TR202013232A2 - Solid oral composition containing eltrombopag choline - Google Patents
Solid oral composition containing eltrombopag cholineInfo
- Publication number
- TR202013232A2 TR202013232A2 TR2020/13232A TR202013232A TR202013232A2 TR 202013232 A2 TR202013232 A2 TR 202013232A2 TR 2020/13232 A TR2020/13232 A TR 2020/13232A TR 202013232 A TR202013232 A TR 202013232A TR 202013232 A2 TR202013232 A2 TR 202013232A2
- Authority
- TR
- Turkey
- Prior art keywords
- solid oral
- oral composition
- sodium
- composition according
- less
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 84
- 239000007787 solid Substances 0.000 title claims abstract description 41
- XDXWLKQMMKQXPV-QYQHSDTDSA-N eltrombopag Chemical compound CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 XDXWLKQMMKQXPV-QYQHSDTDSA-N 0.000 title claims abstract description 38
- 229960001069 eltrombopag Drugs 0.000 title claims abstract description 37
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 title claims description 25
- 229960001231 choline Drugs 0.000 title claims description 25
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 7
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- 238000009472 formulation Methods 0.000 claims description 16
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- 239000007884 disintegrant Substances 0.000 claims description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 9
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 8
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- 206010043554 thrombocytopenia Diseases 0.000 claims description 8
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- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 claims description 6
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
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- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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Abstract
Mevcut buluş; eltrombopag colin ve en az bir farmasötik olarak kabul edilebilir eksipiyan içeren bir katı oral kompozisyon ile ilgilidir. Mevcut buluş ayrıca, basit, hızlı, uygun maliyetli, zaman tasarrufu sağlayan ve endüstriyel olarak uygun bir prosesle de ilgilidir.The present invention; relates to a solid oral composition comprising eltrombopag colin and at least one pharmaceutically acceptable excipient. The present invention also relates to a simple, fast, cost-effective, time-saving and industrially suitable process.
Description
TARFNAME ELTROMBOPAG KOLIN IÇEREN KATI ORAL KOMPOZISYON Teknik Alan Mevcut bulus; eltrombopag colin ve en az bir farmasötik olarak kabul edilebilir eksipiyan içeren bir kati oral kompozisyon ile ilgilidir. Mevcut bulus ayrica, basit, hizli, uygun maliyetli, zaman tasarrufu saglayan ve endüstriyel olarak uygun bir prosesle de ilgilidir. Teknigin Bilinen Durumu Megakaryosit büyüme ve gelisme faktörü (MGDF) olarak da bilinen trombopoietin (THPO), insanlarda THPO geni tarafindan kodlanan bir proteindir. Trombopoietin reseptörü agonistleri, trombopoietinin reseptörü üzerindeki etkisini taklit eder ve megakaryositlerin aktivasyonunu, proliferasyonunu ve matürasyonunu uyararak dolasimdaki trombosit sayilarinda bir artisa neden olur. Trombopoietinin kendisi bu sekilde etki eder, ancak rekombinant trombopoietinler klinik olarak kullanildiginda, muhtemelen anti- trombopoietin antikorlarinin indüklenmesine bagli olarak rebound trombositopeniye neden olduklari bulunmustur. Bu nedenle, trombositopeninin tedavisinde bir yaklasim olarak dogrudan trombopoietin uygulamasi terk edilmis ve trombopoietin reseptörünü aktive etmek için baska yaklasimlar aranmistir. Daha sonra iki trombopoietin reseptörü agonisti gelistirilmis olup su anda kronik idiyopatik trombositopenik purpura (ITP) ve diger trombositopenik durumlar için klinik kullanimdadir. Eltrombopag, megakaryopoez uyarici aktiviteye sahip olan, oral olarak aktif bir trombopoietin reseptör agonistidir. Eltrombopag, hematopoietin reseptör süper ailesinin bir üyesi olan trombosit trombopoietin reseptörüne (TPO-R veya CD110) baglanir ve onu uyarir. TPO-R'nin aktivasyonu megakaryositlerin proliferasyonuna ve diferansiyasyonuna yol açarak kari trombositlerinin üretimini arttirir. Eltrombopagin kimyasal adi 3- [3 - [[2- (3,4-dimetilfenil) -5-metiI-3-okso-IH-pirazoI-4-il] diazenil] -2-hidr0ksifenil] benzoik asittir ve kimyasal yapisi Formül 1'de gösterilmektedir. Formül 1: Eltrombopag Eltrombopag, trombositopeniye yol açan durumlarin tedavisi için eltrombopag olamin olarak GIaxoSmithKIine ve Ligand Pharmaceuticals tarafindan Promacta® ticari adi altinda pazarlanmaktadir. sayili patent basvurusunda ve ayrica 1,294,378 sayili EP Patent basvurusunda açiklanmistir. Eltrombopag bizetanolamin tuzu ve eltrombopag olamin tuzu, sirasiyla WO 03/098992 sayili patent basvurusunda ve 8.052,994 sayili U.S. Patent basvurusunda açiklanmistir. Bazi eltrombopag tuzlari, özellikle de olamin, bu bilesigi arzu edilen bir farmakokinetik profile sahip uygun bir kati oral farmasötik dozaj formu halinde formüle etmeye çalisirken formülasyon sahibinde benzersiz kaygilara neden olur. Endiselerden bazilari kati dozaj formlarindan bilesigin yavas dissolüsyonu, bilesigin koordine metal içeren eksipiyanlarla temas ettiginde çözünmez metal kompleksler olusturmaya yatkinligi ve bilesigin indirgeyici sekerler içeren eksipiyanlarla temas ettiginde Maillard reaksiyonuna gitme yatkinligidir. Yukarida açiklanan eltrombopag sorunlarindan dolayi, yeni eltrombog tuzunu içeren kompozisyonlara ihtiyaç vardir. WO 19/071111A1 sayili patent basvurusunda eltrombopag kolin açiklanmaktadir. Eltrombopag kolinin kati hal formu, kimyasal veya polimorfik saflik, dissolüsyon profili, biyoyararlanim, morfoloji veya kristal aliskanligi, polimorf dönüsümü ile ilgili olarak kimyasal stabilite ve termal ve mekanik stabilite gibi stabilite, dehidrasyona ve/veya saklamaya karsi stabilite, daha düsük higroskopisite, düsük artik çözücü içerigi gibi avantajlari özelliklere sahiptir. Bu bulusta, eltrombopag kolin içeren kati oral kompozisyon, trombositopeniye yol açan durumlarin tedavisi için gelistirilmistir. Bu kompozisyon, etkin maddenin diger tuzlarinin dezavantajlarinin ve yan etkilerinin üstesinden gelmek için kullanilirken, dissolüsyon hizi ve stabiliteyi istenen sekilde arttirir. Bulusun Ayrintili Açiklamasi Mevcut bulusun ana amaci, önceki teknikteki problemleri ortadan kaldirmak ve ilgili önceki teknige ek avantajlar getirmektir. Mevcut bulusun daha açik bir sekilde ana amaci, trombositopeniye yol açan durumlarin tedavisi için istenen dissolüsyon profiline, stabiliteye (kimyasal stabilite veya dehidrasyona ve/veya saklamaya karsi stabilite) sahip eltrombopag kolin içeren kati oral bir kompozisyon sunulmasidir. Mevcut bulusun baska bir amaci, eltrombopag kolin içeren kati oral kompozisyon için bir proses saglanmasidir. Söz konusu proses basit, hizli, uygun maliyetli, zaman tasarrufu saglayan ve endüstriyel olarak uygun bir yöntemdir. Mevcut bulusun bir uygulamasina göre, kati oral kompozisyon, eltrombopag kolin ve en az bir farmasötik olarak kabul edilebilir eksipiyan içermektedir. Eltrombopag kolinin kati hal formu, kimyasal ve polimorfik saflik, dissolüsyon profili, biyoyararlanim ve stabilite gibi avantajli özelliklere sahiptir. Trombositopeniye yol açan durumlarin tedavisi için formülasyon olusturulurken, eltrombopag kolin kullanilarak düsük maliyetli ve üretimi kolay olan etkin tedavi saglanmistir. Mevcut bulusun bir uygulamasina göre eltrombopag kolinin miktari, toplam formülasyonun agirliginca %3.0 ile %40.0 arasindadir. Bu miktar trombositopeniye yol açan durumlarin tedavisi için etkili bir tedavi saglamaktadir. Mevcut bulusun bir uygulamasina göre toplam formülasyonda eltrombopag kolin miktari Mevcut bulusun bir uygulamasina göre, en az bir farmasötik olarak kabul edilebilir eksipiyan seyrelticiler, baglayicilar, dagiticilar, lubrikanlar, glidantlar veya bunlarin karisimlarini içeren gruptan seçilmektedir. Genel olarak, formülasyonda yer alan eksipiyanlar, etkin maddenin çözünürlügü, emilimi, biyoyararlanimi gibi fizikokimyasal ve fizikokinetik özellikleri pozitif veya negatif yönde etkileyebilir. Bu nedenle, bir etkin maddeye eslik eden eksipiyanlar, formülasyon gelistirilirken dikkatle ve bilinçli bir sekilde seçilmelidir. Formülasyonlar, etkin maddeler ile eksipiyanlar arasinda fizikokimyasal geçimsizlik göstermemelidir. Mevcut bulusta, seçilen tüm eksipiyanlar eltrombopag kolin ile geçimlidir. Uygun dolgu maddeleri; mikrokristalin selüloz, nisasta, prejelatinize nisasta, toz halinde selüloz, mannitol, spreyle kurutulmus mannitol, dekstroz, sukroz, sorbitol, ksilitol, inorganik tuzlar, polisakkaritler, dikalsiyum fosfat, sodyum klorür, dekstratlar, Iaktitol, maltodekstrin, sukroz-maltodekstrin karisimi, trehaloz, sodyum karbonat, sodyum bikarbonat veya bunlarin karisimlarini içeren gruptan seçilmektedir. Mevcut bulusun bir uygulamasina göre seyreltici miktari toplam formülasyonda agirlikça Mevcut bulusun bir uygulamasina göre seyrelticilerin miktari, toplam formülasyonun agirliginca %500 ile %850 arasindadir. Mevcut bulusun bir uygulamasina göre seyreltici, mikrokristalin selüloz veya mannitol veya bunlarin karisimlaridir. Simdi sasirtici bir sekilde, baglayicilarin kullanilmasinin istenen dissolüsyon profilini saglamaya yardimci oldugu bulunmustur. Uygun baglayicilar; polivinilpirrolidon, sodyum karboksimetil selüloz, polietilen glikol, polivinil alkol, prejelatinize nisasta, dogal zamklar, sukroz, sodyum aljinat, jelatin, karrageenan, guar zamki, karbomer, polimetakrilatlar, metakrilat polimerleri, jelatin, aljinat, aljinik asit, ksantan zamki, hyalüronik asit, pektin, polisakkaritler, karbomer, poloksamer, poliakrilamit, polioksietilen-alkil eter, polidekstroz, polietilen oksit veya bunlarin karisimlarini içeren gruptan seçilmektedir. Mevcut bulusun bir uygulamasina göre baglayicilarin miktari, toplam formülasyonun agirliginca %0.05 ile %10.0 arasindadir. Tercihen, toplam formülasyonda agirlikça %0.1 ile önemlidir. Oran sayesinde, dissolüsyon problemleri çözülmüs ve sasirtici bir sekilde daha iyi dissolüsyon profili elde edilmistir. Mevcut bulusun bir uygulamasina göre baglayici, polivinilpirolidondur. Etkin madde, polivinilpirolidon ile etkilesime girmemistir ve polivinilpirolidon ayrica kompozisyonun istenen dissolüsyon profiline sahip olmasini saglamistir. Uygun dagiticilar; kroskarmeloz sodyum, sodyum nisasta glikolat, nisasta, krospovidon, düsük substitüye hidroksipropil selüloz, sodyum karboksimetil selüloz, kalsiyum karboksimetil selüloz, karboksimetil selüloz, dokusat sodyum, guar zamki, düsük sübstitüye hidroksipropil selüloz, poliakrilin potasyum, sodyum aljinat, misir nisastasi, aljinik asit, alginatlar, iyon degistirici reçineler, sodyum dodesil sülfat, poloksamer, sodyum glisin karbonat veya bunlarin karisimlarini içeren bir gruptan seçilmektedir. Mevcut bulusun bir uygulamasina göre dagiticilarin miktari, toplam formülasyonun agirliginca %10 ile %250 arasindadir. Tercihen, toplam formülasyonda agirlikça %1.0 ile Mevcut bulusun bir uygulamasina göre dagitici, kroskarmelloz sodyum veya sodyum nisasta glikolat veya bunlarin karisimlaridir. Uygun Iubrikanlar; sodyum stearil fumarat, magnezyum stearat, kalsiyum stearat, çinko stearat, borik asit, hidrojenlenmis bitkisel yag, sodyum klorat, magnezyum Iauril sülfat, sodyum oleat, sodyum asetat, sodyum benzoat, polietilen glikol veya bunlarin karisimlarini içeren gruptan seçilmektedir. Bulusun bir uygulamasina göre, Iubrikanlarin miktari, toplam kompozisyonun agirliginca Bulusun bir uygulamasina göre, Iubrikan, sodyum stearil fumarattir. Uygun glidantlar, kolloidal silikon dioksit, misir nisastasi, talk veya bunlarin karisimlarini içeren gruptan seçilmektedir. Bulusun bir uygulamasina göre, glidantlarin miktari, toplam kompozisyonun agirliginca Mevcut bulusun bir uygulamasina göre glidant, kolloidal silikon dioksittir. Bu tarifnamede kullanildigi sekliyle, "partikül boyutu dagilimi", lazer difraksiyon yöntemi (yani malvern analizi) gibi geleneksel olarak kabul edilmis herhangi bir yöntemle test edilen kümülatif hacim boyutu dagilimi anlamina gelir. D (0.9) terimi, partiküllerin hacimce %90'dan daha ince oldugu boyut anlamina gelir. Bulusun bir uygulamasina göre, eltrombopag kolin 150 um'den küçük veya 140 um'den küçük veya 90 um'den küçük veya 80 um'den küçük veya 70 um'den küçük veya 60 um'den küçük, 50 pm'den küçük veya 40 pm'den küçük veya 30 um'den küçük veya 20 um'den küçük d (0.9) partikül boyutuna sahiptir. Bu özellik, gelismis akis özellikleri saglamakta, ayrica istenen dissolüsyon profilinin saglanmasina yardimci olmaktadir. Bulusun bir uygulamasina göre eltrombopag kolin, 10 um'den küçük d (0.9) partikül boyutuna sahiptir. Mevcut bulusun bir uygulamasina göre, kati oral kompozisyon, tablet, kapsül, serit, toz, pastiller, sase, efervesan kompozisyon, hap, kapli boncuk sistemi, granül, mikroküre, draje ve film formundadir. Tercihen, kati oral kompozisyon, tablet veya kapsül formundadir. Mevcut bulusun bir uygulamasina göre, kati oral kompozisyon; film kapli tabletler, çift katmanli tabletler, inlay tabletler, agizda dagilan tabletler, sikistirilmis tabletler, kapli veya kapli olmayan tabletler, çok katmanli tabletler, mini tabletler, bukkal tabletler, dil alti tabletleri, efervesan tabletler, çabuk salinimli tabletler, modifiye salinimli tabletler, midede dagilan tabletler, çigneme tableti, dagilabilir tablet veya pastiller gibi tablet seklinde formüle edilmektedir. Bulusun bir uygulamasina göre, tercihen kati oral kompozisyon tablet formundadir ve tablet, kaplama maddeleri içeren kaplanmis film kaplamadir. Uygun kaplama maddeleri; kopovidon, polimetakrilatlar, polidekstroz, polietoksillenmis sorbitan, oleik asit, polialkilakrilat kopolimerleri, triasetin, hidroksi propil metil selüloz, kolloidal silikon dioksit, Iaktoz monohidrat, orta zincirli trigliseritler, hidroksipropil selüloz, beyaz mum, polivinil alkol, polietilen glikol, talk, polivinil alkol-polietilen glikol kopolimerleri (Kollicoat® IR) etilselüloz dispersiyonlari (Surelease®), polivinilpirolidon, polivinilpirolidon-vinil asetat kopolimeri (PVP-VA), tüm Opadry® çesitleri, pigmentler, boyalar, titanyum dioksit, demir oksit veya bunlarin karisimlarini içeren gruptan seçilmektedir. Mevcut bulusun bir uygulamasina göre kaplama maddeleri içeren kaplama miktari, toplam formülasyonun agirliginca %0.1 ile %50 arasindadir. Tercihen, toplam formülasyonda agirlikça %1.5 ile %35 arasindadir. Mevcut bulusta, kati oral kompozisyon, tablet formunda hazirlanabilir. Tablet; mini tablet, pelletler, çekirdek, agromelatlar, granüller, toz, Iipozomlar, küresel pelletler veya bunlarin karisimlari gibi en az bir tip partikül içermektedir. Mevcut bulusun bir baska uygulamasina göre, kati oral kompozisyon, kapsül seklinde formüle edilmektedir. Kapsül, mini kapsüller, pelletler, çekirdek, agromelatlar, granüller, tozlar, Iipozomlar, küresel pelletler veya bunlarin karisimlari gibi en az bir tip partikül içermektedir. Mevcut bulusun kati form kompozisyonu, direkt baski, yas veya kuru granülasyon, isiyla eritmeli granülasyon, isiyla eritmeli ekstrüzyon, akiskan yatakli granülasyon, ekstrüzyon/küre haline getirme, çift baski (slugging), spreyle kurutma ve çözücü buharlastirma gibi teknikte iyi bilinen standart teknikler ve üretim prosesleri kullanilarak hazirlanabilir. Ayrica, kati oral kompozisyon, islak granülasyon metodu kullanilarak elde edilebilir ve bu nedenle basit ve düsük maliyetli bir üretim metodu kullanilmistir. Mevcut bulusun bir baska uygulamasina göre, söz konusu kati oral kompozisyon, toplam kompozisyonda o Agirlikça %50 - 30.0 eltrombopag kolin . Agirlikça %450 - 85.0 seyreltici o Agirlikça %005 - 10.0 baglayici . Agirlikça %10 - 25.0 dagitici içermektedir. Mevcut bulusun bir baska uygulamasina göre, söz konusu kati oral kompozisyon. toplam kompozisyonda o Agirlikça %50 - 35.0 eltrombopag kolin Agirlikça %450 - 90.0 seyreltici Agirlikça %005 - 10.0 baglayici Agirlikça %10 - 25.0 dagitici Agirlikça 0.1- 5.0 lubrikan Agirlikça %005 - 5.0 glidant Içermektedir. Örnek 1: Eltrombopag kolin içeren kati oral kompozisyon Içerik maddeleri Agirlikça (%) Eltrombopag kolin 5.0 - 35.0 Seyrelticiler 45.0 - 90.0 Baglayicilar 0.05 - 10.0 Dagiticilar 1.0 - 25.0 Lubrikanlar 0.1 - 5.0 Glidantlar 0.05 - 5.0 TOPLAM 100 Örnek 2: Eltrombopag içeren tablet formülasyonu Içerik maddeleri Agirlikça (%) Eltrombopag kolin 5.0 - 30.0 Mikrokristalin selüloz 25.0 - 75.0 Mannitol 5.0 - 27.0 Polivinilpirolidon 0.1 - 5.0 Kroskarmelloz sodyum 3.0 - 15.0 Kolloidal silikon dioksit 0.05 - 3.0 Sodyum stearil fumarat 0.1 - 5.0 TOPLAM 100 Örnek 3: Eltrombopag içeren tablet formülasyonu Mikrokristalin selüloz 25.0 - 75.0 Mannitol 5.0 - 27.0 Polivinilpirolidon 0.1 - 5.0 Sodyum nisasta glikolat 1.0 - 10.0 Kolloidal silikon dioksit 0.05 - 3.0 Sodyum stearil fumarat 0.1 - 5.0 TOPLAM 100 a) Eltrombopag kolin, mikrokristalin selüloz, mannitol, polivinilpirolidonun karistirilmasi, b) Sudaki karisimin yüksek hiza sahip islak granülatörde granül haline getirilmesi, c) Granülün islak sekilde ögütülmesi ve akiskan yatakli kurutucuda kurutulmasi, d) Karisimin ve elde edilen homojen tozun elenmesi, e) Mikrokristalin selüloz, dagitici (kroskarmeloz sodyum veya sodyum nisasta glikolat), koloidal silikon dioksit eklenmesi ve karistirilmasi, f) Sodyum stearil fumarat eklenmesi ve karistirilmasi, g) Karisimin tablet olusturmak üzere basilmasi, h) Tabletlerinn kaplanmasi. TRDESCRIPTION ELTROMBOPAG SOLID ORAL COMPOSITION CONTAINING CHOLINE Technical Field The present invention relates to a solid oral composition comprising eltrombopag choline and at least one pharmaceutically acceptable excipient. The present invention also relates to a simple, rapid, cost-effective, time-saving and industrially feasible process. State of the Art Thrombopoietin (THPO), also known as megakaryocyte growth and development factor (MGDF), is a protein encoded by the THPO gene in humans. Thrombopoietin receptor agonists mimic the action of thrombopoietin on its receptor and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet numbers. Thrombopoietin itself acts in this manner, but when recombinant thrombopoietins have been used clinically, they have been found to cause rebound thrombocytopenia, presumably due to the induction of anti-thrombopoietin antibodies. Therefore, direct thrombopoietin administration as an approach to treating thrombocytopenia was abandoned and other approaches to activate the thrombopoietin receptor were sought. Two thrombopoietin receptor agonists have subsequently been developed and are currently in clinical use for chronic idiopathic thrombocytopenic purpura (ITP) and other thrombocytopenic conditions. Eltrombopag is an orally active thrombopoietin receptor agonist with megakaryopoiesis-stimulating activity. Eltrombopag binds to and stimulates the platelet thrombopoietin receptor (TPO-R or CD110), a member of the hematopoietin receptor superfamily. Activation of TPO-R leads to proliferation and differentiation of megakaryocytes, which in turn increases the production of blood platelets. The chemical name of eltrombopag is 3-[3-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-2-hydroxyphenyl]benzoic acid and its chemical structure is shown in Formula 1. Formula 1: Eltrombopag Eltrombopag is marketed under the trade name Promacta® by GIaxoSmithKIine and Ligand Pharmaceuticals as eltrombopag olamine for the treatment of conditions that lead to thrombocytopenia. and also disclosed in EP Patent application No. 1,294,378. Eltrombopag bisethanolamine salt and eltrombopag olamine salt are disclosed in U.S. Patent Application No. WO 03/098992 and U.S. Patent Application No. 8,052,994, respectively. Certain salts of eltrombopag, particularly olamine, present unique concerns to the formulator when attempting to formulate this compound into a suitable solid oral pharmaceutical dosage form with a desired pharmacokinetic profile. Some of the concerns include slow dissolution of the compound from solid dosage forms, the tendency of the compound to form insoluble metal complexes when in contact with excipients containing coordinated metals, and the tendency of the compound to undergo a Maillard reaction when in contact with excipients containing reducing sugars. Because of the problems with eltrombopag described above, there is a need for novel compositions containing the eltrombopag salt. The patent application numbered WO 19/071111A1 discloses eltrombopag choline. The solid state form of eltrombopag choline has advantages such as chemical or polymorphic purity, dissolution profile, bioavailability, morphology or crystal habit, stability such as chemical stability with respect to polymorph transformation and thermal and mechanical stability, stability against dehydration and/or storage, lower hygroscopicity, low residual solvent content. In the present invention, a solid oral composition containing eltrombopag choline has been developed for the treatment of conditions leading to thrombocytopenia. This composition is used to overcome the disadvantages and side effects of other salts of the active substance, while increasing the dissolution rate and stability as desired. Detailed Description of the Invention The main purpose of the present invention is to eliminate the problems in the prior art and to bring additional advantages to the relevant prior art. More specifically, the main object of the present invention is to provide a solid oral composition comprising eltrombopag choline having the desired dissolution profile, stability (chemical stability or stability to dehydration and/or storage) for the treatment of conditions leading to thrombocytopenia. Another object of the present invention is to provide a process for a solid oral composition comprising eltrombopag choline. The process is simple, rapid, cost-effective, time-saving and industrially feasible. According to one embodiment of the present invention, the solid oral composition comprises eltrombopag choline and at least one pharmaceutically acceptable excipient. The solid form of eltrombopag choline has advantageous properties such as chemical and polymorphic purity, dissolution profile, bioavailability and stability. In preparing the formulation for the treatment of conditions leading to thrombocytopenia, low cost and easy to manufacture effective treatment has been provided by using eltrombopag choline. According to one embodiment of the present invention, the amount of eltrombopag choline is between 3.0% and 40.0% by weight of the total formulation. This amount provides an effective treatment for the treatment of conditions leading to thrombocytopenia. According to one embodiment of the present invention, the amount of eltrombopag choline in the total formulation According to one embodiment of the present invention, at least one pharmaceutically acceptable excipient is selected from the group consisting of diluents, binders, dispersants, lubricants, glidants or mixtures thereof. In general, the excipients included in the formulation may positively or negatively affect the physicochemical and physicokinetic properties such as solubility, absorption and bioavailability of the active substance. Therefore, excipients accompanying an active substance should be carefully and consciously selected during formulation development. Formulations should not show physicochemical incompatibility between active substances and excipients. In the present invention, all selected excipients are compatible with eltrombopag choline. Suitable fillers are selected from the group consisting of microcrystalline cellulose, starch, pregelatinized starch, powdered cellulose, mannitol, spray-dried mannitol, dextrose, sucrose, sorbitol, xylitol, inorganic salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate or mixtures thereof. According to one embodiment of the present invention, the amount of diluent is between 500% and 850% by weight of the total formulation. According to one embodiment of the present invention, the diluent is microcrystalline cellulose or mannitol or mixtures thereof. It has now been surprisingly found that the use of binders helps to provide the desired dissolution profile. Suitable binders are; polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, natural gums, sucrose, sodium alginate, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, gelatin, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof. According to one embodiment of the present invention, the amount of binders is between 0.05 and 10.0% by weight of the total formulation. Preferably, it is significant between 0.1 and 0.0% by weight of the total formulation. Thanks to the ratio, dissolution problems were solved and surprisingly a better dissolution profile was obtained. According to one embodiment of the present invention, the binder was polyvinylpyrrolidone. The active ingredient did not interact with the polyvinylpyrrolidone and the polyvinylpyrrolidone also provided the composition with the desired dissolution profile. Suitable dispersants are; The disintegrants are selected from the group consisting of croscarmellose sodium, sodium starch glycolate, starch, crospovidone, low substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacrylic potassium, sodium alginate, corn starch, alginic acid, alginates, ion exchange resins, sodium dodecyl sulfate, poloxamer, sodium glycine carbonate or mixtures thereof. According to one embodiment of the present invention, the amount of disintegrants is between 10% and 250% by weight of the total formulation. Preferably, at 1.0% by weight of the total formulation. According to one embodiment of the present invention, the disintegrant is croscarmellose sodium or sodium starch glycolate or mixtures thereof. Suitable glidants are selected from the group comprising sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulphate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol or mixtures thereof. According to one embodiment of the invention, the amount of glidants is by weight of the total composition. According to one embodiment of the invention, the glidant is sodium stearyl fumarate. Suitable glidants are selected from the group comprising colloidal silicon dioxide, corn starch, talc or mixtures thereof. According to one embodiment of the invention, the amount of glidants is by weight of the total composition. According to one embodiment of the present invention, the glidant is colloidal silicon dioxide. As used herein, "particle size distribution" means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (i.e., malvern analysis). The term d(0.9) means the size at which the particles are finer than 90% by volume. According to one embodiment of the invention, eltrombopag choline has a d(0.9) particle size of less than 150 µm, or less than 140 µm, or less than 90 µm, or less than 80 µm, or less than 70 µm, or less than 60 µm, or less than 50 pm, or less than 40 pm, or less than 30 µm, or less than 20 µm. This feature provides improved flow properties and also helps to provide the desired dissolution profile. According to one embodiment of the invention, eltrombopag choline has a particle size of d (0.9) less than 10 µm. According to one embodiment of the present invention, the solid oral composition is in the form of tablets, capsules, strips, powder, lozenges, sachets, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees and films. Preferably, the solid oral composition is in the form of tablets or capsules. According to one embodiment of the present invention, the solid oral composition; are formulated in the form of tablets such as film-coated tablets, bilayer tablets, inlay tablets, orodispersible tablets, compressed tablets, coated or uncoated tablets, multilayered tablets, minitablets, buccal tablets, sublingual tablets, effervescent tablets, immediate-release tablets, modified-release tablets, gastric disintegrating tablets, chewable tablets, dispersible tablets or lozenges. According to one embodiment of the invention, preferably the solid oral composition is in the form of a tablet and the tablet is a coated film coating containing coating agents. Suitable coating agents are; copovidone, polymethacrylates, polydextrose, polyethoxylated sorbitan, oleic acid, polyalkylacrylate copolymers, triacetin, hydroxy propyl methyl cellulose, colloidal silicon dioxide, lactose monohydrate, medium chain triglycerides, hydroxypropyl cellulose, white wax, polyvinyl alcohol, polyethylene glycol, talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), all Opadry® varieties, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof. According to one embodiment of the present invention, the amount of coating containing coating agents is between 0.1 and 50% by weight of the total formulation. Preferably, it is between 1.5% and 35% by weight in the total formulation. In the present invention, the solid oral composition can be prepared in the form of a tablet. The tablet contains at least one type of particles such as mini tablets, pellets, cores, agglomerates, granules, powder, liposomes, spherical pellets or mixtures thereof. According to another embodiment of the present invention, the solid oral composition is formulated in the form of a capsule. The capsule contains at least one type of particles such as mini capsules, pellets, cores, agglomerates, granules, powder, liposomes, spherical pellets or mixtures thereof. The solid form composition of the present invention can be prepared using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, double compression (slugging), spray drying and solvent evaporation. Additionally, the solid oral composition can be obtained using the wet granulation method, and therefore, a simple and low cost manufacturing method is employed. According to another embodiment of the present invention, said solid oral composition comprises, in the total composition: o 50 - 30.0% by weight eltrombopag choline. o 450 - 85.0% by weight diluent. o 0.05 - 10.0% by weight binder. o 10 - 25.0% by weight dispersant. According to another embodiment of the present invention, said solid oral composition comprises: 50 - 35.0% by weight eltrombopag choline 450 - 90.0% by weight diluent 0.005 - 10.0% by weight binder 10 - 25.0% by weight disintegrant 0.1 - 5.0% lubricant 0.005 - 5.0% by weight glidant in the total composition. Example 1: Solid oral composition containing Eltrombopag choline Ingredients By weight (%) Eltrombopag choline 5.0 - 35.0 Diluents 45.0 - 90.0 Binders 0.05 - 10.0 Disintegrants 1.0 - 25.0 Lubricants 0.1 - 5.0 Glidants 0.05 - 5.0 TOTAL 100 Example 2: Tablet formulation containing Eltrombopag Ingredients By weight (%) Eltrombopag choline 5.0 - 30.0 Microcrystalline cellulose 25.0 - 75.0 Mannitol 5.0 - 27.0 Polyvinylpyrrolidone 0.1 - 5.0 Croscarmellose sodium 3.0 - 15.0 Colloidal silicon dioxide 0.05 - 3.0 Sodium stearyl fumarate 0.1 - 5.0 TOTAL 100 Example 3: Tablet formulation containing Eltrombopag Microcrystalline cellulose 25.0 - 75.0 Mannitol 5.0 - 27.0 Polyvinylpyrrolidone 0.1 - 5.0 Sodium starch glycolate 1.0 - 10.0 Colloidal silicon dioxide 0.05 - 3.0 Sodium stearyl fumarate 0.1 - 5.0 TOTAL 100 a) Mixing Eltrombopag choline, microcrystalline cellulose, mannitol, polyvinylpyrrolidone, b) Granulating the mixture in water in a high speed wet granulator, c) Wet milling the granule and drying it in a fluidized bed dryer, d) Sifting the mixture and the resulting homogeneous powder, e) Microcrystalline Adding cellulose, disintegrant (croscarmellose sodium or sodium starch glycolate), colloidal silicon dioxide and mixing, f) Adding sodium stearyl fumarate and mixing, g) Compressing the mixture to form tablets, h) Coating the tablets. TR
Claims (1)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2020/13232A TR202013232A2 (en) | 2020-08-21 | 2020-08-21 | Solid oral composition containing eltrombopag choline |
| PCT/TR2021/050799 WO2022039701A1 (en) | 2020-08-21 | 2021-08-13 | A solid oral composition comprising eltrombopag choline |
| EP21858732.7A EP4199921A4 (en) | 2020-08-21 | 2021-08-13 | SOLID ORAL COMPOSITION CONTAINING ELTROMBOPAG-CHOLINE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2020/13232A TR202013232A2 (en) | 2020-08-21 | 2020-08-21 | Solid oral composition containing eltrombopag choline |
Publications (1)
| Publication Number | Publication Date |
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| TR202013232A2 true TR202013232A2 (en) | 2022-03-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TR2020/13232A TR202013232A2 (en) | 2020-08-21 | 2020-08-21 | Solid oral composition containing eltrombopag choline |
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| Country | Link |
|---|---|
| EP (1) | EP4199921A4 (en) |
| TR (1) | TR202013232A2 (en) |
| WO (1) | WO2022039701A1 (en) |
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| CN117281780B (en) * | 2023-11-24 | 2024-02-02 | 山东则正医药技术有限公司 | Eltrombopag ethanolamine dry suspension and preparation method thereof |
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| WO2017042839A1 (en) * | 2015-09-08 | 2017-03-16 | Actavis Group Ptc Ehf. | Novel eltrombopag salt and preparation thereof |
| WO2018078644A1 (en) * | 2016-10-24 | 2018-05-03 | Hetero Labs Limited | Orally disintegrating tablets of eltrombopag |
| WO2019071111A1 (en) * | 2017-10-06 | 2019-04-11 | Teva Pharmaceuticals Usa, Inc. | Solid state forms of eltrombopag choline |
| EP3409272B1 (en) * | 2018-03-07 | 2020-06-24 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Pharmaceutical composition comprising eltrombopag olamine, reducing sugar, and polymeric binder |
| WO2020055364A2 (en) * | 2018-08-02 | 2020-03-19 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A pharmaceutical composition comprising eltrombopag olamine |
-
2020
- 2020-08-21 TR TR2020/13232A patent/TR202013232A2/en unknown
-
2021
- 2021-08-13 EP EP21858732.7A patent/EP4199921A4/en not_active Withdrawn
- 2021-08-13 WO PCT/TR2021/050799 patent/WO2022039701A1/en not_active Ceased
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| EP4199921A4 (en) | 2024-09-25 |
| WO2022039701A1 (en) | 2022-02-24 |
| EP4199921A1 (en) | 2023-06-28 |
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