ME00731B - Primena dialkil fumarata - Google Patents
Primena dialkil fumarataInfo
- Publication number
- ME00731B ME00731B MEP-2001-299A MEP2001299A ME00731B ME 00731 B ME00731 B ME 00731B ME P2001299 A MEP2001299 A ME P2001299A ME 00731 B ME00731 B ME 00731B
- Authority
- ME
- Montenegro
- Prior art keywords
- disease
- preparation
- application according
- grave
- treatment
- Prior art date
Links
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 title claims abstract description 29
- 238000011282 treatment Methods 0.000 title claims abstract description 29
- 208000023275 Autoimmune disease Diseases 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 title claims description 23
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- 238000002054 transplantation Methods 0.000 claims abstract description 13
- -1 C1-14-alkoxy Chemical group 0.000 claims description 26
- 239000013543 active substance Substances 0.000 claims description 24
- 208000003807 Graves Disease Diseases 0.000 claims description 20
- 208000015023 Graves' disease Diseases 0.000 claims description 20
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 18
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
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- 239000002253 acid Substances 0.000 claims description 16
- 239000002775 capsule Substances 0.000 claims description 16
- LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 229960004419 dimethyl fumarate Drugs 0.000 claims description 12
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 10
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 5
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 5
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
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Abstract
Pronalazak se odnosi na primenu određenih dialkil fumarata za izradu farmaceutskih preparata za primenu u transplantacionoj medicini ili za lečenje autoimunih oboljenja, kao i na preparate u obliku mikrotableta ili peleta. Za ovu svrhu dialkil fumarati mogu da se primene takođe i u kombinaciji sa uobičajenim preparatima transplantacione medicine imunosupresivnim sredstvima, posebno ciklosporinima. Pronalazak se odnosi na primenu određenih dialkil fumarata za izradu farmaceutskih preparata za primenu u transplantacionoj medicini ili za lečenje autoimunih oboljenja, kao i na preparate u obliku mikrotableta ili peleta. Za ovu svrhu dialkil fumarati mogu da se primene takođe i u kombinaciji sa uobičajenim preparatima transplantacione medicine imunosupresivnim sredstvima, posebno ciklosporinima.
Description
Primena dialkil fumarata
Pronalazak se odnosi na primenu dialkil fumarata za izradu farmaceutskih preparata za primenu u transplantacionoj medicini ili za lečenje autoimunih oboljenja kao i na farmaceutske preparate u obliku mikrotableta ili mikropeleta koji sadrže dialkil fumarate.
Naročito se odnosi s jedne strane takođe i na primenu dialkil fumarata za izradu farmaceutskih preparata za lečenje, smanjenje ili suzbijanje reakcija odbacivanja primaoca prema transplantatu tj. host-versus-graft reakcija ili transplantata prema primaocu t. j. graft-versus-host reakcija. S druge strane odnosi se na primenu dialkil fumarata za izradu farmaceutskih preparata za lečenje autoimunih oboljenja kao što su poliartritis, multiple skleroze, juvenilni dijabetis, Hashimoto-tireoditis, Grave's disease (Grave-ova bolest ili Bazedow-a bolest), sistemski Lupus erythematodes, Sjogren Syndroma (Sjorgen's syndrome), pemiciozna anemija, i hronično aktivni (=lupoidni) hepatitis.
Stanje tehnike
Odbacivanje transplantata i autoimuna oboljenja počivaju oba na medicinski neželjenim reakcijama odn. pogrešnim regulisanjima imuno sistema. Bitni posrednici za uticanje na imuni sistem su citokini, kao interleukini ili faktor a nekroze tumora (TNF- a). Oba se obično leče davanjem imunosupresivnih sredstava kao stoje ciklosporin.
Autoimuna oboljenja mogu da se shvate kao rezultat pada podnošljivosti prema materijama sopstvenog tela odn. antigenima. Ova se opšte uzev odražava samo ako antigeni uvek ponovo dolaze u dodir sa imunim ćelijama. Pri gubitku podnošljivosti dolazi do stvaranja autoantitela dakle fumaralnog imuno odgovora prema tkivu sopstvenog tela. Kako u ovom učestvuje TNF-a, nije poznato.
Transplantacije su presađivanja tkiva odn. organa, t. j. prenošenja tkiva kao rožnjače, kože, kostiju (koštani opiljci), sudova ili fascija, organa, kao što su bubreg, srce, jetra, pluća, gušterača ili creva ili takođe pojedinačnih ćelija kao što su ćelijska ostrvca, alfa ćelija ili ćelija jetre, među kojima kao transplantomom organu najvažnije značenje pripada bubrezima.
Prema stepenu srodstva davaoca i primaoca razlikuju se autotransplantacija (prenošenje na drugi deo tela iste individue), izotransplantacija (prenošenje na drugu, genetski istu individuu) i alogena transplantacija (prenošenje na drugu individuu iste vrste). Prema mestu porekla i mestu transplantacije dalje se razlikuje homogena transplantacija (prenošenje na isto mesto) i heterotipna transplantacija (prenošenje na drugo mesto). Navedenim transplantacijama u modernoj medicini pripada značajna uloga.
U transplantacionoj medicini imunoodbrambenim reakcijama primaoca posle transplantacije tkiva, organa ili ćelije probleme stvara pre svega odbacivanje transplantata (engleski: graft-rejections). Odbacivanje transplantata se naziva takođe host-versus-graft reakcija. Imunološka odbrambena reakcija organizma protiv stranog proteina često vodi do odbacivanja transplantata. Kod host-versus-graft reakcija mogu da se razlikuju različiti stupnjevi. Naime različito brzo sledi reakcija već prema stepenu različitosti između primaoca i davaoca, tako da se govori o akutnoj, subakutnoj i hroničnoj reakciji. Reakcija odbacivanja koja se odvija akutno dolazi sa ireverzibilnim gubitkom (nekrotiziranje) transplantata zbog arteritisa odn. arteriolitisa, unutar 48 sati na koji ne može da se utiče medikamentozno. Subakutna reakcija odbacivanja se pokazuje kao kriza odbacivanja od 12. dana čak do 4. meseca sa reverzibilnim funkcionalnim smetnjama zbog vaskulopatije transplantata. Najzad kao reakcija hroničnog odbacivanja se označava gubitak funkcije transplantata koji napreduje nedeljama do godinama, na koji jedva da može da se utiče medikamentozno zbog vaskularnih promena na pr. začepljujuće (obliterirajuće) arteriopatije.
Obratno kod transplantacije imunokompetitivnih tkiva, t. j. pre svega kod transplantacija koštane srži, može da dođe do reakcija odbacivanja transplantata prema primaocu, takozvanih graft-versus-host reakcija. Takođe i ovde treba da se izvrši raspodela prema težini reakcije i u suštini nastaju slične komplikacije kao kod host-versus-graft reakcije, naime arteriopatije i nekroze.
U cilju izbegavanja ovih reakcija odbacivanja t. j. host-versus-graft reakcije kao i graft-versus-host reakcije transplantaciona medicina se služi u suštini imunosupresijom, dakle slabljenjem normalnog imuno odgovora. Za
ovo se upotrebljavaju često anti-limfocitni serumi u kombinaciji sa kortikosteroidima i takozvanim antimetabolitima na pr. Analozima purina kao 6-merkaptopurin i tiogvanin, koji ometaju sintezu nukleinske kiseline i proteina i time sprečavaju deobu ćelija i bujanje (proliferaciju). Ovo vodi do suzbijanja proizvodnje antitela i ćelijskog imuno odgovora. Kod imunosupresivnih sredstava koja se primenjuju za lečenje radi se o supstancama koje imuno reakciju u telu ili specifično ili nespecifično slabe ođn. suzbijaju. Nespecifična imunosupresivna sredstva su citostatici kao na pr. Akilanti ili antimetaboliti.
Pored toga poznaju se aktivne materije, koje bar delimično izazivaju imunosupresiju kao što su kortikosteroidi, antiserumi, antitelo FK-506, Tacrolimus, Mycophenolatfetil i uglavnom ciklosporini, kao što je Cyklosporin A. Upotrebom modernijih imunosupresivnih sredstava, za koja treba da se navedu kao najvažniji predstavnici ciklosporini, naročito Cyclosporin A, u poslednjim godinama mogli su da se poboljšaju rezultati transplantacije. Odnos 1-godišnjeg preživljavanja iznosi sada za transplantacije jetre oko 60%, za transplantaciju srca pribl. 80% i za transplantaciju bubrega iznad 90%.
Sa graft-versus-host reakcijama mogu da se uporede autoimuna oboljenja, kod kojih sada imunosistem sopstvenog tela napada takođe i organe sopstvenog tela, tkiva i ćelije. Takođe se i ovde radi o medicinski neželjenoj reakciji imunosistema, koja može takođe da se leči imunosupresivnim sredstvima.
Opasnost pri primeni imunosupresivnih sredstava leži u slabljenju odbrane sopstvenog tela prema infektivnim bolestima i povećanom riziku zloćudnih oboljenja. Prema tome, cilj pronalaska je da obezbedi
farmaceutski preparat koji može da se primeni u transplantacionoj medicini za lečenje, naročito suzbijanje, slabljenje i/ili ublažavanje host-versus-graft reakcija i graft-versus-host reakcija, ali da ipak ne pokazuje gornji nedostatak.
Dalji zadatak pronalaska se sastoji u tome, da se stavi na raspolaganje farmaceutski preparat, koji može da se primeni za lečenje autoimunih oboljenja naročito poliartritisa, multiple skleroze, jivenilnog dijabetisa, Hashimoto-tireoditisa, Grave's disease (Grave-ove bolesti ili Bazedow-e bolesti), sistemskog Lupus erythematodesa (SLE), Sjogren sindroma (Sjogren's sindrom), pemiciozne anemije i hronično aktivnog (=lupoidnog) hepatitisa, a da ne pokazuje nedostatke imunosupresije.
Opis pronalaska
Rešenje zadatka prema pronalasku leži u primeni određenih dialkil fumarata za izradu farmaceutskih preparata za primenu u transplantacionoj medicini i za lečenje autoimunih oboljenja kao i farmaceutskih preparata u obliku mikrotableta ili mikropeleta koji sadrže dialkil fumarate. Predmeti prema ovom pronalasku su u pojedinosti naznačeni u patentnim zahtevima. Preparati prema pronalasku ne sadrže per se slobodnu fumamu kiselinu.
Poznato je, da farmaceutski preparati, koji posle davanja pri njihovoj biološkoj razgradnji ulaze u ciklus limunske kiseline ili ovome pripadaju, većinom u višem doziranju dobijaju sve više na terapijskoj vrednosti, pošto pomoću njih mogu da se ublaže ili da se izleče kriptogenetski uslovljene bolesti.
Tako fumama kiselina koči rast Ehrlich-ascites tumora kod miševa, smanjuje toksična delovanja Mitocyn-a C i Aflatoxin-a i poseduje antipsorijatično kao i antimikrobijalno delovanje. Visoke doze davanja fumame kiseline ili njenih do sada poznatih derivata kao dihidroksi fiimame kiseline, fumaramida i fumaronitrila imaju pri parenteralnom, dermalnom, ali naročito peroralnom davanju tako neočekivane odnose sporednih delovanja i visoku toksičnost, da se do sada najčešće moralo da odustane od takve terapije.
Istraživanja prijavioca su iznenađujuće pokazala, da metil dihidrogen fumarat metabolit dimetilfumarata inicijalno povisuje endotoksinom sitimulisano TNF-a lučenje u ljudskim mononukleamim ćelijama periferne krvi (periphere blood mononuclear cells = PMBC-ćelije) i u izolovanim monocitima. Osim toga moglo je da se pokaže, da fumama kiselina ima delovanje koje može da se uporedi sa cikloserinom na in-vitro i in-vivo hemoglutinaciju.
Iznenađujuće je sada otkriveno, da dialkil fumarati mogu da se primene za izradu farmaceutskih preparata za primenu u transplantacionoj medicini i za lečenje autoknunoh oboljenja. Preparati koji sadrže ove dialkil fumarate naime dopuštaju na iznenađujući način pozitivnu modulaciju imunog sistema kod host-versus-graft reakcija kao graft-versus-host reakcija i drugih autoimunih oboljenja.
U evropskoj Patentnoj prijavi 18 87 49 su već opisani za lečenje psorijaze derivati fumame kiseline i farmaceutski preparati koji ih sadrže. Iz DE-A-25 30 372 su poznati farmaceutski preparati za lečenje psorijaze, koji sadrže smešu fumarne kiseline i daljih derivata fumame kiseline. Udeo slobodne fiimame kiseline je kod ovih lekova obavezan.
DE-A-26 21 214 opisuje lekove za lečenje psorijaze, koji kao aktivnu materiju sadrže monoetil estar fumarne kiseline i njegove mineralne soli. Iz publikacije *Hautarzt (1987) 279-285* je poznata primena soli monoetil estra fumarne kiseline. Iz Patenta EP 0 312 697 BI su poznati farmaceutski preparati za lečenje psorijaze, psorijatičkog artritisa, neurodermatitisa i enteritis regionalis-a Crohn, koji sadrže smešu soli monoalkil estra fumarne kiseline i diestra fumarne kiseline.
Tačnije se zadatak prema pronalasku rešava primenom jednog ili više
dialkil fumarata formule:
u kojoj R1 i R2, koji mogu da budu isti ili različiti, predstavljaju nezavisno jedan od drugog linearan, račvast, ili cikličan, zasićen ili nezasićen C1-20 alkil ostatak, koji u datom slučaju može da bude supstituisan halogenom (CL, F, J, Br), hidroksi, C1-14-alkoksi, nitro ili cijano grupom, za izradu farmaceutskog preparata za primenu u transplantacionoj medicini ili za lečenje autoimunih oboljenja.
Kod C1-20-alkil ostataka, prvenstveno C1-8-alkil ostataka, najpodesnije C1-5-alkil ostataka, radi se na primer o metilu, etilu, n-propilu, n-butilu, sec-butilu, t-butilu, pentilu, ciklopentilu, 2-etilheksilu, heksilu, cikloheksilu, heptilu, cikloheptilu, oktilu, vinilu, alilu, 2-hidroksietilu, 2- ili 3-hidroksipropilu, 2-metoksietilu, metoksimetilu, 2- ili 3-metoksipropilu. Prevenstveno je najmanje jedan od ostataka R1 ili R2 Cl-5-alkil, naročito metil ili etil. Poželjnije je da su R1 i R2 isti ili različiti Cl-5-aIkil ostaci kao što su metil, etil, n-propil ili t-butil, pri čemu su naročito poželjni metil i etil.
Najpoželjnije je da su R1 i R2 identični metil ili etil. Sasvim posebno su poželjni dimetil fumarat, metiletil fumarat i dietil fiimarat.
Dialkil fiimarati koji prema pronalasku treba da se primene izrađuju se prema u stanju tehnike poznatim postupcima (vidi na primer EP 0 312 697).
Prvenstveno se aktivne materije za izradu oralnih preparata primenjuju u obliku tableta, mikrotableta, peleta ili granulata u datom slučaju u kapsulama ili kesicama. Od ovoga su poželjni preparati u obliku mikrotableta ili peleta, u datom slučaju napunjenih u kapsule ili kesice i predstavljaju takođe predmet pronalaska. Oralni preparati mogu da budu snabdeveni sa prevlakom otpornom na želudačni sok. Kapsule mogu da budu meke ili tvrde želatinske kapsule.
Dialkil tumarati primenjeni prema pronalasku mogu da se primene sami ili kao smeša više jedinjenja, u datom slučaju u kombinaciji sa uobičajenim nosećim ili pomoćnim materijama. Količine koje treba da se primene treba tako da se odmere, da dobijeni preparati sadrže količinu aktivne materije koja odgovara 10 do 300 mg fumame kiseline.
Preparati prema pronalasku koji su poželjni sadrže dimetil fumarat i/ili dietil fumarat u ukupnoj količini od 10 do 300 mg.
Prema obliku kome se daje prednost veličina odn. srednji prečnik peleta ili mikrotableta leži u području od 300 do 2000 µM, naročito u području od 500 µM ili 1000 µM.
Što se tiče autoimunih oboljenja koja treba da se leče paralelno sa grafit-versus-host reakcijom (vidi gore) treba navesti sledeća oboljenja: poliartritis, multiplu sklerozu, graft-versus-host reakcije, juvenilni (mladalački) dijabetis, Hashimoto-tireoditis, Grave-ovu bolest (Grave-ova bolest ili Basedow-a bolest), sistemski Lupus erythematodes (SLE), Sjogren sindrom (Sjogren's sindrom), pemicioznu anemiju i hemijski aktivni (=lupoidni) hepatitis. Autoimuna oboljenja u širem smislu su takođe i psorijaza, psorijatični artritis, neurodermatitis ili enteritis regionalis Crohn.
Farmaceutski preparati za lečenje ovih bolesti su pored gore navedenih preparata za peroralno davanje u obliku mikropeleta, mikrotableta, kapsula (na primer mekih ili tvrdih želatinskih kapsula), granulata i tableta, preparati za kutano i transdermalno davanje u obliku masti, flastera, losiona i sredstava za tuširanje kao i za parenteralno davanje u obliku vodenih mikro-disperzija, U/V-emulzija ili uljnih rastvora za rektalno davanje supozitorija ili mikroklizmi. Farmaceutski preparati u obliku mikrotableta ili mikropeleta su poželjni za terapiju prethodno navedenih autoimunih oboljenja, uključivši psorijazu, psorijatični artritis, neurodermatitis kao i enteritis regionalis Crohn i predstavljaju takođe predmet pronalaska.
Prema pronalasku može lečenje sa dialkil fumaratima da se vrši takođe i u kombinaciji sa jednim ili više preparata tripeldrug terapije koja se uobičajeno primenjuje kod transplantacije organa ili takođe samo sa Cyclosporin-om A. Uz ovo mogu preparati koji se daju da sadrže kombinaciju aktivnih materija u poznatim doziranjima odn. količinama. Isto tako može kombinaciono lečenje da se sastoji u paralelnom davanju odvojenih preparata istim ili različitim putevima davanja. U datom slučaju može na podesan način da se smanji doza aktivne materije koja se daje pored doze derivata fumame kiseline prema pronalasku.
Dalji oblik primene prema pronalasku sastoji se u tome, da se sekvencijalno naizmenično menja terapija sa lekom sa imunosupresivnim sredstvima kao što je ciklosporin sa primenom gore označenih dialkil
fumarata. To jest, da može posle jedno do višenedeljen terapije sa ciklosporinom da se vrši jedno do višenedeljena primena prema prethodnom značenju derivata fumame kiseline. Time može da se snizi doziranje Cyclosporin-a A, čime može da se postigne značajno smanjenje odnosa sporednih delovanja kod dugoročne terapije.
Davanjem dialkil fumarata u obliku mikrotableta, koji su poželjni, mogu gastrointestinalna odn. sporedna delovanja koja su doduše već sa davanjem konvencionalnih tableta prema derivatima fumame kiseline odn. solima umanjena, ali još uvek zapažena, biti još više smanjena prema derivatima fumame kiseline i solima.
Po svoj prilici se pri davanju uobičajenih tableta materije koje sadrže u tableti oslobađaju lokalno u crevu u suvuše visokoj koncentraciji, čime se prouzrokuje lokalni nadražaj sluzokože creva. Ovim lokalnim nadražajem se kratkotrajno oslobađaju vrlo visoke koncentracije TNF-α, koje mogu da budu odgovorne za gastro-intestinalna sporedna delovanja. Kod primene mikrotableta u kapsulama otpornim na želudačni sok se naprotiv postižu lokalno niske koncentracije aktivnih materija u ćelijama epitela creva. Mikrotablete se iz želudca postpno peristaltikom želudca predaju u tanko crevo i dolazi do bolje raspodele aktivnih materija.
Mikrotablete otporne na želudačni sok istog doziranja raspodeljuju se takođe već u želudcu i stoga već u porcijama dospevaju u crevo, gde se oslobađaju aktivne materije u manjim dozama. Tako se izbegava lokalni nadražaj ćelija epitela creva, a isto tako kao i oslobađanje TNF-α. Iz ovog proizilazi po svoj prilici bolja želudačno-crevna podnošljivost mikrotableta u odnosu na uobičajene tablete.
Osim toga poboljšava se resorpcija, pošto se kod dialkil fumarata koji prema pronalasku treba da se primene ne radi o pravoj aktivnoj materiji, već o jednom takozvanom proleku, koji tek u telu mora da se preobrati u pravu aktivnu materiju.
U sledećem se cilju objašnjenja primene pronalaska daju različiti primeri za izradu lekova koji su poželjni.
Primeri izrade
Načelno oralni preparati prema pronalasku u obliku tableta ili mikrotableta mogu da se izrade prema klasičnim postupcima tabletiranja. Umesto ovih klasičnih postupaka tabletiranja mogu da se primene takođe i drugi postupci za izradu tableta, kao Što su direktno tabletiranje kao i postupak za izradu čvrstih disperzija po postupku rastopa i postupku sušenja raspršivanjem.
Tablete mogu da budu snabdevene sa prevlakama otpornim na želudačni sok. Prevlaka otporna na želudačni sok može da se izlije ili prska u klasičnom kotlu za dražiranje kao i da se vrši u aparaturi sa lebdećim slojem. Osim toga tableta može da bude snabdevena sa prevlakom filma.
Primer 1
Izrada u kapsulama mikrotableta otpornih na želudačni sok, koje sadrže 120, 0 mg dimetil fumarata, što odgovara 96 mg fumame kiseline
12, 000 kg dimetil fumarata se isitni i homogenizuje pomoću sita 800 uz odgovarajuće mere predostrožnosti (maske za disanje, rukavice, zaštitna odeća itd. ). Izrađuje se pomoćna smeša sledećeg sastava: 17, 50 kg derivata
škroba (STA-RX® 1500), 0, 30 kg mikrokristalne celuloze (Avicel® PH 101), 0, 75 kg PVP (Kollidon®120), 4, 00 kg Primogel®, 0, 25 kg koloidne silicijumove kiseline (Aerosil®). Celokupna smeša praha se pomeša sa aktivnom materijom, izmeša, homogenizuje pomoću sita 200 i pomoću 2%-tnog vodenog rastvora polivinilpirolidona (Koliidon® K25) na uobičajeni način obradi u vezivni derivat i u suvom stanju pomeša sa spoljnom fazom. Ova se sastoji od 0, 50 kg Mg-stearata i 1, 50 kg talka.
Smeša praha se zatim na uobičajeni način tabletira u ispupčene tablete od 10, 0 mg bruto mase i 2, 0 mm prečnika.
U cilju postizanja otpornosti na želudačni sok ovde se na pr. u porcijama rastvor od 2, 250 kg ftalata hidroksipropilmetilceluloze (HPMCP, Pharmacoat® HP 50) rastvori u rastvarač sledećeg sastava: aceton 13, 00 L, etanol (94 ms. -% denaturisan sa 2% ketona) 13, 50 L i demineralizovana voda 1, 50 L. Gotovom rastvoru dodaje se kao omekšivač ricinusovo ulje (0, 240 kg) i na uobičajeni način se nanese u porcijama na jezgra tableta.
Po završenom sušenju se zatim u istom uređaju nanosi kao filmska obloga suspenzija sledećeg sastava: talk 0, 340 kg, titan-(VI)-oksid Cronus RN 56: 0, 400 kg, Farblack L-Rotlack 86837: 0, 324 kg, Eudragit E 12, 5 %: 4, 800 kg i polietilen glikol 6000 pH 11 XI): 0, 120 kg u smeši rastvarača sledećeg sastava: 2-propanol 8, 170 kg, demineralizovana voda 0, 200 kg i glicerin triacetat (Triacetin) 0, 600 kg.
Mikrotablete otporne na želudačni sok se zatim pune i zatvaraju u tvrde matične želatinske kapsule u 400 mg neto mase.
Primer 2
Izrada u kapsulama mikrotableta otpornih na želudačni sok, koje sadrže 120. 0 mg dimetilfumarata. što odgovara 96 mg fumarne kiseline
12. 000 kg dimetil fumarata se isitni i kao gore homogenizuje. Izrađuje se pomoćna smeša sledećeg sastava: 23, 20 kg mikrokristalne celuloze (Avicel® PH 200), 3, 00 kg Croscarmellose Natrium (AC-Di-SOL-SD-711), 2, 50 kg talka, 0, 10 kg bezvodnog silicijum dioksida (Acrosil® 200) i 1, 00 kg Mg-stearata. Celokupna smeša praha se pomeša sa aktivnom materijom i homogeno izmeša. Smeša praha se potom direktnim tabletiranjem tabletira u ispupčene tablete od 10, 0 mg bruto mase i 2, 0 mm prečnika.
Zatim se izrađuje rastvor od 0, 94 Eudragit® L u izopropanolu, koji dodatno sadrži 0, 07 kg dibutil ftalata. Ovaj rastvor se rasprši na jezgra tableta. Posle toga se izrađuje disperzija od 17, 32 kg Eudragit® L D-55 i smeše od 2, 80 kg mikrotalka, 2, 00 Macrogol 6000 i 0, 07 kg Dimetican-a u vodi i rasprši na jezgra.
Mikrotablete otporne na želudačni sok se zatim pune do 650 mg neto mase u natiČne tvrde želatinske kapsule i zatvaraju.
Primer 3
Izrada mikropeleta u kapsulama koje sadrže 50. 0 mg dimetil fumrata, što odgovara 40 mg fumarne kiseline
5. 000 kg dimetil fumarata se isitni i kao gore homogenizuje. Pored toga se pripremi 2 litra 20 %-tnog (m/z) polivinilpirolidonskog rastvora (Kollidon K-30) u etanolu. 7250 kg nonpareilles peleta se stavi u kotao za dražiranje i prska sa jednim delom rastvora Kollidona K-30 dok ne postane
blago vlažno. Ovaj način postupanja vlaženja/isušivanja se dalje vodi do konačnog dodavanja smeše aktivne materije. Pelete se na kraju pokreću do potpunog isušivanja.
Pelete se posle toga pune (126, 5 mg peleta/kapsuli) u tvrde želatinske kapsule.
Primer 4
Izrada kapsula otpornih na želudačni sok, koje sadrže 110, 0 mg dimetil fumarata, što odgovara 88 mg fumarne kiseline
11, 000 kg dimetil fumarata se intenzivno izmeša sa smešom koja sadrži 14, 00 kg škroba, 5, 65 kg laktoze, 2, 00 kg mikrokristalne celuloze (Avicel®), 1, 00 kg polivinilpirolidona (Kollidon® 25) i 2, 443 kg Primogel® i uz odgovarajuće mere predostrožnosti (maske za disanje, rukavice, zaštitna odeća itd. ) homogenizuje pomoću sita 800.
Celokupna smeša praha se na uobičajeni način sa 2%-tnim vodenim rastvorom polivinilpirolidona (Kollidon® 25) obradi u vezivni granulat i u suvom stanju pomeša sa spoljnom fazom. Ova se sastoji od 0, 350 kg koloidne silicijumove kiseline (Aerosil®9, 0, 500 kg Mg-stearata i 1, 500 kg talka. Homogena smeša se zatim puni u porcijama od 400 mg u odgovarajuće kapsule, koje se posle toga na uobičajeni način snabdevaju sa prevlakom otpornom na želudačni sok, koja se sastoji od stearata hidroksipropilmetil celuloze i ricinusovog ulja kao omekšivača. Punjenje može umesto u tvrde želatinske kapsule da se vrši takođe i u odgovarajuće kapsule otporne na želudačni sok, koje se sastoje od smeše ftalata celuloznog acetata (CAP) i ftalata hiroksipropilmetil celuloze (HPMCP).
U poređenju sa materijama stanja tehnike kao što je to ciklosporin, koji može da izazove masivne bubrežne smetnje ili oboljenja limfoproliferativnog sistema, terapija sa derivatima fumarne kiseline prema pronalasku za gore navedene indikacije retko rezultiraju u ozbiljnim sporednim delovanjima.
Imunosupresivno delovanje ciklosporina je između ostalog uslovljeno kočenjem stvaranja Th-l-ćelija. Kao što je prijavioc pokazao u in-vitro ogledima, fumarati izazivaju pomeranje citokin modela od tipa Thl ka tipu Th2 citokin modela.
Ovo neočekivano delovanje primene prema pronalasku je od najvišeg interesa s obzirom na neprekidno potrebnu dugoročnu terapiju i profilaksu graft-versus-host reakcija ili host-versus-graft reakcija ili drugih autoimunih oboljenja kao multiple skleroze. Kod kombinovane terapije ciklosporina sa derivatima fumarne kiseline mogu znatno na neočekivani način da se smanje toksična sporedna delovanja prvonavedenog jedinjenja. Primena prema pronalasku je osim toga od najvećeg značaja takođe i kod zamene kortikoidne terapije autoimunih oboljenja koja je povezana sa jakim sporednim delovanjima.
PATENTNI ZAHTEVI
1. Primena jednog ili više dialkil fumarata za izradu farmaceutskog preparata za lečenje host-versus-graft reakcija ili graft-versus-host reakcija kod presađivanja organa i ćelija.
2. Primena jednog ili više dialkil fumarata za izradu farmaceutskog preparata za lečenje autoimunih oboljenja izabranih iz grupe koja se sastoji iz juvenilnog dijabetisa, Hashimoto-tireoditisa, Grave's disease (Grave-ova bolest ili Bazedowa-a bolest), sistemskog Lupus erythematodes (SLE), Sjogren sindroma (Sjogrenov sindrom), preniciozne anemije, multiple skleroze i hronično aktivnog (=lupoidnog) hepatitisa.
3. Primena prema zahtevu 1 ili 2 jednog ili više dialkil fumarata formule:
u kojoj R1 i R2, koji mogu da budu isti ili različiti, predstavljaju nezavisno jedan od drugog linearan, račvast, ili cikličan, zasićen ili nezasićen C1-20-alkil ostatak, koji u datom slučaju može da bude supstituisan halogenom (CL, F, J, Br), hidroksi, C1-14-alkoksi, nitro ili cijano grupom, za izradu farmaceutskog preparata za primenu u transplantacionoj medicini ili za lečenje autoimunih oboljenja izabranih od grupe koja se sastoji od
juvenilnog dijabetisa, Hashimoto-tireoditisa, Grave's disease (Grave-ova bolest ili Bazedowa-a bolest), sistemskog Lupus erythematodes (SLE), Sjogren sindroma (Sjogrenov sindrom), preniciozne anemije, multiple skleroze i hronično aktivnog (=lupoidnog) hepatitisa.
4. Primena prema zahtevu 3, naznačena time, što se kod ostatka Ri i R2 radi od metilu, etilu, n-propilu, izopropilu, n-butilu, sec-butilu, t-butilu, pentilu, ciklopentilu, 2-etilheksilu, heksilu, cikloheksilu, heptilu, cikloheptilu, oktilu, vinilu, alilu, 2-hidroksietilu, 2- i/ili 3-hidroksipropilu, 2-metoksietilu, metoksietilu ili 2- ili 3-metoksipropilu.
5. Primena prema zahtevu 3 ili 4, naznačena time, što su R1 i R2 identični i predstavljaju metil ili etil.
6. Primena prema jednom od zahteva 1 do 5, naznačena time, što se aktivne materije formulišu u oralni preparat u obliku tableta, mikrotableta, peleta ili granulata u datom slučaju u kapsulama ili kesicama.
7. Primena prema zahtevu 6, naznačena time, što veličina odn. srednji prečnik peleta ili mikrotableta leži u području od 300 do 2000 µM.
8. Primena prema zahtevu 1 do 7, naznačena time, što se preparat nalazi u obliku mekih ili tvrdih želatinskih kapsula.
9. Primena prema jednom od zahteva 1 do 8, naznačena time, što preparat sadrži količinu aktivne materije koja odgovara 10 do 300 mg fumame kiseline.
10. Primena prema zahtevu 6 do 9, naznačena time, što su jedinične doze leka snabdevene sa prevlakom otpornom na želudačni sok.
11. Primena prema jednom od zahteva 1 do 5, naznačena time, što se lekovi upotrebljavaju u obliku preparata za kutano i transdermalno davanje, preparata za parenteralno davanje i preparata za rektalno davanje.
12. Farmaceutski preparat u obliku mikrotableta ili peleta, naznačen time, što sadrži jedan ili više dialkil fumarata formule:
u kojoj R1 i R2, koji mogu da budu isti ili različiti, predstavljaju nezavisno jedan od drugog linearan, račvast, ili cikličan, zasićen ili nezasićen C1-20-alkil ostatak, koji u datom slučaju može da bude supstituisan halogenom (CL, F, J, Br), hidroksi, C1-14-alkoksi, nitro ili cijano grupom, i u datom slučaju podesne noseće ili pomoćne materije.
13. Preparat prema zahtevu 12, naznačen time, što sadrži dimetil fumarat, dietil fumarat ili metiletil fiimarat
14. Preparat prema zahtevu 12 ili 13, naznačen time, što sadrži količinu aktivne materije koja odgovara 10 do 300 mg fumarne kiseline.
15. Primena jednog ili više dialkil fumarata za izradu farmaceutskog preparata u obliku mikrotableta ili peleta za lečenje autoimunih oboljenja izabranih iz grupe koja se sastoji od po li artritisa, multiple skleroze, juvenilnog dijabetisa, Hashimoto-tireoditisa, Grave’s disease (Grave-ova bolest ili Bazedowa-a bolest), sistemskog Lupus erythematodes (SLE), Sjogren sindroma (Sjogrenov sindrom), pemiciozne anemije i hronično aktivnog (=lupoidnog) hepatitisa.
16. Primena prema zahtevu 15 jednog ili više dialkil fumarata formule:
u kojoj R1 i R2, koji mogu da budu isti ili različiti, predstavljaju nezavisno jedan od drugog linearan, račvast, ili cikličan, zasićen ili nezasićen C1-20-alkil ostatak, koji u datom slučaju može da bude supstituisan halogenom (CL, F, J, Br), hidroksi, C1-14-alkoksi, nitro ili cijano grupom, za izradu farmaceutskog preparata za lečenje autoimunih oboljenja izabranih od grupe koja se sastoji od poliartritisa, multiple skleroze, juvenilnog dijabetisa, Hashimoto-tireoditisa, Grave's disease (Grave-ova bolest ili Bazedowa-a bolest), sistemskog Lupus erythematodes (SLE), Sjӧgren sindroma
(Sjogrenov sindrom), pemiciozne anemije i hronično aktivnog (=lupoidnog) hepatitisa.
17. Primena prema zahtevu 16, naznačena time, što se kod ostatka Ri i R2 radi od metilu, etilu, n-propilu, izopropilu, n-butilu, sec-butilu, t-butilu, pentilu, ciklopentilu, 2-etilheksilu, heksilu, cikloheksilu, heptilu, cikloheptilu, oktilu, vinilu, alilu, 2-hidroksietilu, 2- i/ili 3-hidroksipropilu, 2-metoksietilu, metoksietilu ili 2- ili 3-metoksipropilu.
18. Primena prema zahtevu 15 ili 16, naznačena time, što su Ri i R2 identični i predstavljaju metil ili etil.
19. Primena prema jednom od zahteva 15 do 18, naznačena time, što se aktivne materije formulišu u oralni preparat u obliku mikrotableta ili peleta u kapsulama ili kesicama.
20. Primena prema zahtevima 15 do 19, naznačena time, što veličina odn. srednji prečnik peleta i mikrotableta leži u području od 300 do 2000 µM.
21. Primena prema zahtevu 19, naznačena time, što se preparat nalazi u obliku mekih ili tvrdih želatinskih kapsula.
22. Primena prem jednom od zahteva 15 do 21, naznačena time, kod koje preparat sadrži količinu aktivne materije koja odgovara 10 do 300 mg fumame kiseline.
23. Primena prema zahtevima 19 do 22, naznačena time, što su jedinične doze leka snabdevene sa prevlakom otpornom na želudačni sok.
Claims (23)
1. Primena jednog ili više dialkil fumarata za izradu farmaceutskog preparata za lečenje host-versus-graft reakcija ili graft-versus-host reakcija kod presađivanja organa i ćelija.
2. Primena jednog ili više dialkil fumarata za izradu farmaceutskog preparata za lečenje autoimunih oboljenja izabranih iz grupe koja se sastoji iz juvenilnog dijabetisa, Hashimoto-tireoditisa, Grave's disease (Grave-ova bolest ili Bazedowa-a bolest), sistemskog Lupus erythematodes (SLE), Sjogren sindroma (Sjogrenov sindrom), preniciozne anemije, multiple skleroze i hronično aktivnog (=lupoidnog) hepatitisa.
3. Primena prema zahtevu 1 ili 2 jednog ili više dialkil fumarata formule: u kojoj R1 i R2, koji mogu da budu isti ili različiti, predstavljaju nezavisno jedan od drugog linearan, račvast, ili cikličan, zasićen ili nezasićen C1-20-alkil ostatak, koji u datom slučaju može da bude supstituisan halogenom (CL, F, J, Br), hidroksi, C1-14-alkoksi, nitro ili cijano grupom, za izradu farmaceutskog preparata za primenu u transplantacionoj medicini ili za lečenje autoimunih oboljenja izabranih od grupe koja se sastoji od juvenilnog dijabetisa, Hashimoto-tireoditisa, Grave's disease (Grave-ova bolest ili Bazedowa-a bolest), sistemskog Lupus erythematodes (SLE), Sjogren sindroma (Sjogrenov sindrom), preniciozne anemije, multiple skleroze i hronično aktivnog (=lupoidnog) hepatitisa.
4. Primena prema zahtevu 3, naznačena time, što se kod ostatka Ri i R2 radi od metilu, etilu, n-propilu, izopropilu, n-butilu, sec-butilu, t-butilu, pentilu, ciklopentilu, 2-etilheksilu, heksilu, cikloheksilu, heptilu, cikloheptilu, oktilu, vinilu, alilu, 2-hidroksietilu, 2- i/ili 3-hidroksipropilu, 2-metoksietilu, metoksietilu ili 2- ili 3-metoksipropilu.
5. Primena prema zahtevu 3 ili 4, naznačena time, što su R1 i R2 identični i predstavljaju metil ili etil.
6. Primena prema jednom od zahteva 1 do 5, naznačena time, što se aktivne materije formulišu u oralni preparat u obliku tableta, mikrotableta, peleta ili granulata u datom slučaju u kapsulama ili kesicama.
7. Primena prema zahtevu 6, naznačena time, što veličina odn. srednji prečnik peleta ili mikrotableta leži u području od 300 do 2000 µM.
8. Primena prema zahtevu 1 do 7, naznačena time, što se preparat nalazi u obliku mekih ili tvrdih želatinskih kapsula.
9. Primena prema jednom od zahteva 1 do 8, naznačena time, što preparat sadrži količinu aktivne materije koja odgovara 10 do 300 mg fumame kiseline.
10. Primena prema zahtevu 6 do 9, naznačena time, što su jedinične doze leka snabdevene sa prevlakom otpornom na želudačni sok.
11. Primena prema jednom od zahteva 1 do 5, naznačena time, što se lekovi upotrebljavaju u obliku preparata za kutano i transdermalno davanje, preparata za parenteralno davanje i preparata za rektalno davanje.
12. Farmaceutski preparat u obliku mikrotableta ili peleta, naznačen time, što sadrži jedan ili više dialkil fumarata formule: u kojoj R1 i R2, koji mogu da budu isti ili različiti, predstavljaju nezavisno jedan od drugog linearan, račvast, ili cikličan, zasićen ili nezasićen C1-20-alkil ostatak, koji u datom slučaju može da bude supstituisan halogenom (CL, F, J, Br), hidroksi, C1-14-alkoksi, nitro ili cijano grupom, i u datom slučaju podesne noseće ili pomoćne materije.
13. Preparat prema zahtevu 12, naznačen time, što sadrži dimetil fumarat, dietil fumarat ili metiletil fiimarat
14. Preparat prema zahtevu 12 ili 13, naznačen time, što sadrži količinu aktivne materije koja odgovara 10 do 300 mg fumarne kiseline.
15. Primena jednog ili više dialkil fumarata za izradu farmaceutskog preparata u obliku mikrotableta ili peleta za lečenje autoimunih oboljenja izabranih iz grupe koja se sastoji od po li artritisa, multiple skleroze, juvenilnog dijabetisa, Hashimoto-tireoditisa, Grave’s disease (Grave-ova bolest ili Bazedowa-a bolest), sistemskog Lupus erythematodes (SLE), Sjogren sindroma (Sjogrenov sindrom), pemiciozne anemije i hronično aktivnog (=lupoidnog) hepatitisa.
16. Primena prema zahtevu 15 jednog ili više dialkil fumarata formule: u kojoj R1 i R2, koji mogu da budu isti ili različiti, predstavljaju nezavisno jedan od drugog linearan, račvast, ili cikličan, zasićen ili nezasićen C1-20-alkil ostatak, koji u datom slučaju može da bude supstituisan halogenom (CL, F, J, Br), hidroksi, C1-14-alkoksi, nitro ili cijano grupom, za izradu farmaceutskog preparata za lečenje autoimunih oboljenja izabranih od grupe koja se sastoji od poliartritisa, multiple skleroze, juvenilnog dijabetisa, Hashimoto-tireoditisa, Grave's disease (Grave-ova bolest ili Bazedowa-a bolest), sistemskog Lupus erythematodes (SLE), Sjӧgren sindroma (Sjogrenov sindrom), pemiciozne anemije i hronično aktivnog (=lupoidnog) hepatitisa.
17. Primena prema zahtevu 16, naznačena time, što se kod ostatka Ri i R2 radi od metilu, etilu, n-propilu, izopropilu, n-butilu, sec-butilu, t-butilu, pentilu, ciklopentilu, 2-etilheksilu, heksilu, cikloheksilu, heptilu, cikloheptilu, oktilu, vinilu, alilu, 2-hidroksietilu, 2- i/ili 3-hidroksipropilu, 2-metoksietilu, metoksietilu ili 2- ili 3-metoksipropilu.
18. Primena prema zahtevu 15 ili 16, naznačena time, što su Ri i R2 identični i predstavljaju metil ili etil.
19. Primena prema jednom od zahteva 15 do 18, naznačena time, što se aktivne materije formulišu u oralni preparat u obliku mikrotableta ili peleta u kapsulama ili kesicama.
20. Primena prema zahtevima 15 do 19, naznačena time, što veličina odn. srednji prečnik peleta i mikrotableta leži u području od 300 do 2000 µM.
21. Primena prema zahtevu 19, naznačena time, što se preparat nalazi u obliku mekih ili tvrdih želatinskih kapsula.
22. Primena prem jednom od zahteva 15 do 21, naznačena time, kod koje preparat sadrži količinu aktivne materije koja odgovara 10 do 300 mg fumame kiseline.
23. Primena prema zahtevima 19 do 22, naznačena time, što su jedinične doze leka snabdevene sa prevlakom otpornom na želudačni sok.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853487A DE19853487A1 (de) | 1998-11-19 | 1998-11-19 | Verwendung von Dialkylfumaraten |
| PCT/EP1999/008215 WO2000030622A2 (de) | 1998-11-19 | 1999-10-29 | Verwendung von dialkylfumaraten zur behandlung von host-versus-graft reaktionen und von autoimmunerkrankungen |
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| ME00731B true ME00731B (me) | 2008-09-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MEP-2001-299A ME00731B (me) | 1998-11-19 | 1999-10-29 | Primena dialkil fumarata |
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| DK2139467T3 (da) | 2007-02-08 | 2017-01-02 | Biogen Ma Inc | Neurobeskyttelse i demyelinisationssygdomme |
| DK2629097T1 (da) | 2007-02-08 | 2022-05-30 | Biogen Ma Inc | NRF2-screeningsassays og relaterede fremgangsmåder og sammensætninger |
| EP3318249A1 (en) | 2009-04-29 | 2018-05-09 | Biogen MA Inc. | Dimethyl fumarate dosage regimens for the treatment of multiple sclerosis |
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1998
- 1998-11-19 DE DE19853487A patent/DE19853487A1/de not_active Withdrawn
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1999
- 1999-10-29 DE DE59905954T patent/DE59905954D1/de not_active Expired - Lifetime
- 1999-10-29 TR TR2001/01204T patent/TR200101204T2/xx unknown
- 1999-10-29 PL PL348147A patent/PL205948B1/pl unknown
- 1999-10-29 EP EP99972532A patent/EP1131065B1/de not_active Expired - Lifetime
- 1999-10-29 ES ES99972532T patent/ES2195664T3/es not_active Expired - Lifetime
- 1999-10-29 PL PL385418A patent/PL226074B1/pl unknown
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- 1999-10-29 EE EEP200100266A patent/EE04389B1/xx active Protection Beyond IP Right Term
- 1999-10-29 JP JP2000583505A patent/JP2002530324A/ja not_active Withdrawn
- 1999-10-29 AT AT99972532T patent/ATE242633T1/de active
- 1999-10-29 BR BR9914606-1A patent/BR9914606A/pt not_active Application Discontinuation
- 1999-10-29 MX MXPA01005007A patent/MXPA01005007A/es unknown
- 1999-10-29 HK HK02103958.2A patent/HK1042242B/zh not_active IP Right Cessation
- 1999-10-29 NZ NZ510247A patent/NZ510247A/en not_active IP Right Cessation
- 1999-10-29 RU RU2001116566/14A patent/RU2215524C2/ru active
- 1999-10-29 ME MEP-2001-299A patent/ME00731B/me unknown
- 1999-10-29 US US09/831,620 patent/US6509376B1/en not_active Expired - Lifetime
- 1999-10-29 SK SK576-2001A patent/SK285601B6/sk not_active IP Right Cessation
- 1999-10-29 HU HU0103182A patent/HU226689B1/hu active Protection Beyond IP Right Term
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- 1999-10-29 CA CA002346438A patent/CA2346438C/en not_active Expired - Lifetime
- 1999-10-29 RS YUP-299/01A patent/RS49995B/sr unknown
- 1999-10-29 IL IL14272899A patent/IL142728A0/xx active IP Right Grant
- 1999-10-29 DK DK99972532T patent/DK1131065T3/da active
- 1999-10-29 CN CNA200410011769XA patent/CN1615839A/zh active Pending
- 1999-10-29 WO PCT/EP1999/008215 patent/WO2000030622A2/de not_active Ceased
- 1999-10-29 CN CNB998123889A patent/CN1182844C/zh not_active Expired - Lifetime
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2001
- 2001-03-12 NO NO20011242A patent/NO333257B1/no not_active IP Right Cessation
- 2001-03-30 BG BG105396A patent/BG64837B1/bg unknown
- 2001-04-22 IL IL142728A patent/IL142728A/en active Protection Beyond IP Right Term
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2002
- 2002-03-22 ZA ZA200202335A patent/ZA200202335B/en unknown
- 2002-07-17 US US10/197,077 patent/US7320999B2/en not_active Expired - Lifetime
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2004
- 2004-12-21 JP JP2004368948A patent/JP2005097323A/ja active Pending
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2007
- 2007-06-20 US US11/765,563 patent/US7612110B2/en not_active Expired - Fee Related
- 2007-06-20 US US11/765,578 patent/US7619001B2/en not_active Expired - Fee Related
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2009
- 2009-03-17 US US12/405,661 patent/US7803840B2/en not_active Expired - Fee Related
- 2009-03-17 US US12/405,665 patent/US7915310B2/en not_active Expired - Lifetime
- 2009-08-10 JP JP2009185402A patent/JP5828614B2/ja not_active Expired - Lifetime
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2011
- 2011-03-04 US US13/040,914 patent/US8759393B2/en not_active Expired - Fee Related
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2012
- 2012-08-24 JP JP2012185136A patent/JP2012255020A/ja not_active Withdrawn
- 2012-09-12 US US13/612,221 patent/US8524773B2/en not_active Expired - Fee Related
- 2012-12-07 NO NO20121479A patent/NO20121479L/no not_active Application Discontinuation
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2013
- 2013-03-13 US US13/800,128 patent/US20140066505A1/en not_active Abandoned
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2014
- 2014-06-25 FR FR14C0051C patent/FR14C0051I2/fr active Active
- 2014-06-26 BE BE2014C040C patent/BE2014C040I2/fr unknown
- 2014-06-26 NO NO2014016C patent/NO2014016I2/no unknown
- 2014-06-27 LU LU92488C patent/LU92488I2/xx unknown
- 2014-06-30 LT LTPA2014023C patent/LTC1131065I2/lt unknown
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- 2014-07-16 CY CY2014027C patent/CY2014027I1/el unknown
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2015
- 2015-10-22 JP JP2015207653A patent/JP2016047830A/ja not_active Withdrawn
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2017
- 2017-08-03 JP JP2017150481A patent/JP2017226681A/ja not_active Withdrawn
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2019
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