge mim dn LAS YDA ay we em eon ox © Po a ve a a 2 Cl md å mr må — me Fod wm ES weno 2 2 fore MO DOM 4 Syred bore "en s AT DC re OD 3U UI fFerent VOM DFOGESS D3aTaMSLSTSI iNealliNg ANG oiling Times wry ed bmn Yes Fra TT em kd 3 DEEL YTEY sn Pry om beng sev altar Ties that PNY Ea oN ANA TERDESTI3LUTER) WHEY SV INSatlLed DONSLIGTI? i LMA ania of
IE
FE Nemrasiation frase gveee For BO TIE hoørrir st TAO TD es 1 Cyt GAEGTAdaT ION Drogassas Far An fl& DSgin AT Lad iL. ne Lowey oo eg og re os + 1 . ed 2 ave I TUE DENY Neen ratios the lower was the onerat ino Was AS FLEIPEQ Die au Tatil, Tha LOWBY WIE LNG OODOPSYKATANG TOE ES TT AT TT NU OVE ENSTE SP OS MY Mrigsv fm On sm ia i SANPED: ON Sart MT ww vb khomosanntte LOMGEeLLAaTUTNe NSAGERQ LV QFQEY LO SONLEVS a VLMI WLUD MNOMOGSNOUS N N J . \ Eo : Vo 5 g onlour that did not show white vartim:lates on the surfao: colour that dio not show white D&AYTLUULATER OF the surface F a og A bier 3a STG ewer op Don fey be Fo Yeu mer ov or ene den ave on oy dt Ey de pve 1 aA ery ay DA 2 ag those an Kiqure Xa, For the three chosen TOrmulallons (AY vue DN +. gm ar TY Lim 7 "org mr 205 aa Yu oy ON MAN HA ay SAN Se a & ~~ 4a rr SEs IY kli id Si em F Pe fh Ihe "21 Se LY tha navman adds SN a Ae SM Fler PRO N-80 of 20:84, 50:79, 5050) the aooeptabdle operating . . . , ove x åre . mr I Torn nes gb eg Er ve gn mr Lady em re on, t at sevi td FOA sen, i Yi ed dR ey envy TUE RR es gn en ob LØMDEFALUKMES WMNENS MOT SLonliilantiy Lh Ln mR] Lvifferent ho. 2 . . 5 i a + en. ae x Aye Am af ins ANDS. meme) Tore TIL OMA Sel onrm Panto sr TIT a 3 Lar YEON NVSAT ING And 2001100 TIES Wee S030 TESTS. LVENTUALLY, L144 ÅL Lem ITO minintøn Fi 1 Swe kg Toma mont Pr i 3 mere showed Foy be na LOKF LU MINDLES LDOLLOW&T 2 Of MINULEGSE QCOGLIDE SMOWEQ LO DE A nn sn , . ” , er 2 - . : . i øn cr ents ends dog eden § org Trip ee oo $d Fo vomit i sv t å ram es ar rese vue + 1 FØRSOLSDLILS OnGOLCS KOK MOST GE TAS LOLMULLALLONS since gave ANSAT ah lo Mn mil be JA Parma AF HKD TFrrwmitfs an ory ety fro 1 1 SOUND TADLD 230108 LN Tams OL UNLELOKMLEVY ang COLDOUYK LOE ALL Ae ee em nt Ae o LMnKSE FALLOS, Wananga Tob
NESE LUE 7 fle 3 set ære dene Rom ae Aeon tit dom hon i -- Eem WY ET PY DANE 18 The first oreljiminarv dissolution test run for DCTs of D&S-MTX PAL TTY MOSE SD SNIT NOV ie t -~ EE Tun FR mr mf io mere rao ste oN SENDER zontaining equivalent of [2 and 209 mo of metholrexzate, showed mt bs Yee LØB IN ES TE Ean arn A en FLE RANT 5! Somme vMEnØS Ott yt OA re TYTN em that the mean valves for DE-MYX dissolved were 4% for DCTsS of “= ae me - [I oe … rant FEN 4 = - VT me med BOR Frie HT © CS nr FT eye 3 Seer FR he 05 MI SKE 2,38 LON LL TS3 OK 23 MI figure ii; ar ter Sh the ~~ No - , + am gå ke DYNEN MI MWR PNE … ge RL pet pen NE oe an II i + ws an an de + dissolution test running at 30 røm at pH 1.2 and after the - . os : S rr 2 = \ 2 mn 3 mimik en pr a PR ree Be 25 ay 4 Pe et PL ørnen Så DO 8 LITLE ATLA SLi OE Lal Lom Dox SUMAN WEE periormadd, LA. LS . a an . + bat me 3 . Co LL N.S | e. MEE GS thi vw evr) i md al? mb RTUS AT he ned elvan ferm + US lonzervegd thnely CWlindrlcCa8Ii aha De and When WiTODOranwmn Doom Toe SÅS meeen Tat å eget yriened 3 os: SRT EN ] rr Føl SR 0 ENSNS OEY si wy eet i va CLES INTIONT Msg USVeaEalsd 8 porous BTYUCTUNTE. The dissolution orofile obtained from the AS 716 only D0Ta ir DB CQISBLÅULLON PFOLLIE ODLALNTC Tol LOS AS FLE GRAY IIS ID 28 mye ed åre Ormang3 3 Srey FA en EN doy de AoC fig sogn Ayi Sv i RF FT SY SP eye rå 3 ROIQLY megdla CONLIYTMecG Thal AS Jie LE Malniyv unionized ana er it gt rt am 3 ia Tada ley oad ob h fer] tre ES i ry ti = t co Dyvrengr end i oo rd eee WALSY-TULNDSOULUDAS al LA ULVESD DA, and va ALVES KALILSTACDLOETEY aen era 3 dt er SL SA AS eN GAS PN NS VS ET ben Gren oe en Er em A TREN RATES dan an ee ded de results in terms of control of the release of OS-MIX in acidic em ti gen, een — Kr 2 at oe his ~ ron tj red ENvICFONMmEDT Sun as Une suid dn. > Fy The second ovseliminstv dissolution test - agt eye TVET es ae 2 hm 3 NY hvem mi DR, MfS my 3 3 es tant fg NYY I TTT a. oy = aU fhe second praliminary dissolutien test was run on BOTs In oa == — met TREN kær £3 am dn Nm Et i mA er, - oor Sy on - 3 ae -] FI sær vere 3 STH DEO Al Yo mat ir sy FO maner re RU oder iay OD Ar gay : TOT Ya AS FLOLFEU N-SU PaLLOU GL JOLF ana Linh ware taavaed (pigure
DK 2020 70049 A1 26 2). After oh at a pH of 1.2, for D0Ts AS 716:FEC N-80 30:79 the mean value of DS-MTX dissolved 22,6 % and after Sh was 42,2 % showing a good control of the release of DS-MUX, but SEES såden Fm tjejer HEY Så Ble Tahoe a tt ) YA 33 re eye i rene mr ALLSE CAME INLINLEV SDAA, CNE VANLETS Totally G)13S80iVER ana Qa eg År eN AN. er. ~ + rr ap near + Ye o fr pen ene ade ey Yon an ST mea = - dew % Yo 3 shape was not preserved bur residuals of AS 716 were visible og the bottom of the vessel, for AS 716:FPEO N-80 50:50 the mean value of DE-MTX dissolved after 2 5 was 18% and 230,1% after 3 h showing aa grsatsr control of thes relsass of Q3- MTX, Even after the Infinity spin, the shape was partially preserved and the DS-MTX dissolved was 36,9%, UCTe of both AS T18:PEO N=-80 ratios 30:70 and 50:50 showed a good control of the dissolution of DS-MYN in the acidic media. However, these tests were run to evaluate the ability of AS 1& 718 in different ratics to hinder the dissolution of DS-MTX at a pH of 1.8 assuming a hypothetical situation where the gosage la retained in the stomach for us to 5 h. However, if the dosage form is sdministered right after a light meal, the time of exit from the stomach would be reduced. In the worste- case scenario the DOT would work as gastro-retentive device that releases the API in the stomach that would De graduslly drained io the small intestine without compromising the absorption of DE-MTX.
The dissolution profile of BOTs and VCMTs 30:70 is shown in figure 3. Two of the VOMTas totally dissolved after 3% h. One of them, tLovally dissolved in 4 h; the three DCTs showed the rer he, Ty mmr 3 gr gr Te Em pr: em SA 7 + ba on + + br må 5 entreen 3 HE Så mar see - Vd rd de TE same behavlor,. fr seems that the dissolution rate slightly increased after 20 minutes in phosphate buffer pi 8058, Overall, the toval dlascliutlon time was about 3 == 4 Mn. No
Tsar frøs pre re vr ey 3 59 = on t Pe byen be de OM 0 z he vesse ye om t t be ser ER: SHEE SAP 2 LL LAD 220 ism VD AD LD al LUISE nile a wn 2 vas . . ~F ho Micenlntinn Food OL TNS ALDSOLUTLLON LET.
Th an od dae meen) ibe dene ment dS Toe må ene) of aes ren od TPO SES TY bø og at yg feb deny mn de Senior es THEE 2 Se 7 » I er ne OQLSSOLH=LIONn provide DUALS Krom LUS Aang YLES Si Sin) » : : me hg ? ; . er romeo . | ; Iw bad TE rr, 30 såå es bre teret od " et re i ØL nem odd SE ede reen Se, åre 2 LUD pukfer meGdla showed no slani2kfilceant OQlLlfereMncle An drug AT mær it en rate [etwosr he For nNjiffarent manufacturing LAL SN SEND 3 AL A ALT JED LON ED EA LITE LMR AR AK LL EDDI lL KANE RIAA LE CR RL I EAD DER i renga IY ey ey då mn a h 4 a Pen WAS Fan Fey OVA Ty ate + i, en Peyton HAG ARENAS Led + ain RAE ETA VG Leo AASE LN She ARE KAGE NE LAV Lohd ER AL Sissolution time that showsd to be 3 —- & | The dissolution AE AS LE LAL Se A LEA ud DER ÅL ALAA RIAL SA RRR TE a lie + +18 må KO ID Ra RAN dt rat so do gm Som Bbuffæar TASTY om might =les ba af interest in tha SA EN ALLA 3. 8) rAd Kr LAST aerial SELE RASIN. <R 2 han Le? Qi i fri ef er AD OL EDER aoa 30 fly 5 3 he ta nNigpbae fnyane Forma ALE FOT SHOOS sf? or he Tu rv H a+ hud DER ke LAA Salam LS FOLIE AE AES 0 Hn anal La, LE Liaw II ayes dye af the stomach of healthy individuals Fey 3 == nm, valvnes of the stomach of healthy individuals, This can Da Des Tm gwd rom NE SES OSL? SYN DT RO i SE roan tl I fy er US RUE? SAINT SNG SDK DE LIL eKLISMme CASSE AS JASCTLILC FOSSBOLILODN OF mors OMNSMOR Cases as hvooehlorhvder i: AVDOCRAOPNVYVOE LA, FN -—- 2 . eo srry PUN. . 3 . \ = ie ; meen] ied em Ere Te LÆ TTT med RTCTRET pe 3 om od mrgre Sow A be LG DA al SEQ 1 BLLON proyiie on LG Fa ang VOMTs 18 shown 15 the 3 a ere … ar qn mye A on Wd i en 5 vw a i HØ] ot I srt + eg 2, on maar oat 3 LFissiere £ R+ anes 2 mm o3irm My y y r Qiadram KSCDISSOntead In LZAGUCLDS 4, AMLTSE == 9 20 SL Wal Ny LLIS 3 od - 3 5 ~ mo a ad $0 Te wit ge 2 Frisen FE a oo UT = CL 23 TY Waite mr > 3 fæ Dyr SYD a IT 3 Fyre OD t fig mv ar FLEJSAaSESK a mean ved der GL op fS Lol LAUT LUN e EW QU LAER LANGE SF let Tar då moms Tyree cad + ir Le Tn omen ed serves ow © Se ir tad RRS vw BO Le I TOTALLY Q18S3OLVeGd WITHIN § WOR and ou DL Tem WATLhAn 3 ow De Bode oe 3 dy dw WTS TW VMITs roslessed a mean value of 27.223 garner I oan MLIL ued Ny wNMULE Fesilaedlad Aa oMSAN VALUS ob £2.40 i > dr my MT 6 Mees re he den ar NFIVERAN we ydet - brint i mor, ide en, et & Q T UL LM TUPLLAÅ Two ol tne Yih na Daealdiicdd a LAFLEE LAL ET OFA ain ll cd år dr 4 le 5 mm på år dn ge > PIN ee 4% = : nthin d 3 oR snd one of then within 5 3s 3 FTE ære dd tin <en within 4 % OD and one of them within 5 % nn (Fa TUre& &; .. DAVE , aris} Gh Stå CY RO J Shyam — frgr må ; nes biomer, Ten vy on Wisldan HBSESSMONM, at ne DASOINADInG a I EE (ALESOLUVIKCT Fron gr LILY RAT Tp onen år do Bey hae en dy ov gen ae re ad fm i NME Tay arge ny Wave ed a FORE rev hst y al mre: med — SÅS Parmer evra EVE en de Fon LEER, Viel RB KEE LEA LE SNU RISE GLS SOLVEG MODMDGONSOUNIY, Sine On ØS & Pm ed TUT an ri Yee and eroded mA + by SS Ye oy E abe NLOSFORS Tha LA DS SWOLLEN ang zrodeQ.
AL CHE @&mwd OX Lhe 25 imens Tiida tomt Fi mead gir oa vi cr mot Tog aT Fa og + run 0 FrEgoiuvion test no residuals were detecotlahle on the bottom ET Fo oN PE 3 OL TAS vasIed.
Så la % ae, br der TUNITY LL 1 + TARE oa JUIN =D MER, TN re NY TD re hmm ae - mt ae mu hg. me Fyr br TET - FORAY of & PE TE Plow SPSK wmode dem on TEN. i + É or both BOTs ang VOCMTS of AS fL6:FEG N-BO rat32o of 20:80 the = — £ mg RYES 25 gs 1 - -3 5 4, 3 F -- rå ed fer de er ee 3 i re pe 3 = mV hole ae NE Im Dr VED TT Y TES TY ow fa Im SNE Fr mr FEED IIT To + ET of DE-MYX dissolved in the acid æt age ALA NODE EOS TO DE ar ep 8 AT AE we pe and both - + is er dn = =. ser: ? så PTT mt j Så Fev SY Pi ; a: + hey = hy nr = CY eed 3U FLINK LTRART LY Jgiinayant, ane moth OF Enhnem shoWwao a good SONY Tend SE ma MTX SE mame Tid em <r mend 3] gr + sær 3 TE ferm l COULTON RIS DE BIA ULESOLULLUF 3 KARLA ES LA Raia.
AA LOLA
DK 2020 70049 A1 28 dissolution time {acidic media and Duffer stage) was between & % and 5 %, If the dissolution test wirrors the lio-vivc tablets behavior, it can be assumed that the dissolution time, once passed the stomach, oould be about S.5 ~ 3 h for both 3 ACTs and VCMYs. Therefore, considering that the transit time in the small intestine is 3h, formulations with this polymer ratio ave good candidates for the delivery of methotrexate to the small inteæstine., 138 The dissolution profile of DCTs and VOMTs of 30:70 iz shown in the diagram reorssented in floure 5. After ? h in HOL C.L LALA AED HEL AM: DRT LRT LD 10 Ix UULT 2. SLÅ LAT 2 32 53 FILL Af. NW, DCOTs relsased a mean value of 21.03 % of D3-MTXK,. Two of kablets reached a total dissolution in 5 & and ane in 5 &+ > LAMNLETLS FS&TNeSd & Load QOLSSOLUNTLILOFP LF 3 0 and Que Ln I = Nf. After 2 h in HCL 0.12 N, WVOMTs released a mean value of 20,06 in % of DS-MTX, One of tablets reached a total dissolution in 3 hy and 2 im 5 3% he Afler 1 h in the avidic media the msan value of the + dissolved was 13.63 and 11.83 respectively for uCTs and VvOMTs. At the end of the dissolvtlon test no residuals wers detectable on the bottom of the vessel.
The dizscolution profile of BOTs and VOMTs of AS 718:FPEO N-80 ratio of 30:70 showed better control of DS-MTX dissolution in avidie medla in comparison with those of AS TL82:FECO N-HO ratio af 20:80, But there were no significant differences betwsen WOMTs and DOTs. The torval dissolution time {acidic medis and buffer stage) was between 5 and 5 WH. If the diasolution best mirrors the in-vivo tablets behavior it can be assumed that for both DUTs and VONTs the dissolution time once nassed the stomach, would be 3 ~~ 3 &x h. Considering that the transit time in the small intestine 13 3h, formulations with this polymer ratlo are slse good coandjdates for the delivery of an de dn ende ge an ae oy de es rad de a de Sød rr eV de ON Øg ØS ped mn bem er dr en pa PAGES Er Tae methotrexate with the advantage of a better control of the Farinas m3 meen Tar dean eT mea El xrn finn DUG AISAOLVTIONA AV LOW Dn VALSE. The dissyn)l sl men gen en fd] STAT ce ed LESAGE mr en EY he Y mere DU HOS, my ry + i ™ Ty SYN ATOR mi 3 3æ SUEY SLY POE OALSKYOLUDVILOPV ØOKOTYLLE OX LULTYS ATUY YLMILE OX oo 2:80 iz shown Qa x v oe he + ri om Øv nyrer me Ng ED EE TY rr gø + 3 r fy & Sa - a ET ey rn == h 3 æ py SY i 3 2 25 CMS JHiEgranm Feonresentead in Klgure o. alter JL M 259 BLE Ud NI TMD sæ en Do SN tår SN ØR OS nay 229 rs ae AF TS UT ER SE AGT Free ae BF WN, DOTS relsasad a mean walue of 18,17 $ of DE-MTX, One of Pak ety wan ch on s tøs) Aignersluyttøar ir £ ås ho mn ej sne oy F + Pen yve LA CAR LED 4 dr UCAS FANE RA OL Lidar I ADA EL LÆSTE EL FR IX TEE RNAse Wk TL RASA i vo AO fn 3 3 4 LIMET M 3 HE Crema men ig må = vr = ra i ”. im Om Fron > nn RY Tn FØDTE ny Tm gi TY Sra ya in f oh. After £ h in HCL 001 N, VOMTs relsasegd a mean vajue pe EY fy Soo TNT BETTIS IN F £ + om in 3 de om = ele a + om, - Tt Må mee gu 2 orm + DE IK.L5 % DE-MTA. One of tabletle reachsd total dissolution in 70 Toy bait t FoOm them bara 1 er 3 xml vist vedr oa Fdare dus en i wf 3 vd boy a+ i få 0 ÅFRA LD. ONE WRENN LIL SAV NES DS STRA, vias Wry fr ILA Lila Art LY ard oF TT ved mest ana mb TET FERN SEE: at 3 spin of si minutes at 150 rpm. Toe DS-MIA disgolvysd 3Iilel o % on - på = — - . + - + — 3 aL oo er AS a a Ty — Hor = ; ce sygt ARTE IY viet +r For aodisrenitimrnritiktr LM LIAISE £000 ACIC slags Seamed not TO ALELLDY ILgNLIIidaniiy. Rowagysy, Sane TFEIRANY om slås de en fe om, Er eben ed be bea ok Bode de dye for VCMTs the total dissolution fins ezxoseded the f he At the nem od ET I er 2 z an Ene gn 3p Ee ed en gen he am ie 7 SEN, EN 3 so Toe > og Sletten mede dm, 3 an end of the diszoluation test oo residuals were detectable on “i fem Beene A en A Tray wen ae or TNE en vy wor rå NEAT an on no TYSKE RU en ed + Sgt SE DN sd ry vd wo DUTs ang VOMTs of AZ ?18:FE0 N80 ratio of 30:30 showed no aionificant difference in the dizsolution ooofils For byt i sigomnigflocant difference in the Silssolution profile. For polh DCTa and VI's showed 3 no0ogd control of the Siszolutior Doran DOT and VOTs showed a good control of the dissolution of DE TF RAS sey peed ol We ren H PUTTS TT I" ob i + t mt AA mme lok id men + ves dr kd 20 MTX in acid stage. However, the total dlssolutlon time may be Fee orig ye [Ege oe ype to 3 em & mæ ra + by IR ome it ren fm a TO Long LOK 3006 appiiganions. It The dissclution test mirrors the in-vivo tablets behavior ib can be sszumed that FLETTE Me 20-VLVO LAaNLSTSE DSOAVLOF 10 C3S DE ASSUMSQA nat fr r na i gm 1 ed i syn dd TEE DIE ha ass A Phe Storm MY Led buen an ht Lo Me le Lae od LW Le LAS She BLT VALLE RAGE 3 ART AA Lori BLOK TH, WOULG KE a Tow h Fr = Fm Fl > SR TIERS TTT de on tt ey SU SN SØG PLN PÅ EL YN re dn oy Av 4 + h and above 5 h for VCMTa,. Therefors, considering that 8 tha trane: tr 3 Fie 3rn tha om? ? jvtomot i ne jo 2 5 Fermin omit oyna a ne TANI LL vIME An Uns shall INnTegiing IS 59, LOCYBULSLLOSS fo HO 3 it 3 ro 3 or 3 Pal 2 c ib RI firmer yt enon be ol sm mink yen Fen F 2: 3 KA tre gå gt retter or WLLD LIAS POLYyMmer atid aay DO t be ideal for the deliver WDE
ENS FLS ES MEN SEE SP MESTNOLFeKaTE. mt Ge > . = e APR " mr re + 5 le FY mor iii ret mary i le SE FN la FV FI Ay pe en NYY pen Føl tg 111 GHLEBOLILILGE DEFDTIL1IE OF LE T 3 x SEL FU WEE IV > sonlination of ILtLOt and E+10% N {13 shown in the disoram ZU application of Liu ana avid HAF ESfhOoOWwWn An The GALAFTAM . . han på 2 J . - ee CL ~~ ey - Få en aa ea mars TE gavtb gad 3 fy TE evry veay TT After 2 h in HOL 0.1 B UT gn ryg y ea renreæsænted in Ligure VL. After + h in HOL 0.1 N Ts, produces
DK 2020 70049 A1 30 34 by applying a force of 14104 NM, raleased a mean valve of 20.83 % Of DE-MTX.
Two of tablets reached a total dissolution in 5 h and 30 minutes and one of them in $ bh.
After © h in HOL 2,1 & DCTs, groduced by appliving a force of 3+104% BN, veleased a 3 mean valve of 19,583 % of DE-MTX., All tablets reached a total dissolution in Ste bh.
The disscluvion profile of DOTs produced by 110% and 2710? N, except for the outlier DOT &, smesmed nob to significantly differ from sach other.
At the end of the ft amølutinon boat Så MATS Lm Limes 3 aot aint sm ft # hnttrm dissolutlon tlest no residuals wars odetectlabile on one DOTLOm 19 of the vessel.
For RCTs of AS 718:FPE0 N-80 ratio of 30:70 produced by apolving forced of 142100? N ane 3%10% No the dissolution test af the two forces applied did not show algnificant difference 13 in the dissolution pattern.
The dissolutlen profile of DCTs of 39:70 with and without MOSE and dsyozil ie shown in the diagram represented in figure ø,. åfter 2 h in HOU 09,2 N, DØVs without åerosil and Malt released a mean value of 25,83 % of DS-MTX.
ALL thres tablets reached & total dissolution in 2 bh, After 2 h in BCL 9.1 NW, DOTs with Rerosil and MgSt released a mean values of 19,83 % of DS-MTX.
All three tablets resched a total dissolution in S h.
Av the end of the disszolutien test no residuals were detectahle on the bhaottom of the versa! Fr Nis ha Se her TR RS NI 3 hed 3 Em hat br NORTE Na ie ADA WIA SETA For DOTs of AS 716:PE0 N-80 ratic of 30:70 produced with and without Aercsil and MgSt the dissolution Lest showed no significant impact of the exoiplent in the dissolution profile meaning that the two sxcipients used in the given amounts old + Sa I rn ra år en rt, rd 3 pre | & 3 er åt Ar er not influence the dlssolutjon pattern.
= +
SÅ ET TCT SET INS
EMBODIMENTS 3 x harmaceutlos] erne Sd . Fe mened 3 PI med es ) EN yoo © ; 7 Sid PRI any Sev CNET i ti nr ot weed SP med HE | EN men i & Fe Fr DATED LOE CORLOSLLLAQTN LOE HERRED LAR TOØLGSAST LL et dd pe me år cori on na om me hon or ett 3 mn 3 nr END Å + I eN a methotrexate, whereln the vharmaosuticel COMPOSITION : 1 . fa + FYEVYSLEN ey arama nat h AT FEMTE AS I AVA FOA Seit Yen i dkr osoemart a by PÆN sent oomprjises methotrexate or a pharmacevutilcailjiy acceptable salt
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Gom er | Cs + _— so … i Tha nharmsårent i is? OMME ir APrmrdiniø ts SEs Are SE 18, The DSarnmaoeute ialt COMDOSICSL OD aCCoraring TO any one OT > bh mrad Smarte i + MO wherein the enterioc-resistant agent a0 ll ODO LSD ELL SS A Wl Fy WHDJaSKFORM TNE ENVOFQLO-KFØBLSTANT agant Gs - 3 oe em åt Æ rr vor Jee re NC - Tu - 3 3 F 373 7 er - - pm dr am øge walart ard ya Vo ¥ en ep op er: nemt gs 3 egl Tn vas ay ead ay i SE SOT a0 From REO TORY TCV Lei a CaLLU LOSE ACSLS3LlE oy 33 Sana amen dae SN Re pm, SARIN TY i sean od ay Pe Age 1 RA ae tå 3 k PN NANA Dom fe sn eno bY vp en SYS ay SUCCINATE (NUML ARI , MIKESOG ADTFVLATSSALEVI acrylates TODQLYMSYSB, rom ae 3 og ad Som me el -, — a mr qe dr a - Årg ~. r - ve re Se wont errr dN mdr sen matr amor? = menn igemmen y sne « MERAY LAT 3CLA AN BLY AVLYLSCD DODO YIG, SEONG methacorvlate coon lume am vind ders methacrylate cCODOlvmer MOTIAN GT SCD LIE, RRL VINEE KVI MECLMaCTE VISTE OPL OLYIY ot bial ac earl st oy met ovr} matharryliate mr vmer bs gtylaran 2 IY LL ACL YY Ladi SER LER NOE SLED LL ALFA YLE WOL L ÆG FRANSKE Inn LL AFA VORE LES mothacryviate SOS Lymer cet into 3cetute mhthalato 3 KELODATE VISLE CULOLVIDDL, CELIUIODSE AUSTALE DDU ALL, mej Tax) me i ment SM Synd havre cal inlmae aod ats trimel! irate LOL LLL DT alms lle Ly TL Len OLA LX ED yy lana Lona Ls, 2 3 3 Ox, fa 4 5 3 > : > 9.0 huder ons) gi ri mee ribb hea l oa bog hvædromgoroovvi ethvicellalose oY Q(IOXL LOT Vd DELLUALGES DN CUDnalLate po AVULDE La VODWVL SUV LCS L LULOse
5.5.3 4 | x + < Co + Go oa + mnrhal nt FE Ta EN i ATR AT Pd meat my] men | 7 slosge mihi alata DRLTOSIALE, DVArGOKVE DYODY A MELD DELLULOSE InUIMBaLaT,
5.08. rthvicsliules hthal le aaa a bh a Mer red gt rå sten TTY øse mt tan? mt ne såmen t Ten d mare — om 4 Wt må fy AroXvet LY LL CRIT LOSE DNMTNAaLS3StTE, ME&LKYyLCSLLULGSE on thalate z 4 2 : a 3 : 3 5 3 . % : ~ 2 : 3 > i egy ORIN fans menes oan dte vid inn fox dug WROD oNKUPS vig To 9 steg de fx Ef on SP AAEN EY + UI POLYVINYL ATSlale MILIMBLBSTLD, BDOLVVALRDYLECS ALS AVOarogen iela nd om te ment Tan nes SR foe dm rm Tom Pam ellulos FE whirhalate cel lun loas BR vyhthalgtes me nyse athay ToT Lane, LET LAL SSL DI CALA LEE, LELLULOSE BELOSE te i} CR. 3 rt Ya - . ads om 2 2 en on ene 3 vin, + e+ mg met 1 met Tart rs meet onto hthalste atm gabe Nå d PEMNCNAa1atsa, SOJlunm O81LIULOSE, ACs tate ohthajate, stlareh 3010 ohvthalste sellulose ucobate butvrate ren Tan 0 ppt gt acetabe KOL ILØd ARLES Lem I bond lads CALLED LN LE Qala ans Laid Ll LAE RAL LN LE “ : nvm : : . Wy oss rn. men i ut gm ven? la i em EM amet tide Sodom: TY db mee mal Tind omen een oa ed WE ADL, calivioss acetate trimellitate, TOLIDM LOSE A&TSLATE + TRI NT 3 PATY A rn ST Yyrons MI enim Aart #1 ards) Hh ERAT stø FOSS ur i RYOP1iDKHRale, STYFSne M3L8LVT 3010 ALDULYI PDLUMAAatLg COLOLVISE, et rae a am got et mis melsert must smart ate mitt mf enero |e st vyrenese WRaieild atid DGLYVINVI acetals QDMIMals Le DGPALYMEE | x 2 5 . Ls . 0 . ab lam mløryrovoant ao oa metal alritvatn STIG IA, LOL ACA MY LA. Safina, arhovmmaethuwjathulra Tn 1 oy Frey LOLITA YE DO mr methavrwvl 3 CSLDOKYBBLIODVIBUMLVYICBLEIGULOSE, LDO-DOL VEST BRETAAVKEYLIGC oy ana FÅ Fran he Kar ey i Me Dm ew vn aw VE ne, he Var ep 7 an wn der ay gm on ge or å nr de SN, ER de Tey ane ger gan wn 0 ACI MSTHACTV ILO BOLI methyl asters, OY mix tures thereof. + a ev i . 4 0 se p" HE q ms OMA TIA CE 5 oo~a DUDMNDSIT LON RIMO IO rr Dr DIE sr ide Cite FADE dod LIL CORINA LU AO RAR TI 1.0 SEY IE LF . Lo + 4 : : : x 5 Chen Tr Pia Erma east i mem toa 3 doe in obven een Sr KS PA gr At ev wwe do vornede Sos LITEM R LINE SHODOCGLDENTLS I LE Ld, Weal SODLSTYLIO Fr VIBE lg HEMOAR 0 mme 3 OL . RA a mm 3 OL. SEITEN VD TST TTY TS 4 TU bs we roid mares vis i] SOWIE RD ATI Al SS Fs rat evi UMD C ISL 47 VE OY Walght SVYDTLAYFIL goog PE and 4-409 OF Walidn 1 J ) PERS PNV ALER such as 929-202 bv weioht søuoccinvl orogvs and 4 acetyl groups, such as 3-30% by weloht zuoginvl gro HE andl os oe … Pm : - 5 : et Gog vey 3 60 28 PY Fy aE Yeh rent ar i SY RST mn mitt omk i 4 i RE SE TED 1 oe eh 3 128 Dy waloht acet VA QFOUDS, and SULTADLE lå-las Oy WLG C sucocinvl onroucs and 4-9% bor weloht sacetvi grouns SUYUCCLAVL Qrougs and Av sT OY WDSLINL ATSOTVI YCOVPDS. iz Tha oharmmaceuticel comnoslition aooording to any one of FN dL Arsalan DISK ALEN RAE. em RALANIRSLESS LL TAER AARNE LI 25 RW LELJE? LIL + lg ømbnrlimant i +p Ti hem rev the “at io betwecor Se cne mood rtnent0s i TO ii, WIESE LN ie ravio SOTWOENn LOE 2 A a hn a sd pa gv de = wt ed . hwvdrovhilig onde nå xe Se 2 ub en Oa dt EM SR 9 op & yay Soya t 3 = FE I ST YY 3 Tu toy og mani my Ju gnteric-rasiatant sageont and a nydrænilig matrix forming
SA 38 - ay ne, me 2 i UI ng DF wen de. an Ey AM, am OM . 3 ag om ee om dn Io eu frei + en Mas EY a SYST rinder ex Ve ÅD, SEN 29% 8 0% NE 3 AGENT, LE Dou, SUCH AS 1 v4UVIYLvnU., ANA SULTADLY 10 SE ac LC ad aan fy 2 PENA TN a NY 3% Tha PO Py rmacent Spø ? O LTR FE om az pt etn ne dd na to AYrV one 0 & Las LAT — KASPER (SER RAE LI La EL SoA an LN KÅRDE I TE EA) ER Lad ERY ALDE MAL. bie embed i meer dre 0 gees YO dy os rende de bre rr ne em rende En SN ERA ON on 2 the enohodimhents Loto åg, wWwherein thie amount of methotrexate . 5% 5% 0 2 om TTY we, TY ee AS LÅ, LO DAP ME - 4 3 < ot + sat ; ~ i Tin mm MA DEG 3 mn 3 SYNS, i i Å ven ADD Sri ur bem, nr ey jr i4. The pharmansutical ocompesitlon according to any one of TEE een 3 Th aT + t =~ TR WHE rain t he ow kh vee alae dead SSO TF oe SMOCKI1ImeØeNnSE LTO ih, WwWwhereln nis LNAFMACSUE I Cal Con HOSTED n 4 om x … : : rl x mr x, R i SED ANTLERS NSSS ST SES IY sal saan SN OSTER GÆT N yet ones 1 Phen an AY een Fy rør INAS Ad MN YAY A il + UI LER 0OVereg E y All SALES AU DAY DH 3 SLECGLSG LFOM NVOAEFDEV DYEODVYIL er ar 3 3 — TT ax Y em - mdt nt or av Fa FRI PRI Morn NO XP en od - rr l omdr usb hy cel inlomas Rant afse anroinars Lh y i Mel aoruviatae MELNYIL COLLIULGOSE ACSTALS SUCOTCINALTE (HFBMLAD), MIXaed 3BOYVIATE ai ber aor ata NE Sl ET Ey matbhoarrwiir mir am + ori ai Kyi ACYKWLSLE SOR L YH TS, MOLNAaCEVALD AE aL SIDVA SE Øm ASTER ED LEE SY IL 6 methacorwliate Serres boaters y ATV LALS CRG DT, AKMMNYOTLA GO MOETNACKYLATE COOL YDEr, nm neal kw mathaorvyiata CROW OTE et ethvl horviæte mn hyd clit TER Fri I NOE AL ISLE Ad EKO LAI LYRE I ITLL Y LY aes SERVE 3.82 SO i ane: 3 må - ~~ + - ag dexe tt o I een + f xx ym om se te mf bene) tm øens i Fre Hog fort mest et immer mee ere Torre ey v i VWELDACFYLatS DODO YDE, hutvistled mMelhacrylate COpOlVYMer, møs 3 far i eva mat ate bt ba 1 at FÅ Fr 3 11] EE acetate Ore mate UMD IA LE DLO EE lola MAILS R LOE LT RE AL LA lines alsa le RL Ladd Ey aL : . ng ; > « awn mi iyulmnse goat abe brimellitate ECE Ye WY nn I sl ial ogee OBILULOSE ALSTALE, trimeiilCatlg, DYXYKOKD TYDE YÅ DBLLIULOSE byd dis 3 om fr hvdroøsnrovt mf be Toman T bild ome — mit hr dom ét es heri seer i BM TALTE, IVIKOXKDLODYL BLOVLCEBLIRLOSE DOT LaL3TE, AIVOKORXRVÅ ? 9 3 Wy Yeo de Ben "åen 3 fedora oan Ven eg SR yen be IS gr så Tod ewe nd de by Tos de A Her ernven fø 3 yen DLOEYI metnvi SeLLIULGOEO pr thalatve F h VvALrOHVET hvicellalosge 5 biblen dom methvloellulose shthalatbe met tret ryg, rende må piifaiane, MOTNYLCDOLIULGSE PNULUDALGTLE, BOLYVLDYE ACELATE ; 1 4 : + : + . : \ Nan + “ mite lab “eternal acetate el Ye EE J mi om tom mal tulle DAYMA Late, POLVVIDVLISCSTatle hvoarogen phthalates, DSLIAULOSE , an + - - 3 Ser de pe ee 2: en ca fr gm Gr bist dm Foote cellulose et hs bide i nd en em? Åen ve BALSE nRItnELaTesy, CE LLELOES SUNY pr thalates 7 EO LUM mi inion soot abe mhthadlaras staroh am nhthalate ar KE WA WS SA es LT RA SID DE Lr AA Ghd AS TA Nar a NÅ FELASA LID nd tas) rime ere de må er Tr 3 $e gs im åt 2 sellulose een dem åv a oem mt mm 3 i) me mi nt Fang? on te Se MOSEN mr SM Malm COLLOULOSE [ORNATE DULYLSTE, TDSLIRLOSE ACE TATE MALCGALD, melluniløose asetaste trimealliitabe nel loaliosgs aretats orøopionate pos QRT L.A LE LANDER alia LUT Lh EGNEDE Aa mind, OVE AE DANNES CE RLET LD LEN RAE GE AARC LUT ad rr Ey en malate ded Fl bane as okthalaste npn dg rime, vr ed APN PS eo STYLES MALER aa CLIT VO DNKLASIATE COD LINE 0 SLyyenge mealejin acid vmolvwinvi asacetate vuhthalavte ocogvolvner shellæ Mad elå0 all POLVVIFYI ACSTATE DBNTMALALTS COPOLYMSE, SMNBLLST, aløginic acid re tal = ioimate carboxvmethvlaethnyvlocellujlose WLLL Ti AR We ÅRG nar lb IX AG ER EN pg Kei JL RSLIØS LISE LTL YO ED LIB WORSE ED ER CY TY vars ga 2 om rd rd + Foose lowe medl Sng a erp as 1) oe a 3 mat hr? DUT DO LYRE TI Sad HOTUDaUTrWL1I1LD SKUVLAFMELDAVEYIL BUILD MATE SY > Fy På råt 2 SE rr pred ae dante me be em we 3U CECTEFB, DK MIKVUKLES CNBFKFSDTE.
oe 33 + Men de de em oA rr ye dp - sh re de deny NE ey 4 Æt en La METIS SL TOLL OG 3 CDNaFMACSULEOSE TOMPASIL LON aocoord ing to anvorne of the æmbod i manta 2 ta iå DOME i Siv aloes LAB LAR Lhd aly LARS — AE LAR EHF SD RE LL SETS ELLEN * LAY KO LARS LL Lrg $m oe eo © LR STÆDS of ele . > . . : yo fi OAC Ye render ør mme Pron how ent on de es oN 2 vt Demant tomt Tx MINIT LOWER YE SY METAOVTFØKSATE OY & DAA FRacCENT LIA LLY ga Smøre nb så rr $b vee BO a Seen RN we ÅD am Pe oY Ed 3 gr ry Sere de yes od 2 AUTSBPLAaDIS SALT Lhersedl, an enlerLC-Fes2stant agent, AN, ange år ds wm TF hvaroohkt li rn ay ås gå 2 a Ey ye 4 i ag de i ensom TY wr = hat seende ti MATAR TY Er SV en nere mg Ddr AN DELLONnal1V, a MNVAKrCGDni liv matrjk forming agent, ang 3 + + 3 | ud i Mir, Pram sy <3) eg Dø Så 0 Mbym ym ører) 5 3 een 1 SANE AY EY OTT syr CaOMDressing Lo a pharmaceutical composition.
FN x . " . . 2 " 2 is den TO met oF Pn EAN TY TY = Y h ze FREA0% 0 3 sum SNE EN YF 3 LD.
MeTNGd GE YNIUC LYNG a DNa3rmaceut 1.88 4 on UT OSTELLOD 10 according to anvonzs of the oembodiments li to 314 comorising a+ SER: 3 SALVA LIT ER LIG All LUNES RS LA Log vh ASLIRG RES 2. ESTA & Im Dont ri Cog STSDS GOI mt owt Mor nude ra 5 mat hast rere a a fr 3 uoharmaceutics EY MIAKHLIG FORMERS EOS Lk SSL LD AS KR LÆS LA ps Aral I HAGEN STAA Ed Led ly a everyday Ey eo XA 1 SEY TEN PY am ras + + HI) t Dør apn ed ened Lem gd 1 sr Fr ALCSPLANLS SALL, ESDTEeLLOTSVORLSTSANT agent, A&M, ARAL LIRA LLY, a ‘ie A ean la 3 0 a rr BT je 3 a eg - rr orl intr Tir ma rd oe frsyn i rift seventy EX ALGONLILCT Dati IDrmin Li aT x 48 rears då mr, Fhe misrt isme dm om doe id RPYOVIGLING The MIKLUES 18 as 216, STS, 23 fit 3 mme + ben 3 dit Range NET TNA SE OSS 0 RFIRøti 3000 compacting the mizture usin a 3 wWaoiiam, J oo . . . . “ > > matt, > + omit wtih on Pemmeratiyirs af jon myrrh ia maling NEAT IN od CRE MLNVUKG VO 4 Laos ratyrs AT LAST we ArT LY MOLLY 18 "i, pm PPS ER Sr 5 yt the powders, and menn i 5 we Eos nt Sd Ad myte end, Ser Så gader ge cociing for salidification of the mixbure, + 20 3 The method aconrding to enbodiment i 5 ubherein tha mivtuyr Lf ANG method SCODYDNALNMG TO embodiment 10, WDEKSID LAS MINTUFS FR dy en ce pvr Eg bd re ga et må 4? we fed i Tver rs lubricsnts TLRS COMODYISES D1nNnD0F8. LIELLETSFGLIVSDTLS, IY LOANS, disinbtecrants and før co lidants ALR ALLER LEAL ANS LL Llane « x sr Lo: x fo. c: . I. 28 PR Y Afa TR tel Tn PKA Id 3 eva 3 CTE Ye Eo Fen Bd not k: oo ad Fry 25 18, ÅA pharvmaceutioai composition For use in a method for modified release of methotrexate, wherein he pharmaceutical TEE NE 3 dt Ne JR LE I oem red mdt teen ay mi To JEN = øm h ==, YUS ISEN i? 3 ser bY gr COMO LE LON CODE LET MECTNGE LEKA LD DE 2 Canal Oa LLY fo at oo i as . 2 . : Co arm able malts fame Fo imbacararocd TT osm matt er serviet od od fer ary ROTVPLANLE SALL THe Liiadiatad IN a ÆKALLAN COmprising an FR ES YY fen FEIT 3 Ki AYE Sys earii save Fru rey ixr ma hi seler To 3 ger wer voy we SLLSYIODTFES1SLARNL Agent and, DØDTIONALIY, sa FMVOIFOGMNILIIC MAT FIK 2M AY gn ge = pv 3 2 Fr Tr Seve yd au Farming agent.
oy 30 i The nharmaeocevutical comooaitiop accorsiin to embodiment La Lis NAA TMACeTiITaLR com Wha I. STATE cr lola RALL. 1 LA SRO Leal LL sm Co . ot - = wd Ce 3 5 oe i wharoin the alsase of methobtrezate naasurad at OH 8.8 iz Al, WMIOKSIN COME KILDASE ol suid trekale measured at DA 9.9 LE 3 + EN 3 ems mae } 5 — 3 mm & 3 - + 25 ing a + nano 3 sa urs me reer ey mand ne 0 5% mn mf DD ap at jesst 10% by weight per hour, such as at jesst 15% by ed she vene OPSI 390 mo oh 5 ome loaarzt 70% be wadioaht mor hen HwOLINT Pel DOUY, SVON 83 ST Least VE DY WEXLQOTL er neovur.
2 Yo ev y i + ru > . . » 4 Th ES NI IS emp yan em EY SND FO 0 Peer 8 NOON een a aad eN +, Se a very TR SP. SLS DARATMAOSUTIDAL CORMDOS ITION &COSGrMGing LO SMODALMEDT La 3 ! 3 oe + , i. 2 o . . , . 0 0 mr 19 wharejin the relsase of methobltferssatle maasured at nH : ØVE 19, WISKSI1D LHe KOLSAES DL MOLTKOLFØSKALE MSASLLSO at pH oo.
. Tyr, re - \ arve + ri De nt mme SMS ber rad rib mr bruse zob ne AM hu mad sb ur LE AL MOST SUR Dy WeIghU fer MOVE, Such As UT DY weight psy % -, - — 3 im sen Re - cam Thon In i i - — ere Fey TE = MIT] Tome do xr + vr, LT rar ud ro mag YE HOU, ANG SULTALIY SL MUST Jus OY W salont per hour.
+ 1 51 mam ymin perm mid å mn 1 Ar A ry PE = > 0 MINA TTA im Seacoast tion acocoyvgding DO Ar nn or Lo I 330 ISG MAaCEUTLLCTSL CO ALSO LLL QDR a Ls LA dy we ne ER + de sm PN oT be TEN They en 3 ri The wr rr ” - +h rd form + ne embodiments is LO SU, wherelin the rejsease of methotltrerate 4 cee nm my Mm 0% foi x 5 qo ses ray en od a PET SK a TORS ER Br mad bt ver Best ye cried gr YN am HORSUFSCG AL DS oo. 183 ÅU-DU OS Oy WeLINT Per Dour, SUON 4% 10 AF 0 bear ead svda de vre — . møl enn tm dn I GPL FSL bees ware eek NE.
SE: er NENT nr arv ball ou …— & bur uret orl EY SR OY WE LOT DGL RO, ANCL BULTADLY L0-30% 2 y WED Lard END Se |
LR ESR IAN 3 Minas bid dern pnd 3 ren, 3 rus i & 5 ro mime wråå re rs es ve: 7 oo MPLS TITRA Ma Ven Series Ploy Acro rei mn i UV Om 0 me The BALI MATSET LOL a CINE GSLLLOMN ACLOFOLN Ld LA Sli Me OY the embod imens IR tr BY wherein the release of methotrexste LM ÆSMDOKIiTeENnTS LS LG Ji, WDRBFeLN Ing reiaeasd DL MET NOT CEKARTE SAN SWAN SEN ØS ay Se t5 7 vi Fo FL ds En Så eN da de pen pe ASA EN RS ems eN en ar —— > an HMNØRBSUFSC AT DN b.2 18 VE DV WOLANT per nour af LSSE, Zen as TES hr owed ahd rv Bvemitwe em Yoon a and suitably 102 bv woight 3 ja + ven uy mur Ty yy Ser yo en et Si ae to ag On TA, Sel evi za LØ DIV WOLBMT Par AOUE DE L885, ANA SULTADLY AVE IY WELGRUT rune mit orn ooo el DOWN GE 1883.
9 Ths ohsrmaceutiocsl rus res dd ro meme ved A re Aree oes ye dT 7 3 EE yo POSEN D då ery a eve ved vee ; BTS? OY SÅ le Law PhallacoaTlidad fer CATES GVSLELOR A&CCOOLØÆLD Ld Ll Wildy one og sån mrmde med 2 re i es + & 30 es ste i pes pp Se a co Bae the embodiments LE to £4, whearsin the proportion of the nm r 3 or rr To ae a - md de re, he r R- . i tr on Oy 5 3: mb Pr i ” 3 oe aay ope FE I ED 0) EA En Y Fier gt mo TIE Mig FEAR 5 El um = FJ - 2 IN bs 3 3 0 rejsaze per nour or, MetlhnolcreNkaste al Dhow & ANM PR 1.2 213 3 C 3 nomen de FA od me må Tse I GM cored yar ord Ten ende Toe 9 ms rå least Z:l y 0 BUC aS ST LSRKST 2 ..DLÅ, SUD AS AT Last srl, ang Le 8 0 >= mr 0% 2s PAM ar mf lost + Ce zultably at least 3.3:12, 24, The PRAarfmafe dV Cal DOmPOSI Ion aCCoraring TO any one OF > Fy the smbodiments 18 to 23 herein the release of methotrexate Få ho mr SEY ment eg i es, "bag Ee) v + inn gg I EO ct gb 6 et Sa een mY ey ZU the eømpoadiments iB LO 23, wherein the release of methotltrekatle FRED TAY Thanet GX vi Fo Per WR > vom 3 gta FRIE TR YES ANT Y Trend van measured at we ow. 8 28 DUS hb vVoWELOGDNT OK Mere Dover 3 DOUYS,
DK 2020 70049 A1 37 such as 80% by welght or more over 3 hours, such as 70% by weight or mors over 3 hours, and suitably 8HO% by weight ov IMAM PE MmVver 3 h DIYS Moers ver 3 MAOUYS., 3 25. The pharmaceutical composition according to anv one of the embodiments 18 to 24, wherein the hydrophilic matrix forming agent ig selected from — polvetnhylerns ok ide (FEO)/polyethyleæne glycol (BEG, hydroxyethyleslliuloss, øn geder rust sr? mg? Ir sg me i vredt has Yoda ~ røgen 3 Sinsrryvinte CACO OXY MBLAVLOSIIUIOSE, LOLVET MY LANE FAVYCO Sladiyviane LPEGDA), gelatin, gelatin-PEGDA copolymer, hvaluronic acid, chitosan, hydroxypropyiosliluloge, avdroxypropylmethyl- cellulose, sodlum acrylate, and mixtures thersof.
26. The pharmaceutical composition according to anv of the 18 gmbodiments 18 to 25%, wherein the molecular weight of the øolylethylene oxide) 1s from 20,000 vo 7,000,000 daltons, such as From 100,300 no 1,000,000 daltons, and suitably from L0G, 000 vo €00,000 dalvens, 27, The pharmaceutical composition according to anv one of the embodiments 18 Yo 26, wherein the enteric-resistant agent is selected from hvdrøoky propyl methyl cellulose acetate succinate (HPMCAS), mixed aorvlate-alkyl acrylate copolymers, methacrylic acid and ethyl acrylate copolymer, anmonio £5 methacrylate copolymer, aminoalkyvl methacrylate copolymsy, ethyl acrylate wmebthyl methacrylate copolymer, butylated methacrylate copolymer, cellulose acetate phthalste, me 3 o rer rr eat ew ae yey te Am gm ge, + 0 Toa mn am he ee dee br te ce EY de er cellulose acetate succinate, cellulose avetate, trimellitate, hydrozpropyl veliulose phthalate, hydraxpropyl ethyleellulose 20 phthalate, hydroxyl gropyl methyl cellulose phthalate, hvdroxvethylvellulose phthalate, methvlicellulose phthalate,
=> 35 oer Lewd yd acetate nmhthalave nolvrivgvissretate byrel romer IN VOLLEY Aga RALLL IIR LAL PALLY LLY DGL ale SAL ode dome øm i 34%) - en, an Får deem Tom, A — 1 1 Va - + 3 i. nwhrhalate col innloas Hata vyhthalgtes mg lan mht DLCNGLATLE, COLLLGSE gatar DNTIDALSTOS, collins VLDSE
6.3 Ne 3 PR . h 0 1 x - enn de ir Fr, Go mi YE me mime mme mt hh i ay be en ne en ny mo rå BOV hnalales, sodium ocesilluloEe, 308 tate whthalats sg SUS TON BOLIG ohthalste sellulose acetate butvrate meal iv) mas arotate PALI AIA Amy Let Lhd iA CARLED KR Ls BULE KEDE 2 SE RAS ET CELL EDER LÆG za mn is oe lille, ent bon fe Fron mme: VY ben es sem i Ton Yen am tes de nt pg 2 MALDSALE, celiuiose acetave trimellitate, CSLIMLOSES ACSTLATLEÉ I - . Mt i . ¢ - i AG % 2 3 3 ta 3 4 Ge & ” % Fat SNG SE PG Ae AAS PE OMA do SNÅSN sy atte] wii Toa fS MENS) TE SO PSPLØS ER RDYDEIOR3atEe, STyFone MAaLSilC ACLOA ATDUCVI DOACN3L&LS CTOPOIVMSE, + + - - — pu + . . ii + , « ; ht... 3 2 mb reven — Mid oath gt mød rhe Parr vvs I mores aber mt hal ato SLUTS EY FAT YY 3t WIENS MALSLO 301d DOGOLIYVINVA &CSCaleé QPMYNna2LATEe Oo GR QLYMEE 6 ahel mn slainio ao metal afoingste SALE LE LL CRM Rab Ng Rd ae GAs LLY LL GA LI LT om ebm rr rey ht other? sol? Tan] eee vm pom rr: or ET CAELLDONVYMDLAVISTAVLCSLIDLOSSE, LO-FI I Zen MOELNAOFYILD = » 5 + = so os yo 0 os 5 . ? fy = i Evy ed finnen dy evens) Tey oh em År men dt Foes 3 an dann Sd ONES NØ Iya nes a bo My pn yen en & 4 1 RADLAFMSTASOTVLLGT ACTLA MSLAVIL SSTSTYS, GX mixtures LOGKEGE. EN Tha rbnemnrantinst ASM + ny Arve Tes + mtr ATS oT A hs Raa MRACSNL1SIL COMPOESILLON agQording LO an Yy one cor hve owed dynes boar TD Eee 2 rb onaeen hey ER Må oem of en con Torrie er 4a LITEM ROD the embodimertse 18 to 27, wherein enlerio polymer is HEMOAS oo me fo i Ca a mee 0 8 TRY NT YO SE NM SY 4 ME BR, JENA rev mare) MM 7] YT e Av Saw TED Fx: rt ev COMDYLSIDND 4v< LE DDV WOLOUNT SUDTANAVYIL grow PS ANG 4-38 QF WSLIN t + eran så MEMS AAA EN nue ag B-202 by wa lar succinvl arouns wl A i KODK yl AYOUDS, UCN AS BID DY W2 LOnt sUuNiNnyvl grow DE ang 4 mm « + - + " ore a : in AF RES? SN = eg zr Se ATTY ss me crit tab og i d~T5% NF TAT 2L0ht 120 DyY Wald ht acet yld QLOUDNSE, and sultlanle lå-let Dwy WESLINUT SBucninvi arouss and 4-93 br we i AY acetyl gronm SRA Er MA. SL BALAN CE EA x PU SY WIT Lr i Di. CR LED LL VOEL I ER E se om MM Tr cw ene 3 de 4 ney} wn rapa, 29 gS de ae a an ax en ed ham a " vene. er, 4 At
29. The pharmaceutical composition according to any one of 3 : + 3 - Lt 2 as : - =- 2 . . | . x Fi the prvi lme nia ] Få fr 78 wie re yy bhun mroanortion Det user the LIMO OMDOGTABERCLS Le TO 28, WDSFEALN LOS BYOBPOKLIOR DELWBeNn LOS : . . J - x . . " : SATS ER YO A so 0 KME 3 SD Å9 sun, Ae mera de oe nv x rend ar ae ie 3 FO 3 em opm tr an a xp en pT SNTSKLCTKESLETAnT agent Ana 3 h VIrGDn2i111e MaLYAN forming 2 eo MA ME ES 2 > AASE i Fm. 04% re Afvent zoom LB. Ro EU ry rede eo Ft AD e CAEN TY => ood suitable TR agent 218 3-30:85-5hU, such as 10-40:90-80, and suiitand vo
FE LRT LEE de DTT. ES 20 es kan ern EST i dt rrr 1 veep rer SF Å eng sper eres werd mer dees PS MATS susvay end 0 30. The SNArmaCeul1083, COMDOELULOR adooraing TO any one OT - 2 3 : non ~~ » . Ly . - . de er, ELEN eS 3 TTI AN YE an 1 oo do 2 weber en Pte va FR cesar any nope be - AT es ay Be ny der et ge ate the øembogdiments 18 LO 29, wherein Lhe amount of metholrexate 3 AO em TEN røre LE Av LO au HE.
31. The DSarnmaoeute ialt COMDOSICSL OD aCCoraring TO any one OT 2 mbodiments 18 to 30 Arme em fe, PN rd evn yo nm | rives 3 4 5 ror ZU enmbadiments 18 to 30, wherein the pharmacentioajl composition ÅR NYE TOERE ger ME sb md dr mr tot vy Dr et Faren Xu 1 ett ge Fm en re is coonvered D voAn SNLSKIC CTCORLANG Ssaagisd rol Select gd Crom
=> < 5 ; dar nas ke vm pm emp pæn de ? med txt e arten Æt og den nn pm SOTERA KEY FRÅ SNE RE KNEE SND vei hl fren Talo ed Sorte oe ax apn i Pibe sn SRD AVFAKONY DFORDWI MSTLAVI CSLIVLUBSE aaa ts SUQQLATE (BYNLAD) . 2 + Ties 3 . 2 + Cas PE wil wor aørvigteealkul sorviate somo ume ra mathasvvlir noir MIKS SOF VLALOTALKVIL SCTYEVISRLE COODOLYMEYS, MÆTNICYYLLD adid hm su mig i meme) natt, ery Te ey IE 2 TNM: Ye SOI EY Yr YO it bud mm Yury 3 Beem STYK EY IV eT YO ang STOVE SLYVLALTES DDLDOIVMEY, afm etna oy ¥ LAVE CO BO LV, ~ 5 w + ~~ 5 ~ ~~ aminovslkvl mathacrviats ry ome er eth aorviats mother An mL) NA FESD SØE RL 2 VOL ES KLA ols isl vin ÅL gg LA) all WORK SLET SLED ALY z met dan mee tr Tob ren | + nn % eget mb råd od Ty x eg To bo meen Ty . i? es Fy oy ee to Seve Yous yy cab ened rey by oye Poa Frenne Tare 2 MELNATEVI&LE COPOLVYMSE, hutylated methacrylate copolymer; vow TT 4x 3 es yon de ny Ahthæslate Selbulg ag or og de oa ag de Am Vac} myg NA md hes To sp mø] Toy | PS me EY PS fa SYG SN ES a CEJLUIOSS acetate PIRTNALAaTS, zellulose acetate svncinate, mn I Tay denen acetavte ty Swen Yt ba {a Fe ENR FR TON LS I seat Ford erase CSLLULOSE ATELALS. CAMS LLL TENE, HAVAVONDYEOPYL COLLILOSE
2.3 4 + + x - “oa 5 - a + Wwhrhadl ate hvwiroKnronvi auf AL pn bh eT Wiha ate hxrøblersynrner I DICDnSSIALE, LY FOKDLODVYL STDVICSALULGSES DRETNaLSLE, AVATQEYL J 5% + HL. a + 3 + om i Yrs ren de bars enes tt % sad me 3 et er mel Taal ae " = i om e rød wn tren åt dare" 2 veg ene Fr og MI mæt NYA CBLÉINULORE BP" thalate z h Y AraOKvVeEr hvioellulose M J : £ I s i ei gi 3 3 og dr er me t ås ny? eve 37 bi 3 ane vt t ion Tay eo, vel rå; Sort a oot a gå whe KOEN LEGE SE LS SEAT LSE WA NT VR LAA SD NI BALL 2 RER RR 6 2g E MOM VA LV fr nmihthaslavte solLvvinviscetate ho rnner nohthalate gal ining PALLIAT RE y p SALE VAIL VA ONE a LS Så WAS ripe FELLA LL ELAD NO LA BAL NE RS ent dr en en Td fee 3 md en er cellulose dr in a addet eo ene 4 tae SELEY ohtinalates, celluloses ginax phthalates, sodium mes? Tua Yeas sn eN gt dr 2 år in de dn sy Yeoh 2 sb avek åd på brod in Tay de Tan) ea een day påby ds be og bom de ad men så så vyb:d bys Toa de CSLUULOSE, ATESLATS OTS Late, SLAarTn ALG OLIE ALE, og? itn liane mme Dom brybyurste rug 2 1 limen aratata wa i gb ad LTA AE EA ES LÆS LE Lad LALLA LDL KEDE LEE LAS ENT ALLA LE LL KO ANE LTO LE p “a Ya 3 ge enes de on Ae en År om ae TNA aa ent fas Ge me en de ne em am Re mn Sem Den iy År i 3 cellulose acetlatle Crimaeijiitatle, celiulose acetals propionate, + : > + : , + : x , sf rae eno “ Le mø abs Freq dx I sg + h = 1 or ena ev Ym PAGES 1 RTT st yrene ma Jlæiv AQILÆ AILENITOWOE OMLUnalate COBOL YE SLYLSDE malinger 30 i omer Tou ing aoatate Wi h 2 ] sf Sr I nD) r aka? Ian AC LA ED LM fe JL p KA MOM SEN GL SELLA LOR LÆS BAAR LL EUR 4 TÅ NG REN HR. WAAL gr DRE RR ip ER ery od metal 2osinate Carhokyvmethwlethvleæelinlose ALULIELTU ald, Manas SLUGTE, LÆLEND SVIE LIV IR LAY LOR LLULDNEG SOT LTE YL ras spb ay eva ev Soid/methaeocrvliie må mat hard LAdTYRM LV LS mid MELNGSGOFVLIC Så fn LAV SED neni oy IA Lalli SER LILY A “i grå ea ae md wb rire ae bbe one FF CELEFA, QF MLIKLUKGS Lnarsgin.

Claims (10)

DK 2020 70049 A1 40 CLAIMS
1. A pharmaceutical composition for modified release of methotrexate, wherein the pharmaceutical composition comprises methotrexate or a pharmaceutically acceptable salt thereof integrated in a matrix comprising an enteric- resistant agent and, optionally, a hydrophilic matrix forming agent.
2. The pharmaceutical composition according to claim 1, wherein the release of methotrexate measured at pH 6.8 is 10- 50 % by weight per hour, such as 15-40 % by weight per hour, and suitably 20-30% by weigh per hour.
3. The pharmaceutical composition according to claim 1 or 2, wherein the release of methotrexate measured at pH 1.2 is 20% by weight per hour or less, such as 15% by weight per hour or less, and suitably 10% by weight per hour or less, and/or the release of methotrexate measured at pH 6.8 is 50% by weight or more over 3 hours, such as 60% by weight or more over 3 hours, such as 70% by weight or more over 3 hours, and suitably 80% by weight or more over 3 hours.
4. The pharmaceutical composition according to any one of the claims 1 to 3, wherein the hydrophilic matrix forming agent is selected from polyethylene oxide (PEO) /polyethylene glycol (PEG), hydroxyethylcellulose, carboxymethylcellulose, polyethylene glycol diacrylate (PEGDA), gelatin, gelatin- PEGDA copolymer, hyaluronic acid, chitosan, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium acrylate, and mixtures thereof.
DK 2020 70049 A1 41
5. The pharmaceutical composition according to any one of the claims 1 to 4, wherein the enteric-resistant agent is selected from hydroxy propyl methyl cellulose acetate succinate (HPMCAS), mixed acrylate-alkyl acrylate copolymers, methacrylic acid and ethyl acrylate copolymer, ammonio methacrylate copolymer, aminoalkyl methacrylate copolymer, ethyl acrylate methyl methacrylate copolymer, butylated methacrylate copolymer, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate, trimellitate, hydroxpropyl cellulose phthalate, hydroxpropyl ethylcellulose phthalate, hydroxyl propyl methyl cellulose phthalate, hydroxyethylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinylacetate hydrogen phthalate, cellulose ester phthalates, cellulose ether phthalates, sodium cellulose, acetate phthalate, starch acid phthalate, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate propionate, styrene maleic acid dibutyl phthalate copolymer, styrene maleic acid polyvinyl acetate phthalate copolymer, shellac, alginic acid, metal alginate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, or mixtures thereof.
6. The pharmaceutical composition according to any one of the claims 1 to 5, wherein enteric polymer is HPMCAS comprising 4-20% by weight succinyl groups and 4-16% by weight acetyl groups, such as 8-20% by weight succinyl groups and 4-12% by weight acetyl groups, and suitable 14-18% by weight succinyl groups and 4-9% by weight acetyl groups.
DK 2020 70049 A1 42
7. The pharmaceutical composition according to any one of the claims 1 to 6, wherein the ratio between the enteric-resistant agent and a hydrophilic matrix forming agent is 5-50:95-50, such as 10-40:90-60, and suitably 15-35:85-65.
8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is covered by an enteric coating selected from hydroxy propyl methyl cellulose acetate succinate (HPMCAS), mixed acrylate- alkyl acrylate copolymers, methacrylic acid and ethyl acrylate copolymer, ammonio methacrylate copolymer, aminoalkyl methacrylate copolymer, ethyl acrylate methyl methacrylate copolymer, butylated methacrylate copolymer, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate, trimellitate, hydroxpropyl cellulose phthalate, hydroxpropyl ethylcellulose phthalate, hydroxyl propyl methyl cellulose phthalate, hydroxyethylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinylacetate hydrogen phthalate, cellulose ester phthalates, cellulose ether phthalates, sodium cellulose, acetate phthalate, starch acid phthalate, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate propionate, styrene maleic acid dibutyl phthalate copolymer, styrene maleic acid polyvinyl acetate phthalate copolymer, shellac, alginic acid, metal alginate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, or mixtures thereof.
9. A pharmaceutical composition for use in a method for modified release of methotrexate, wherein the pharmaceutical
DK 2020 70049 A1 43 composition comprises methotrexate or a pharmaceutically acceptable salt thereof integrated in a matrix comprising an enteric-resistant agent and, optionally, a hydrophilic matrix forming agent.
10. The pharmaceutical composition according to claim 9, wherein the release of methotrexate measured at pH 6.8 is 10- 50 % by weight per hour, such as 15-40 % by weight per hour, and suitably 20-30% by weigh per hour.
DKPA202070049A 2020-01-27 2020-01-27 Pharmaceutical composition for modified release of methotrexate DK202070049A1 (en)

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