TR202001040A2 - Vorti̇okseti̇n hi̇drobromi̇di̇n kri̇stali̇n c formu - Google Patents
Vorti̇okseti̇n hi̇drobromi̇di̇n kri̇stali̇n c formuInfo
- Publication number
- TR202001040A2 TR202001040A2 TR2020/01040A TR202001040A TR202001040A2 TR 202001040 A2 TR202001040 A2 TR 202001040A2 TR 2020/01040 A TR2020/01040 A TR 2020/01040A TR 202001040 A TR202001040 A TR 202001040A TR 202001040 A2 TR202001040 A2 TR 202001040A2
- Authority
- TR
- Turkey
- Prior art keywords
- crystalline
- vortioxetine hydrobromide
- present
- vortioxetine
- mdd
- Prior art date
Links
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Abstract
Mevcut buluş; majör depresif bozukluğun (MDB) tedavisinde kullanılmaya yönelik vortioksetin hidrobromidin kristalin C formu ile ilgilidir. Ayrıca buluş, vortioksetin hidrobromidin kristalin C formunu içeren bir kompozisyon ve C formunu içeren kompozisyonların hazırlanmasına yönelik prosesler sunmaktadır.
Description
TARIFNAME VORTIOKSETIN HIDROBROMIDIN KRISTALIN c FORMU Teknik Alan Mevcut bulus; majör depresif bozuklugun (MDB) tedavisinde kullanilmaya yönelik vortioksetin hidrobromidin kristalin C formu ile ilgilidir. Ayrica bulus, vortioksetin hidrobromidin kristalin C formunu içeren bir kompozisyon ve C formunu içeren kompozisyonlarin hazirlanmasina Teknigin Bilinen Durumu Majör depresif bozukluk (MDB), düsük benlik saygisi ve normalde keyif alinan aktivitelerden zevk almama durumu ile birlikte, her seyi kapsayan düsük ruh hali epizodlari ile karakterize, disabiliteye neden olan, siddetli bir mental bozukluktur. Hastalik kronik olma egilimindedir ve epizodlarin tekrarlanmasi yaygindir. MDB'nin diger semptomlari arasinda iritabilite veya hayal kirikligi, uyku bozukluklari, yorgunluk ve enerji eksikligi, istahta degisiklikler, anksiyete, ajitasyon, huzursuzluk, degersizlik veya suçluluk hissi, düsünmekte ve konsantre olmakta zorlanma ve sirt agrisi veya bas agrisi gibi açiklanamayan fiziksel problemler sayilabilir. MDB'nin kesin nedenleri bilinmemekle birlikte, beyin kimyasi ve fiziksel beyin farkliliklari, hormonlar, kalitsal özellikler ve yasamdaki olaylar gibi çesitli faktörlerin etkili olabilecegine inanilmaktadir. Vortioksetin, majör depresif bozukluk ve jeneralize anksiyete bozuklugunun tedavisinde kullanilmasi amaçlanan multimodal bir serotonerjik bilesiktir ve 5-HT3, 5-HT7 ve 5-HT1 D reseptör antagonisti, 5-HT1 A reseptör agonisti ve 5-HT1 B reseptörü kismi agonisti ve serotonin transporter (SERT) inhibitörü oldugu gösterilmistir. Vortioksetinin kimyasal adi 1- [2- (2,4-dimetilfenil) sülfanilfenil] piperazindir. Kimyasal yapisi asagida verilen Formül l"de gösterilmektedir. Formül I: Vortioksetin Vortioksetin hidrobromid, majör depresif bozuklugun (MDB) tedavisinde endikedir. MDB tedavisi için etki mekanizmasi oldugu düsünülen bir serotonin (5-HT) geri alim inhibitörüdür. Piyasada, bir antidepresan olan Vortioksetin hidrobromidin beta ([3) polimorfunu içeren BRINTELLIX markasi adi ile bulunmaktadir. hidrobromidin hemihidrati ve etil asetat solvati da dahil çesitli kristalin polimorflari ve psödo polimorflari, kristalin vortioksetin hidroklorür ve bunun bir monohidrati ve vortioksetin mesilat, hidrojenfumarat, hidrojenmaleat, mezohidrojentartrat, L - (+) - hidrojentartrat, D-(-)- hidrojentartrat, hidrojen sülfat, dihidrojen fosfat ve nitratin kristal formlari açiklanmaktadir. adsorbanin farmasötik bir kompozisyonu ve bunu üretme prosesi açiklanmaktadir. Teknikte hala, biyoyararlanima ve uzun süreli stabiliteye sahip kristalin vortioksetin hidrobromür formu kullanilarak majör depresif bozukluk (MDB) için gelismis hizli ve etkili bir tedavi sunulmasina ihtiyaç vardir. Vortioksetin hidrobromidin kristalin C formu, majör depresif bozuklugun (MDB) tedavisinde kullanildiginda, vortioksetin hidrobromidin beklenmedik sekilde hizli ve etkili tedavi ve biyoyararlanim sagladigi bulunmustur. Bulusun Ayrintili Açiklamasi Mevcut bulusun ana amaci, majör depresif bozuklugun (MDB) tedavisinde kullanilmaya yönelik bir vortioksetin hidrobromid kristalin C formu saglanmasi ve böylece hizli ve etkili tedavi ve biyoyararlanim sunularak ilgili önceki teknige göre ek avantajlar getirilmesidir. Mevcut bulusun baska bir amaci, majör depresif bozuklugun (MDB) tedavisinde kullanilmak üzere istenen stabilite ve dissolüsyon profiline sahip olan ve kritstalin C formunda vortioksetin hidrobromür içeren bir kompozisyon saglanmasidir. Vortioksetin hidrobromid suda hafifçe çözünür; ortam sicakligindaki çözünürlügü yaklasik 1.3 mg baz/mL'ye esdegerdir, pH degeri ise doymus çözeltide 5.5'tir. Kristalin polimorf formlarinin çözünürlügü, amorf formlarin çözünürlügüne göre daha yüksektir. Sasirtici bir sekilde, vortioksetin hidrobromid kristalin C formunun kullanilmasinin, majör depresif bozuklugun (MDB) tedavisinde daha iyi stabilite ve hizli ve etkili tedavi sagladigi bulunmustur. eslesen XRD paterni, vortioksetin hidrobromürün kristalin C formuna karsilik gelmektedir. Vortioksetin hidrobromidin kristalin C formu, majör depresif bozuklugun (MDB) tedavisinde kullanilmaya yöneliktir. Vortioksetin hidrobromidin kristalin C formu için önerilen normal kullanim dozu, 65 yasindan küçükler için günde bir kez 10 mg'dir. Majör depresif bozukluk (MDB) tedavisine verilen cevaba göre, doktor bu dozu günde maksimum 20 mg'a veya günde en az 5 mg'a çikarabilir. 65 yas ve üstü hastalar için baslangiç dozu günde bir kez 5 mg'dir. Bu tarifnamede kullanildigi sekliyle "partikül boyutu', lazer difraksiyon yöntemi (Malvern analizi) gibi konvansiyonel olarak kabul edilmis herhangi bir yöntemle test edilen kümülatif hacim boyut dagilimi anlamina gelmektedir. d (0.1) terimi, partikül hacmince %10'un daha ince oldugu boyut, d (0.5) terimi, partikül hacmince °/050,nin daha ince oldugu boyut ve d (0.9) terimi ise partikül hacmince %90'in daha ince oldugu boyut anlamina gelmektedir. Lazer difraksiyonu ile partikül boyutu dagilimlari, bir lazer isini dagilmis bir partikül numunesinden geçerken saçilan isik yogunlugunda meydana gelen açisal degisim ölçülerek belirlenir. Asagida gösterildigi gibi isik, büyük partiküllerden küçük açilarla saçilim göstererek geçerken, lazer isini ve küçük partiküllerden büyük açilarla saçilim göstererek geçer. Daha sonra, saçilimi olusturan partiküllerin boyutunu hesaplamak için açisal saçilma yogunlugu verileri analiz edilir. Partikül boyutu, hacim esdegeri küre çapi olarak bildirilmektedir. Mevcut bulusun bir uygulamasina göre, majör depresif bozuklugun (MDB) tedavisinde kullanima yönelik kristalin C formunda vortioksetin hidrobromidin partikül boyutu degeri, dissolüsyon hizi ve dolayisiyla yüksek biyoyararlanim ve uzun vadeli bir stabilite saglamaya yardimci olmasi açisindan önemlidir. Mevcut bulusun bir baska uygulamasina göre, vortioksetin hidrobromidin kristalin C formu, 100 boyutuna sahiptir. Mevcut bulusun bir baska uygulamasina göre, vortioksetin hidrobromidin kristalin C formu, 200 um'den az, 20 um'den az bir (:1 (0.5) partikül boyutuna sahiptir. Mevcut bulusun bir baska uygulamasina göre, vortioksetin hidrobromidin kristalin C formu, 250 pm'den az bir d (0.9) partikül boyutuna sahiptir. Mevcut bulusun bir baska uygulamasina göre, vortioksetin hidrobromidin kristalin C formu, 100 boyutuna, 250 pm ile 10 um arasinda d (0.9) partikül boyutuna sahiptir. Mevcut bulusun bir baska uygulamasina göre, majör depresif bozuklugun (MDB) tedavisinde kullanilmak üzere vortioksetin hidrobromidin kristalin C formunu içeren kompozisyon, kati oral dozaj formunda veya injektabl formda formüle edilmektedir. Mevcut bulusa ait farmasötik kompozisyon, kati oral dozaj formunda sunulmaktadir. Kati oral dozaj formlari arasinda, bunlarla sinirli olmamak üzere, tabletler, sert veya yumusak kapsüller, kapletler, pastiller, haplar, mini tabletler, tabletler, pelletler, boncuklar, granüller (örn. sase ambalajinda) yer almaktadir. Kati oral dozaj formuna yönelik kompozisyonlar, farmasötik kompozisyonlarin ve bu tür kompozisyonlarin üretimine yönelik teknikte bilinen herhangi bir Mevcut bulusun bir uygulamasina göre, tablet; kapli tablet, film kapli tablet, üç katmanli tablet, iki katmanli tablet, çok katmanli tablet, agizda dagilan tablet, mini tablet, pellet, bukkal tablet, dil alti tablet, efervesan tablet, çabuk salinimli tablet, modifiye salinimli tablet formundadir. Mevcut bulusun kati oral dozaj kompozisyonu; istenen dissolüsyon profilini saglamak amaciyla dolgu maddeleri, baglayicilar, dagiticilar, Iubrikanlar, glidantlar veya bunlarin karisimlarini içeren gruptan seçilen en az bir farmasötik olarak kabul edilebilir eksipiyan içermektedir. Uygun dolgu maddeleri; mikrokristalin selüloz, mannitol, Iaktoz monohidrat, nisasta, dibazik kalsiyum fosfat, tribazik kalsiyum fosfat, trehaloz, izomalt, sodyum karbonat, sodyum bikarbonat, kalsiyum karbonat karboksimetil selüloz, polidekstroz, polietilen oksit, hidroksipropil metil selüloz, metil selüloz, polietilen glikol veya bunlarin karisimlarini içeren gruptan seçilmektedir. Mevcut bulusun bir uygulamasina göre dolgu maddesi miktari, toplam kompozisyonun agirliginca %30.00 ile %950 arasindadir. Mevcut bulusun bir uygulamasina göre tercihen dolgu maddesi, mikrokristalin selüloz veya mannitol veya bunlarin karisimlaridir. Uygun baglayicilar; hidroksipropil selüloz, polivinilpirolidon, sekerler, aljinatlar, karbomerler, karboksimetilselüloz sodyum, selüloz asetat ftalat, kitosan, kopovidon, prejelatinize nisasta, nisasta müsilaji, akasya müsilaji, dekstratlar, dekstrin, dekstroz, etilselüloz, gliseril behenat, hidroksietil selüloz, hidroksietilmetil selüloz, hidroksipropil nisasta, hipromelloz, magnezyum alüminyum silikat, maltodekstrin, maltoz, metilselüloz, poloksamer, polikarbofil, polidekstroz, polietilen oksit, polimetakrilatlar, alüminyum hidroksit, stearik asit, sukroz, bentonit, setostearil alkol, polioksietilen-alkil eterler, pullulan veya bunlarin karisimlarini içeren gruptan seçilmektedir. Mevcut bulusun bir uygulamasina göre baglayici miktari, toplam kompozisyonun agirliginca Mevcut bulusun bir uygulamasina göre baglayici, tercihen hidroksipropil selülozdur. Uygun dagiticilar; sodyum nisasta glikolat, krospovidon, çapraz bagli karboksimetil selüloz (kroskarmeloz sodyum), prejelatinize nisasta, sodyum karboksimetil selüloz, kalsiyum karboksimetil selüloz, karboksimetil selüloz, dokusat sodyum, poliakrilik potasyum, sodyum aljinat, alginatlar, iyon degistirici reçineler, magnezyum alüminyum silika, poloksamer, sodyum glisin karbonat veya bunlarin karisimlarini içeren gruptan seçilmektedir. Mevcut bulusun bir uygulamasina göre dagitici miktari, toplam kompozisyonun agirliginca Mevcut bulusun bir baska uygulamasina göre tercihen dagitici, sodyum nisasta glikolattir. Uygun Iubrikanlar; magnezyum stearat, kalsiyum stearat, çinko stearat, hidrojenlenmis bitkisel yag, sodyum klorat, magnezyum lauril sülfat, sodyum oleat, sodyum asetat, sodyum benzoat, polietilen glikol, gliseril palmito sülfat, sodyum stearil fumarat, sodyum lauril sülfat veya bunlarin karisimlarini içeren gruptan seçilmektedir. Mevcut bulusun bir uygulamasina göre, Iubrikan miktari toplam kompozisyonun agirliginca Mevcut bulusun bir uygulamasina göre tercihen Iubrikan, magnezyum stearattir. Uygun glidantlar; kolloidal silikon dioksit, talk, alüminyum silikat, kolloidal silika, kalsiyum silikat, magnezyum silikat, magnezyum oksit, nisasta veya bunlarin karisimlarini içeren gruptan seçilmektedir. Mevcut bulusun bir uygulamasina göre, glidant miktari toplam kompozisyonun agirliginca Mevcut bulusun bir uygulamasina göre tercihen glidant, kolloidal silikon dioksittir. Mevcut bulusun bir baska uygulamasina göre, majör depresif bozuklugun (MDB) tedavisinde kullanilmak üzere vortioksetin hidrobromidin kristalin C formunu içeren kompozisyon, injektabl formda formüle edilmektedir. Mevcut bulusun bir uygulamasina göre, injektabl form, intravenöz, intramüsküler, intraarteriyel, intratekal, intrakapsüler, intraorbital, intrakardiyak, intradermal, intraperitoneal, transtrakeal, subkutançz, subkütiküler, intraartiküler, subkapsüler, subaraknoid, intraspinal ve intrastemal enjeksiyon ve infüzyon yoluyla uygulanmaktadir. Mevcut bulusun bir uygulamasina göre, injektabl form, koruyucu maddeler, yüzey aktif maddeler, çözücüler veya bunlarin karisimlarindan seçilen en az bir farmasötik olarak kabul edilebilir eksipiyan içermektedir. Mevcut bulusun kompozisyonu, direkt baski, yas veya kuru granülasyon, isiyla eritmeli granülasyon, isiyla eritmeli ekstrüzyon, akiskan yatakli granülasyon, ekstrüzyonfküre haline getirme, çift baski (slugging), spreyle kurutma ve çözücü buharlastirma gibi teknikte iyi bilinen standart teknikler ve üretim prosesleri kullanilarak hazirlanabilir. Örnek 1: Vortioksetin hidrobromidin kristalin C formunu içeren kati farmasötik kompozisyon (%) Miktar (ala) Vortioksetin hidrobromidin kristalin C Dolgu maddesi %30.0-95.0 Baglayici %0.1-10.0 Dagitici %1.0-10.0 Lubrikan %0.1-5.0 Glidant %0.1-5.0 Toplam 100 Örnek 2: Vortioksetin hidrobromidin kristalin C formunu içeren kati farmasötik kompozisyon (%) Miktar (ala) Vortioksetin hidrobromidin kristalin C Dolgu maddesi %60.0-90.D Baglayici %0.1-5.0 Dagitici %1.0-6.0 Lubrikan %1.0-3.0 Glidant %1.0-3.0 Toplam 100 Örnek 3: Islak granülasyon ile islenmis vortioksetin hidrobromidin kristalin C formunu içeren bir film tablet (%) Miktar (ala) Vortioksetin hidrobromidin kristalin C Mannitol 60 ve mikrokristalin selüloz %60.0-90.0 Hidroksipropil selüloz SSL %0.1-5.0 Sodyum nisasta glikolat %1.0-6.0 Magnezyum stearat %1.0-3.0 Kolloidal silikon dioksit %1.0-3.0 Toplam 100 Örnek 3'te belirtilen vortioksetin hidrobromidin kristalin C formunu içeren film tableti hazirlamaya yönelik bir proses olup, asagidaki adimlari içermektedir: a) Mannitol 60 ve mikrokristalin selüloz, vortioksetin hidrobromidin kristalin C formu, hidroksipropil selüloz SSL, sodyum nisasta glikolat karistirilir, b) Karisim, su-etanol karisimi ile granül haline getirilir, 0) Karisim, nem %2.0'in altina düsene kadar kurutulur, ardindan elenir d) Kalan mannitol 60, sodyum nisasta glikolat ve kolloidal silikon dioksit eklenir ve karistirilir, e) Magnezyum stearat eklenir ve ardindan karistirilir, f) Ardindan, basilarak tablet olusturulur ve kaplanir. TR TR
Claims (1)
1.ISTEMLER2.Majör depresif bozuklugun (MDB) tedavisinde kullanilmaya yönelik vortioksetin3.hidrobromidin kristalin C formudur.4.Istem 1'e göre vortioksetin hidrobromidin kristalin C formu olup, özelligi; formun günlük TR
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| EP21744455.3A EP4093402A4 (en) | 2020-01-23 | 2021-01-15 | CRYSTALLINE FORM C OF VORTIOXETINE HYDROBROMIDE |
| PCT/TR2021/050028 WO2021150188A1 (en) | 2020-01-23 | 2021-01-15 | Crystalline form c of vortioxetine hydrobromide |
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| CN102614179B (zh) * | 2006-06-16 | 2015-11-25 | H.隆德贝克有限公司 | 作为用于治疗认知损伤的、具有结合的对血清素再吸收、5-ht3和5-ht1a活性的化合物的1-[2-(2，4-二甲基苯基硫烷基)-苯基]哌嗪 |
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| AU2015254949A1 (en) * | 2014-04-28 | 2016-10-06 | Alembic Pharmaceuticals Limited | Novel polymorphic forms of Vortioxetine and its pharmaceutically acceptable salts |
| US20190224192A1 (en) * | 2016-08-29 | 2019-07-25 | Cipla Limited | Stable Pharmaceutical Composition of Vortioxetine Hydrobromide |
| WO2018065348A1 (en) * | 2016-10-05 | 2018-04-12 | Hexal Ag | Novel enteric-coated tablet comprising vortioxetine |
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