RS55316B1 - Novi oblik kristalnog vi agomelatina, postupak pripreme i njegove farmaceutske kompozicije - Google Patents
Novi oblik kristalnog vi agomelatina, postupak pripreme i njegove farmaceutske kompozicijeInfo
- Publication number
- RS55316B1 RS55316B1 RS20161012A RSP20161012A RS55316B1 RS 55316 B1 RS55316 B1 RS 55316B1 RS 20161012 A RS20161012 A RS 20161012A RS P20161012 A RSP20161012 A RS P20161012A RS 55316 B1 RS55316 B1 RS 55316B1
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- agomelatine
- disorders
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- crystalline
- treatment
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- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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Description
Ovaj pronalazak se odnosi na novi kristalni VI oblik agomelatina ili ,V-[2-(7-metoksi-l-naftil)etil]acetamid formule (1):
postupak njegove proizvodnje, kao i na farmaceutske kompozicije koje ga sadrže. Agomelatin iliN-[ 2-( 7-metoksi-l-naftiI)etil]acetamid ima korisna farmakološka svojstva.
Ispoljava dejstvo dvostruke osobenosti, da je sa jedne strane agonist na receptorima melatoninergičnog sistema, a sa druge strane je antagonist receptora 5-HT2C- Ova svojstva mu daju aktivnost u centralnom nervnom sistemu i. preciznije, u lečenju opšte depresije, sezonskih depresija, poremećaja spavanja, kardiovaskularnih patologija, patologija digestivnog sistema, nesanica i umora kao posledica vremenske razlike, poremećaja apetita i gojaznosti. Agomelatin, njegova proizvodnja i njegova upotreba u terapeutske svrhe, opisani su u evropskom patentu EP 0 447 285.
Kristalni oblici agomelatina su već objavljeni u stanju tehnike, kao na primer u EP 1752444.
Uzimajući u obzir farmaceutsku korist od ovog jedinjenja, prioritet će biti dobijanje istog u stanju odlične čistoće i, pre svega, u obliku koji ima perfektnu reproduktibilnost, koji ima povoljna svojstva rastvorljivosti i jednostavno formulisanje koje omogućava njegovo čuvanje u dužem vremenskom periodu bez posebnih uslova u pogledu temperature, svetla, vlažnosti ili sadržaja kiseonika.
Podnosilac zahteva sada ističe postupak dobijanja agomelatina u kristalnom obliku koji je dobro definisan, reproduktibilan i naročito, ispoljava povoljne osobine u pogledu rastvaranja i jednostavnog formulisanja. Ovaj novi oblik, pored toga, ima izvanrednu održivost tokom vremena omogućavajući optimalno čuvanje bez posebnih mera opreza, što predstavlja najvažniju prednost u farmaceutskoj industriji.
Preciznije, ovaj pronalazak se odnosi na kristalan oblik VI jedinjenja formule (I), koji je naznačen sledećim dijagramom difrakcije X zraka na prašku, koji je izmeren na Bruker D5000matic difraktometru {bakarna antikatoda) i izražen u vidu međuravanske udaljenosti d. Braggovog ugla 2 teta i relativnog intenziteta (izražen kao procenat u odnosu na najintenzivniju liniju) :
Kristalni VI oblik jedinjenja formule (I) je. takođe. opisan sledećim dijagramom infracrvene spektroskopije: pikovi zabeleženi na 907,5 cm"<1>; 866.7 cm"'; 852,8 cm'<1>; 827,4 cm"<1>; 754,6 cm"<1>; 734,6 cm"<1>: 698.4 cm"<1>; 672.1 cm"<1>; 650,9 cm"<!>; 611,9 cm"<1>: 588.1 cm"<1>.
Pronalazak se, takođe, odnosi na postupak proizvodnje kristalnog oblika VI jedinjenja formule (I), koji je naznačen time što se rastvor agomelatina u izopropil etru zagreje do ključanja, zatim se naglo ohladi na 0°C. Posle filtriranja pod vakuumom, obiik VI se dobija čist. Za postupak kristalizacije prema pronalasku, može se koristiti jedinjenje formule (I) koje je dobijeno bilo kojim postupkom.
Pronalazak se, takođe. odnosi na drugi postupak proizvodnje kristalnog oblika VI jedinjenja formule (I), koji je naznačen time što se izvrši kristalisanje agomelatina u smeši voda/etanol (50/50 v/v) na temperaturi sredine pod visokim pritiskom, tokom 24 sata.
Poželjno, u drugom postupku kristalizacije prema pronalasku, agomelatin se rekristališe pod visokim pritiskom, koji iznosi 10 Kbar.
U drugom postupku kristalizacije prema pronalasku, može se koristiti jedinjenje formule (I) koje je dobijeno bilo kojim postupkom.
Dobijanje ovog kristalnog oblika ima za prednost omogućavanje proizvodnje farmaceutskih formulacija koje će imati konstantan sastav i biti reproduktibilne, ispoljavati odličnu održivost tokom vremena.
Tako, dobijeni rezultati farmaceutskog istraživanja oblika VI, pokazuju njegovu veoma važnu aktivnost u centralnom nervnom sistemu, kao i na mikrocirkulaciju Što mu omogućava primenu u lečenju stresa, poremećaja spavanja, anksioznosti, opšte depresije, sezonskih depresija, kardiovaskularnih patologija, patologija sistema za varenje, nesanica i umora kao posledica vremenske razlike, Šizofrenije, napada panike, melanholije. poremećaja apetita, gojaznosti, nesanice, bola, psiholičnih poremećaja, epilepsije, dijabetesa, Parkinsonove bolesti, senilne demencije, različitih poremećaja povezanih sa normalnim ili patološkim starenjem, migrene, gubitka pamćenja, Aizheimerove bolesti, kao i poremećaja cerebralne cirkulacije. U drugom domenu aktivnosti, jasno je da se u lečenju, oblik VI agomelatina može koristiti kod seksualnih disfunkcija, on ima svojstva inhibitora ovulacije. imunomodulatora i može da se koristi u lečenju kancera.
Kristalni oblik VI agomelatina bi se koristio, pre svega, za lečenje opšte depresije, sezonskih depresija, poremećaja spavanja, kardiovaskularnih patologija, patologija digestivnog sistema, nesanice i umora zbog vremenske razlike, poremećaja apetita i gojaznosti.
Pronalazak se, takođe, odnosi na farmaceutske kompozicije, koje kao aktivan princip sadrže kristalni oblik VI jedinjenja formule (I) zajedno sa jednom ili više inertnih podloga, koje nisu toksične i koje su odgovarajuće. Od farmaceutskih kompozicija prema pronalasku, mogu se navesti preciznije one, koje su prikladne za oralno, parenteralno (intravensko ili subkutano). nazalno primenjivanje, jednostavne pilule ili dražeje. granule, sublingvalne tablete, želatinske kapsule, tablete, supozitorije. kremovi, masti, gelovi za kožu. injektabilni preparati, suspenzije za pijenje i paste za žvakanje.
Doziranje, koje će se primeniti, prilagodljivo je s obzirom na prirodu i težinu bolesti, način primenjivanja, kao i starost i težinu pacijenta. Ovo doziranje varira od 0.1 mg do 1 g dnevno, u jednoj ili više doza.
Primeri u nastavku ilustruju pronalazak, ali ga ne ograničavaju ni na jedan način.
Primer 1: Kristalni oblik VI A^2-(7-metoksi-l-naftiI)etil]acetamida
U epruvetu se uvode 0,74 g A-[2-(7-rnetoksi-l-riaftiI)etil]acetamida i 36,06 g izopropil etra. Ova suspenzija se zagreje do ključanja (temperatura od 73°C) tokom 2 sata. Zatim se izvede naglo hlađenje na 0°C. Nakon jednog sata na 0°C. izvede se filtriranje pod vakuumom kroz staklenu fritu poroznosti 3. Dobijena čvrsta materija se opisuje pomoću njene tačke topljenja i pomoću sledećeg dijagrama difrakcije X zraka na prašku, koji je izmeren na Bruker D5000matic difraktometru (bakarna antikatoda) i izražen u vidu međuravanske udaljenosti d, Braggovog ugla 2 teta i relativnog intenziteta (izražen kao procenat u odnosu na najintenzivniju liniju) :
Tačka topljenja: 94°C
Dijagram infracrvene spektroskopije: 907,5 cm"'; 866.7 cm"<1>; 852,8 cm'<1>: 827.4 cm"<1>: 754,6 cm"<1>; 734,6 cm"<1>; 698,4 cm"'; 672,1 cm"'; 650.9 cm"'; 611,9 cm"<!>; 588,1 cm"'.
Primer 2 :Kristalni oblik VI A-[2-(7-metoksi-l-naftil)etil]acetamida
2 g<y>V-[2-(7-metoksi-l-naftil)etil]acetamida se postavljaju u 20 ml smeše voda/etanol (50/50 v/v) na 25<C>C. Ova suspenzija se filtrira kroz staklenu fritu poroznosti 4. Ovaj zasićen rastvor V-[2-(7-metoksi-l-naftil)etil]acetamiđa se podvrgne pritisku od 10 Kbar. Posle 24 sata, završena je kristalizacija i dobijena čvrsta materija se opisuje pomoću njene tačke topljenja i pomoću sledećeg dijagrama difrakcije X zraka na prašku, koji je izmeren na Bruker D5000matic difraktometru (bakarna antikatoda) i izražen u vidu međuravanske udaljenosti d, Braggovog ugla 2 teta i relativnog intenziteta (izražen kao procenat u odnosu na najintenzivniju liniju) :
Tačka topljenja : 94°CDijagram infracrvene spektroskopije: 907,5 cm'<1>; 866,7 cm"<1>; 852,8 cm"'; 827,4 cm"<1>; 754,6 cm"<1>; 734,6 cm'<1>; 698,4 cm''; 672,1 cm"<1>; 650,9 cm"<1>; 611,9 cm''; 588,1 cm"<1.>
Primer 3: Farmaceutska kompozicija
Formula za izradu 1000 tableta doze 25 mg :
Primer 4: Farmaceutska kompozicija
Formula za izradu 1000 tableta doze 25 mg ;
Claims (6)
1. Kristalni oblik VI agomelatina formule (I):
naznačensledećim dijagramom difrakcije X zraka na prašku, izmerenim na Bruker D5000matic difraktometru (bakarna antikatoda) i izraženim u vidu međuravanske udaljenosti d, Braggovog ugla 2 teta i relativnog intenziteta (izražen kao procenat u odnosu na najintenzivniju liniju) :
2.Postupak pripreme kristalnog VI oblika jedinjenja formule (I) prema zahtevu 1,naznačen time štose rastvor agomelatina u izopropil etru zagreje do ključanja, brzo ohladi na 0°C, zatim filtrira pod vakuumom.
3. Postupak pripreme kristalnog VI oblika jedinjenja formule (I) prema zahtevu 1.naznačen timešto agomelatin kristališe iz smeše voda/etanol (50/50 v/v) na sobnoj temperaturi, pod pritiskom od 10 kbar. tokom 24 sata.
4. Farmaceutske kompozicije koje kao aktivan princip sadrže kristalni VI oblik agomelatina prema zahtevu 1, zajedno sa jednim ili više farmaceutski prihvatljivih, inertnih i netoksičnih nosača.
5. Farmaceutske kompozicije prema zahtevu 4. za upotrebu u proizvodnji iekova za lečenje poremećaja melatoninergičnog sistema.
6. Farmaceutske kompozicije prema zahtevu 4. za upotrebu u proizvodnji lekova za lečenje poremećaja spavanja, stresa, anksioznosti, sezonskih depresija ili opšte depresije, kardiovaskularnih patologija, patologija sistema za varenje, nesanica i umora kao posiedica vremenske razlike, šizofrenije, napada panike, melanholije, poremećaja apetita, gojaznosti. nesanice, bola, psihotičnih poremećaja, epilepsije, dijabetesa, Parkinsonove bolesti, senilne demencije, različitih poremećaja povezanih sa normalnim ili patološkim starenjem, migrene, gubitka pamćenja, Alzheimerove bolesti, poremećaja cerebralne cirkulacije ili seksualnih disfunkcija. kao inhibitora ovulacije ili imunomodulatora ili za lečenje kancera.
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| FR0707861A FR2923482B1 (fr) | 2007-11-09 | 2007-11-09 | Nouvelle forme cristalline vi de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| EP08291042.3A EP2058296B1 (fr) | 2007-11-09 | 2008-11-07 | Nouvelle forme cristalline VI de l'agomélatine, son procédé de préparation et les compositions pharmaceutiques qui la contiennent |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2934856B1 (fr) * | 2008-08-05 | 2010-08-13 | Servier Lab | Nouveau procede d'obtention de la forme cristalline v de l'agomelatine |
| CN101585779B (zh) * | 2009-03-10 | 2014-04-02 | 上海医药工业研究院 | 阿戈美拉汀的晶型vi及其制备方法和应用 |
| WO2011006387A1 (zh) * | 2009-07-11 | 2011-01-20 | 浙江华海药业股份有限公司 | 阿戈美拉汀的制备方法、阿戈美拉汀晶形及其制备方法 |
| CN101955440B (zh) * | 2009-07-17 | 2014-04-09 | 江苏万特制药有限公司 | 一种阿戈美拉汀新晶型及其制备方法 |
| CN102001959B (zh) * | 2009-09-01 | 2014-07-02 | 北京本草天源药物研究院 | 一种药物晶体及其制备方法和用途 |
| EP2319827A1 (en) | 2009-11-09 | 2011-05-11 | Ratiopharm GmbH | Process for the production of polymorph form I of agomelatine |
| CN101781226B (zh) * | 2009-12-23 | 2012-03-28 | 天津泰普药品科技发展有限公司 | 阿戈美拉汀及其药物组合物 |
| EP2558440B1 (en) | 2010-04-15 | 2016-11-16 | ratiopharm GmbH | Process for the production of polymorph form i of agomelatine |
| WO2012046253A2 (en) * | 2010-10-08 | 2012-04-12 | Msn Laboratories Limited | Process for the preparation of n-[2- (7-methoxy-l-naphthyl) ethyl] acetamide and its novel crystalline forms |
| CZ303787B6 (cs) | 2011-01-21 | 2013-05-02 | Zentiva, K.S. | Metastabilní krystalové formy agomelatinu a jejich farmaceutické kompozice |
| CN102690209A (zh) * | 2011-03-23 | 2012-09-26 | 上海医药工业研究院 | 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物 |
| WO2012130837A1 (en) | 2011-03-28 | 2012-10-04 | Ratiopharm Gmbh | Solid agomelatine in non-crystalline form |
| CN102206864B (zh) * | 2011-04-13 | 2012-10-03 | 吉林省博大伟业制药有限公司 | 阿戈美拉汀的ⅵ晶型单晶及混合晶型和制备方法 |
| PH12012000132A1 (en) * | 2011-06-09 | 2014-10-20 | Servier Lab | New co-crystals of agomelatine, a process for their preparation and pharmaceutical compositions containing them |
| EP2771312B1 (en) | 2011-11-30 | 2017-05-31 | ratiopharm GmbH | Agomelatine-urea complex and crystalline forms thereof |
| CZ2012108A3 (en) | 2012-02-15 | 2013-02-27 | Zentiva Ks | A method for the manufacture of a polymorphously stable pharmaceutical composition containing agomelatine |
| WO2014012571A1 (en) | 2012-07-16 | 2014-01-23 | Ratiopharm Gmbh | Complex of agomelatine and cyclodextrin |
| CN102988315B (zh) * | 2012-09-28 | 2017-11-17 | 浙江华海药业股份有限公司 | 阿戈美拉汀固体制剂的制备方法 |
| WO2014072998A1 (en) | 2012-11-07 | 2014-05-15 | Cadila Healthcare Limited | An improved process for preparation of agomelatine |
| WO2014096373A1 (en) | 2012-12-21 | 2014-06-26 | Laboratorios Lesvi, S. L. | Process for prepararing n-(2-(7-methoxy-1-naphthalenyl)ethyl) acetamide and solid forms thereof |
| EP2810647A1 (en) | 2013-06-06 | 2014-12-10 | Zentiva, a.s. | Pharmaceutical formulations comprising agomelatine in the form of agomelatine co-crystal with an organic acid |
| ES2645223T3 (es) | 2013-06-06 | 2017-12-04 | Zentiva, K.S. | Formulaciones de agomelatina que comprenden agomelatina en forma de co-cristales |
| CZ2013621A3 (cs) | 2013-08-13 | 2015-02-25 | Zentiva, K.S. | Termodynamicky stabilní tuhý roztok agomelatinu pro použití ve farmaceutické formulaci |
| WO2015124496A1 (en) | 2014-02-19 | 2015-08-27 | Synthon B.V. | Pharmaceutical composition comprising amorphous agomelatine |
| ES2959460T3 (es) | 2015-03-31 | 2024-02-26 | Fis Fabbrica Italiana Sintetici Spa | Forma sólida de agomelatina |
| EP3466923A1 (en) | 2017-10-09 | 2019-04-10 | KRKA, d.d., Novo mesto | Process for the preparation of agomelatine in crystalline form |
| EP3466413A1 (en) | 2017-10-09 | 2019-04-10 | KRKA, d.d., Novo mesto | Pharmaceutical composition containing agomelatine and process for the preparation thereof |
| CN114028335A (zh) * | 2021-12-24 | 2022-02-11 | 山东京卫制药有限公司 | 一种阿戈美拉汀溶液鼻喷剂及其应用 |
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| IT1146164B (it) | 1980-07-16 | 1986-11-12 | Selenia Ind Elettroniche | Dispositivo di filtraggio doppler adattivo alla situazione di clutter ed ecm esterna per impianti radar |
| FR2658818B1 (fr) * | 1990-02-27 | 1993-12-31 | Adir Cie | Nouveaux derives a structure naphtalenique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
| ES2277937T3 (es) * | 2000-07-27 | 2007-08-01 | Teva Pharmaceutical Industries Ltd. | Modafinilo puro y cristalino y su procedimiento de preparacion. |
| US6992219B2 (en) * | 2002-08-09 | 2006-01-31 | Cephalon France | Modafinil polymorphic forms |
| FR2866335B1 (fr) * | 2004-02-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'agomelatine |
| US7358395B2 (en) * | 2005-08-03 | 2008-04-15 | Les Laboratories Servier | Crystalline form V of agomelatine, a process for its preparation and pharmaceutical compositions containing it |
| US7645905B2 (en) * | 2005-08-03 | 2010-01-12 | Les Laboratoires Servier | Crystalline form IV of agomelatine, a process for its preparation and pharmaceutical compositions containing it |
| US7635721B2 (en) * | 2005-08-03 | 2009-12-22 | Les Laboratoires Servier | Crystalline form III of agomelatine, a process for its preparation and pharmaceutical compositions containing it |
| FR2889522B1 (fr) * | 2005-08-03 | 2007-12-28 | Servier Lab | Nouvelle forme cristalline iv de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
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