TR2023003089T2 - PHARMACEUTICAL COMPOSITIONS CONTAINING MESALAMIN AND RELATED EXcipients - Google Patents
PHARMACEUTICAL COMPOSITIONS CONTAINING MESALAMIN AND RELATED EXcipientsInfo
- Publication number
- TR2023003089T2 TR2023003089T2 TR2023/003089 TR2023003089T2 TR 2023003089 T2 TR2023003089 T2 TR 2023003089T2 TR 2023/003089 TR2023/003089 TR 2023/003089 TR 2023003089 T2 TR2023003089 T2 TR 2023003089T2
- Authority
- TR
- Turkey
- Prior art keywords
- eudragit
- enteric
- weight
- layer
- tablet
- Prior art date
Links
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- 239000000546 pharmaceutical excipient Substances 0.000 title claims abstract description 29
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Abstract
Mevcut buluş, mesalamin ve ilgili eksipiyanları içeren ve enterik kaplı tablet üretim yöntemi için geliştirilmiş bir formülasyon tasarımına sahip farmasötik kompozisyonların hazırlanması ile ilgilidir.The present invention relates to the preparation of pharmaceutical compositions containing mesalamine and related excipients and having an improved formulation design for the enteric coated tablet production method.
Description
TARIFNAME MESALAMIN VE ILGILI EKSIPIYANLARI IÇEREN FARMASÖTIK KOMPOZISYONLAR Bulus Alani Mevcut bulus, mesalamin ve ilgili eksipiyanlari içeren ve enterik kapli tablet üretim yöntemi için gelistirilmis bir formülasyon tasarimina sahip farmasötik kompozisyonlarin hazirlanmasi ile ilgilidir. Teknigin Bilinen Durumu Mesalamin gibi aminosalisilat yapidaki ilaçlar, hafif ve orta siddette enflamatuvar bagirsak hastaliginin (IBD) tedavisinde kullanilir. 5-aminosalisilik asit (5-ASA) olarak da bilinen mesalamin, Crohn hastaligi ve ülseratif kolit de dahil olmak üzere, inflamatuar bagirsak hastaligi (IBD) gibi gastrointestinal sistem bozukluklarinin tedavisinde kullanilan bir anti- inflamatuar ilaçtir. Mesalamin; pembemsi beyaz kristal veya morumsu-bronz rengi toz görünümünde ve kokusuzdur. Kimyasal adi 5-Amino-2-hidroksibenzoik asit olup moleküler agirligi 153.135 g/mol'dür. Kimyasal yapisi Sekil 1,de gösterilmektedir. Sekil 1: Mesalamin Mesalamin, ilk olarak tedavisinde uzun yillardir kullanilmaktadir. Su ana kadar piyasada bulunan dozaj formlari tablet, lavman, supozituvar, kapsül, granül veya toz seklindedir. Inflamatuar barsak hastaligi, gastrointestinal (GI) sistemin kronik inflamasyonu ile karakterize edilen Crohn hastaligi ve ülseratif koliti kapsayan bir terimdir. Crohn hastaligi, sindirim sisteminin kronik enflamatuar bir hastaligidir ve semptomlari karin agrisi, ates, yorgunluk, siddetli ishal, kilo kaybidir. Crohn hastaligi için bilinen bir çare olmamasina ragmen, tedavi uygulamalari hastaligin belirtilerini ve semptomlarini büyük ölçüde azaltabilir. Ülseratifkolit, sindirim sisteminde uzun süreli iltihaplanma ve ülserlere neden olan inflamatuar bagirsak hastaliklarindan (IBD) biridir. Bu hastaligin baslica belirtileri karin agrisi, kanli ishal, kilo kaybi, ates ve kansizliktir. Kalin bagirsak ve rektum astarinda tahrise, iltihaplanmaya ve ülserlere neden olur. Gastro-dirençli kaplama tableti olarak da bilinen enterik kapli tablet; ilacin emilebilecegi ince bagirsaga ulasana kadar salinmasini önleyen aktif bilesen(ler) ile kaplanmis olan tablet türüdür. Çogu enterik kapli tablet, midenin oldukça asidik pH'ina karsi kararli bir yüzeye sahiptir, ancak bagirsak yolunda daha az asidik (nispeten daha bazik) bir pH'ta hizla parçalanir. Enterik kapli tabletler ince bagirsakta çözünebilir. Enterik kaplama malzemelerde aranan mide ortamina dirençlilik, bagirsak sivilarina karsi geçirgenlik, yüksek uyumluluk, toksik olmayan aktivite ve sürekli film olusturabilme gibi parametreler, enterik kapli bir tablet ürün için kritik öneme sahiptir. Eksipiyanlar, bu parametrelere ve ayrica etken maddenin özelliklerine göre seçilmelidir. Enterik kaplama; ilaçlari mide asitliginin bozucu etkilerinden korumak, mide mukozasini tahristen korumak ve belirli ilaçlarin emilimi artirma amaciyla bagirsaklara tasinimini kontrol etmek için kullanilir. Enterik salimli film kaplama için kullanilan baslica polimerler; selüloz asetat ftalat, selüloz asetat trimelitat, hidroksil propil metil selüloz ftalat, hidroksil propil metil selüloz asetat süksinat, polivinil asetat ftalat ve metakrilik asit kopolimerleridir. Mesalaminin oral ve rektal olarak kombine uygulamasi kullanildiginda semptomlarda iyilesme orani %88 olarak bulunmus; ancak sadece rektal uygulamalarin kullanildigi tedavilerde bu iyilesme orani %54 olarak tespit edilmistir. Bu sonuçlar "Distal ülseratif kolit tedavisinde oral ve rektal mesalamin kullanimlari ile bunlarin kombine tedavisinin çift-kör karsilastirmasi" Bulus Özeti Mevcut bulus, mesalamin ve ilgili eksipiyanlari içeren enterik kapli farmasötik tablet kompozisyonlari hazirlamak üzere gelistirilmis bir formülasyon tasarimina iliskindir. Mevcut bulus, mesalamin içeren enterik kapli bir farmasötik tablet kompozisyonu saglar. Söz konusu kompozisyonda, birinci katmandaki enterik kaplama polimeri Eudragit L100'dür. Ikinci katmandaki enterik kaplama polimerleri Eudragit 8100 ve Eudragit L100'dür. Toplam tablet kütlesi 1400 ile 2000 mg araligindadir. Bulusun Detayli Açiklamasi Mevcut bulus, mesalamin ve ilgili eksipiyanlari içeren enterik kapli farmasötik tablet kompozisyonlarinin hazirlanmasi için gelistirilmis bir formülasyon tasarimina iliskindir. Mesalamin içeren bir farmasötik kompozisyon ortaya koyan mevcut bulusta; birinci katmandaki enterik kaplama polimeri Eudragit L100, ikinci katmandaki enterik kaplama araligindadir. Mevcut bulus, asagidakileri içeren bir mesalamin farmasötik kompozisyonu ile ilgilidir; a) Bir enterik kaplama polimeri olarak Eudragit L100 ve farmasötik olarak kabul edilebilir en az bir eksipiyan içeren bir birinci katman, b) Enterik kaplama polimerleri olarak Eduragit 8100 ve Eudragit L100 ve farmasötik olarak kabul edilebilir en az bir eksipiyan içeren ikinci bir katman, burada enterik kapli farmasötik tablet agirligi belirli bir aralik arasindadir. Mevcut bulus, mesalamin içeren bir enterik kapli farmasötik tablet bilesimi ile ilgilidir; a) bir enterik kaplama polimeri olarak Eudragit L100 ve farmasötik olarak kabul edilebilir en az bir eksipiyan içeren bir birinci katman, burada birinci katmandaki Eudragit L100 agirliginin toplam tablet agirligina orani 2,5 ile 5,0 arasindadir. b) enterik kaplama polimerleri olarak Eduragit 8100 ve Eudragit L100 ve farmasötik olarak kabul edilebilir en az bir eksipiyan içeren ikinci bir katman, burada ikinci katmandaki Eudragit SlOO agirliginin Eudragit L100 agirligina orani 0,5 ile 0,8 arasindadir. burada enterik kapli farmasötik tablet agirligi l400mg ile 2000mg arasindadir. Enterik kaplama, polimerlerin kullanildigi oral bir ilaç türüdür. Bu polimerler, tabletleri yuttuktan sonra midedeki gastrik asitlerin ilaçlari çözmesini veya parçalamasini önlemek için bir bariyer görevi görür. Farmasötik ürünlerde enterik koruma kullanilmazsa, ilaçlarin çogu mide asitleriyle hizla parçalanir. Enterik polimer kaplama, tablet dozaj formlari için gecikmeli bir salim saglar. Bu islem sonucunda ilaçlar, ince bagirsaga veya sindirimin ulasmasi gereken diger asamalarina hedeIlenir. Mevcut bulus, Eudragit L100 enterik kaplama polimerinin birinci katmanda ve Eudragit 8100 ve Eudragit L100 enterik kaplama polimerlerinin ikinci katmanda oldugu bir enterik kapli farmasötik tablet bilesimi ile ilgilidir. Mevcut bulus, birinci katmandaki Eudragit L100 agirliginin toplam tablet agirligina orani 2,5 ile 5 ,0 arasinda olan farmasötik bir kompozisyona iliskindir. Mevcut bulus farmasötik bir kompozisyon ile ilgilidir; burada birinci katmandaki Eudragit L100 agirliginin toplam tablet agirligina orani tercihen 2,7 ile 3,5 arasinda, daha fazla tercihen 2,84,tür. Mevcut bulus bir farmasötik kompozisyon ile ilgilidir; burada ikinci katmanda bulunan Eudragit SlOO agirliginin Eudragit L100 agirligina orani 0,5 ile 0,8 arasindadir. Mevcut bulus, farmasötik bir kompozisyon ile ilgilidir; burada ikinci katmanda bulunan tercihen 0,68,dir. Mevcut bulus, enterik kapli bir tablet dozaj formunda mesalamin ve ilgili eksipiyanlari içeren bir farmasötik kompozisyon ile ilgilidir. Bu dozaj sekli ile mesalamin tabletlerinden etkin madde salinimi 3-4 saat sonra baslar. Yaklasik 5 saat sonra maksimum plazma konsantrasyonuna ulasir. Açlik durumunda ileum ile kalin bagirsak arasindaki bölgeye 3-4 saatte, kolonun üst kismina ise 4-5 saatte ulasir. Kolonda yaklasik 17 saat kalir. Mevcut bulus, Eudragit ve onun farkli türleri ile ilgilidir. Eudragit, metakrilik asit kopolimerleri içeren bir yapiya sahiptir. Metakrilik asit kopolimerleri, serbest karboksilik asit gruplari içerdiklerinden dolayi enterik kaplama tabletlerinde yaygin olarak kullanilmaktadir. Bu enterik polimerler, özellikle Evonik (eski adiyla Röhm GmbH) tarafindan tescilli Eudragit markasi altinda pazarlanmaktadir. Birçok Eudragit enterik polimer türü, sulu dispersiyon, organik çözelti, granüller ve tozlar gibi farkli fiziksel formlarda ticari olarak temin edilebilir. Eudragitler, metakrilik asit ve metil metakrilat bazli anyonik kopolimerlerdir. Eudragit L100, Poli(metasilik asit-ko-metil metakrilat) l:l,dir. Eudragit SlOO, Poli(metasilik asit-ko-metil metakrilat) 1:2,dir. Genel olarak, enterik kaplamalar için kullanilan Eudragit ürünleri, metakrilik asit ve metakrilatlarin anyonik polimerlerinden olusur. pH=5,5 ile 7 araliginda çözünür. Bazi Eudragit ürünleri Tablo l,de görülebilir. Tablo 1: Eudragit ürünlerinin özellikleri Uygulama Eudragit ® Sinifi Görünüm Çözünme Özellikleri Jejunumda ilaç tasinimi Eudragit L100 Toz pH 6,0,nin üzerinde çözünme Ileumda ilaç tasinimi Eudragit SlOO Toz pH 7,0,nin üzerinde çözünme Eudragit ürünlerinin enterik kaplamada öne çikan özelliklerinden bazilari: pH,a bagli ilaç salinimi, mide sivisina duyarli etken maddelerin korunmasi, agresif etken maddelerden mide mukozasinin korunmasi, ilaç etkinliginin artmasi, iyi depolama stabilitesi, gastrointestinal sistem ve kolon hedefleme. Mevcut bulus, ürün hedefinin insan vücudundaki kolon bölgesi oldugu, enterik kapli bir tablet kompozisyonu ile ilgilidir. Mevcut bulus, mesalamin, enterik kaplama polimerleri ve ilgili eksipiyanlardan olusan iki katmana sahip enterik kapli bir tablet kompozisyonu ile ilgilidir. Mevcut bulus, mesalamin ve ilgili eksipiyanlari içeren farmasötik bir kompozisyon saglar, burada söz konusu farmasötik kompozisyon, "birinci katman" ve "ikinci katman" olmak üzere iki katmana sahiptir. Mevcut bulus, birinci tabakasinda Eudragit L100,ün bir enterik polimer olarak kullanildigi enterik kapli bir tablet kompozisyonu ile ilgilidir. Mevcut bulus, enterik kapli bir tablet kompozisyonu ile ilgilidir, burada Eudragit L100 ve Eudragit SlOO, kompozisyonun ikinci katmaninda enterik polimerler olarak kullanilir. Mevcut bulus, enterik kapli tablette toplam tablet kütlesinin 1400 mg ile 2000 mg arasinda oldugu, mesalamin ve ilgili eksipiyanlari içeren farmasötik bir kompozisyon saglar. Bir uygulamada; mesalamin ve ilgili eksipiyanlari içeren farmasötik kompozisyon olup, enterik kapli tablette toplam tablet agirligi 1400 mg ile 1800 mg arasindadir. Eudragit enterik polimerlerin (Eudragit L100 ve Eudragit SlOO) agirliginin toplam tablet agirligina oraninin, yukaridaki paragraIlarda belirtilen belirli araliklar arasinda oldugunda, sinerj ik etki gözlenmistir ve ayni zamanda söz konusu enterik kapli tablet ürünü için optimum bir formülasyon tasarimi sagladigi tespit edilmistir. Bir uygulamada, mesalamin içeren enterik kapli tablet kompozisyonu, Crohn hastaligi ve ülseratif kolit dahil olmak üzere inIlamatuar bagirsak hastaliginin tedavisi için kullanilir. Mevcut bulusun hedeIlerinden biri, kabul edilebilir biyoyararlanim sonuçlari sergileyen ilacin hemen salinmasini saglayan enterik kapli bir tablet olarak oral dozaj formunda farmasötik bir kompozisyon saglamaktir. Bir uygulamada, kararli farmasötik kompozisyonu hazirlama prosesi asagidaki basamaklari - Eudragit L100 ve farmasötik olarak kabul edilebilir eksipiyanlar içeren bir birinci enterik tabakanin hazirlanmasi, - Eudragit L100, Eudragit 8100 ve farmasötik olarak kabul edilebilir eksipiyanlar içeren ikinci enterik tabakanin hazirlanmasi, - ardindan enterik kapli tabletin basimi ve - koruyucu bir tabaka ile kaplanmasi. Baska bir uygulamada, farmasötik kompozisyon ayrica bir seyreltici, bir baglayici, bir disintegrant, bir glidant, bir lubrikant, bir plastizer, bir enterik kaplama polimeri ve bir film kaplama malzemesi arasindan seçilen en az bir eksipiyan içerir. Avantajlar Bir enterik tablette Eudragit L100 ve Eudragit 8100 gibi enterik polimerler kullanilarak, hasta kullanimina uygun optimum toplam tablet agirligi elde edilir. Bulusun farmasötik kompozisyonlari özellikle oral uygulama için uygundur. Mevcut bulus, uygun eksipiyanlardaki stabilite özelliklerine bagli olarak iyi fiziksel özellikler gösterir. Temel fiziksel stabilite saglamak için iyi özellikler gösterir. Mevcut bulus, enterik kapli dozaj formunda mesalamin ve ilgili eksipiyanlari içeren farmasötik kompozisyon saglar; i) Basit ve özgün bir üretim prosesi ii) Stabil formülasyon Enterik tablet dozaj formu, gastrointestinal (GI) sistemdeki ülseratif kolit gibi barsak hastaliklarinda kullanima uygundur, dolayisiyla hasta uyuncu yüksektir. Enterik kaplama polimeri tabakasi, biyoaktif maddeyi gastrointestinal sistemdeki degredasyona karsi korur. Mevcut bulus, ürün hedefinin insan vücudundaki kolon bölgesi oldugu ve mesalamin içeren Mevcut bulus, enterik kapli dozaj formuna sahip, mesalamin ve ilgili eksipiyanlari içeren i) iyi tasarlanmis tablet olusumuna bagli olarak, etken maddelerin salinimini kontrol etmek/ programlanmasi ii) akilli ve iyi tasarlanmis bir üretim prosesi Mevcut bulusta, Eudragit L100 ve Eudragit 8100 gibi enterik polimerler ile formülasyonda minimum yardimci maddeler kullanilarak, bagirsak hastaliklarinda kullanima uygun bir enterik tablet ürünü elde edilmistir. Mevcut bulus, mesalamin ve ilgili eksipiyanlari içeren farmasötik kompozisyon saglar; burada söz konusu kompozisyon, enterik kapli bir kompozisyon için 1400 mg ile 2000 mg arasindaki toplam tablet agirligiyla kullanima uygundur. Tablet ürünün 2000mg,den daha büyük olmasi, yutabilma sorunu nedeniyle hastalar için pek uygun degildir. Mevcut bulusta "kompozisyon" ifadesi, bir farmasötik kompozisyonu veya bir tibbi cihaz kompozisyonunu veya bir ek kompozisyonu veya bir gida kompozisyonunu ifade etmek için kullanilir. dahil olmak üzere herhangi bir tedavisi anlamina gelir: 1) hastalik veya durumun önlenmesi veya bunlara karsi koruma saglanmasi, yani klinik semptomlarin gelismemesine neden olunmasi; 2) hastaligin veya durumun engellenmesi, yani klinik semptomlarin gelisiminin durdurulmasi veya bastirilmasi; ve/veya 3) hastaligi veya durumu hafifletmek, yani klinik semptomlarin gerilemesine neden olmak. Mevcut bulusun farmasötik kompozisyonlari, bir veya daha fazla farmasötik olarak kabul edilebilir eksipiyan içerebilir. Farmasötik olarak kabul edilebilir eksipiyanlar, tabletler gibi oral uygulamaya yönelik çesitli dozaj formlarinin fiziksel formülasyonunu kolaylastirmak için seyreltici, disintegrant, glidant, plastizer, baglayici, surfaktan, lubrikant, enterik kaplama polimeri, çözücü ve bunlarin karisimlarini içerebilir ancak bunlarla sinirli degildir. Seyrelticiler; kalsiyum hidrojen fosfat kalsiyum karbonat, kalsiyum fosfat, kalsiyum sülfat, karboksimetilselüloz kalsiyum, karboksimetilselüloz sodyum, maltodekstrin, mannitol, mikrokristalin selüloz, potasyum klorür, toz selüloz, prejelatinize nisasta, sodyum klorür, sorbitol, nisasta, sükroz, seker küreleri, talk, tribazik kalsiyum fosfat ve ksilitol maddeleri arasindan veya bunlarin bir karisimi olarak seçilebilir, ancak bunlarla sinirli degildir. Tercih edilen seyreltici, mikrokristalin selülozdur. Baglayicilar; metilselüloz, sodyum karboksimetilselüloz, kalsiyum karboksimetilselüloz, etil selüloz, hidroksipropil metilselüloz, hidroksietil selüloz, hidroksipropil selüloz, polivinil pirolidon (Povidon), jelatin, polivinil alkol, sikistirilabilir seker, sivi glikoz, dekstratlar, dekstrin, dekstroz, maltodekstrin, magnezyum alüminyum silikat, polimetakrilatlar, sorbitol maddeleri arasindan veya bunlarin bir karisimi olarak seçilebilir, ancak bunlarla sinirli degildir. Tercih edilen baglayici, polivinilpirolidondur. Disintegrantlar; aljinik asit, koloidal silikon dioksit, kroskarmeloz sodyum, krospovidon, guar sakizi, magnezyum alüminyum silikat, mikrokristalin selüloz, metil selüloz, polivinilpirolidon, çapraz bagli polivinilpirolidonlar, polakrilin potasyum, nisasta, prejelatinize nisasta, sodyum alj inat, hidroksipropil nisasta maddeleri arasindan veya bunlarin bir karisimi olarak seçilebilir, ancak bunlarla sinirli degildir. Tercih edilen disintegrant, kroskarmeloz sodyumdur. Glidantlar; kolloidal silikon dioksit, kolloidal silika, misir nisastasi, talk, kalsiyum silikat, magnezyum silikat, magnezyum trisilikat, amorf silika, kolloidal silikon, silikon hidrojel, toz selüloz, silikon dioksit, talk, tribazik kalsiyum fosfat maddeleri arasindan veya teknigin bilinen durumuna dahil benzer maddeler arasindan seçilebilir, ancak bunlarla sinirli degildir. Tercih edilen glidantlar, talk ve kolloidal silikon dioksittir. Lubrikantlar, bunlarla sinirli olmamakla birlikte, hidroj ene bitkisel yag veya hidroj ene hint yagi gibi bitkisel yaglar, polietilen glikoller; stearik asit; magnezyum stearat, sodyum stearat, kalsiyum stearat, çinko stearat, gliseril monostearat, gliseril palmitostearat ve sodyum stearil fumarat gibi stearik asit türevleri; talk gibi mineral tuzlar; ve poliVinil alkoller, mikrokristalin selüloz, sodyum lauril sülfat, silika, kolloidal silika, misir nisastasi, kalsiyum silikat, magnezyum silikat, silikon hidrojel maddeleri arasindan seçilebilir. Tercih edilen lubrikant, kalsiyum stearattir. Plastizerler; asetillenmis monogliseritler, trietil sitrat, asetil trietil sitrat, tribütil sitrat, asetil tribütil sitrat, trioktil sitrat, asetil trioktil sitrat, triheksil sitrat, asetil triheksil sitrat, bütiril triheksil sitrat, trimetil sitrat, PEG, epoksidize bitkisel yaglar, bis(2-etilheksil)adipat, dimetil adipat, monometil adipat, dioktil adipat, dibütil sebakat, tribütil sebakat, dibütil maleat, diizobütil maleat maddeleri arasindan veya teknigin bilinen durumuna dahil benzer maddeler arasindan seçilebilir, ancak bunlarla sinirli degildir. Tercih edilen plastzer, PEG 6000'dir. Enterik kaplama polimerleri; bunlarla sinirli olmamak üzere, selüloz asetat ftalat, selüloz asetat trimelitat, hidroksil propil metil selüloz ftalat, hidroksil propil metil selüloz asetat süksinat, poliVinil asetat ftalat, metakrilik asit kopolimerleri (Eudragit L-100, Eudragit S-100) maddeleri arasindan veya teknigin bilinen durumuna dahil benzer maddeler arasindan seçilebilir, ancak bunlarla sinirli degildir. Tercih edilen Enterik kaplama polimerleri, Eudragit L-100 ve Eudragit S-100'dür. Çözücüler, etanol, etil alkol, polietilen glikol, propilen glikol, izopropil alkol, distile su maddeleri arasindan veya teknigin bilinen durumuna dahil benzer maddeler arasindan seçilebilir, ancak bunlarla sinirli degildir. Tercih edilen çözücü distile sudur. Mesalamin etken maddesi düsük çözünürlügü ve düsük geçirgenligi ile BCS IV sinifinda bir moleküldür. Bu ürünün gelistirilmesi sirasinda; in Vitro çalismalar, kolon hedeIli biyobenzer kimyasallarla hazirlanan tamponlar kullanilarak tasarlanmistir. Uygun yöntemle etken madde ve yardimci maddeleri belirlendikten sonra; prototip formülasyonlarin ürünleri, farkli pH,lardaki tamponlarda Vücut siVilarini simüle eden dissolüsyon testlerine tabi tutulur. Farkli pH,lardaki tamponlar ile çalisilmistir; pH: 1,2, pH:4,5 asetat tampon, pH:6,0 fosfat tampon, FaSSCoF ve FeSSCoF. * 400 I I SÜRE (DAKIKA) Sekil 2: Referans ürün ve test ürününün (0.1N HCl followed by pH 6,0 Phosphate buffer, pH 7,2 Phosphate buffer (QC ortam) dissolüsyon profillerinin karsilastirmasi 96 ILAÇ SALIMI SÜRE (DAKIKA) Figure 3: Biorelevant ortamda (FaSSCoF) referans ürün ve test ürününün dissolüsyon profillerinin karsilastirilmasi Test ürünü, 1,2 - 7,5 araligindaki tüm gastrointestinal pH,larda test edildi ve tatmin edici sonuçlar elde edildi. FaSSCoF ile birlikte QC ortaminda test ürününün, referans olarak seçilen 1g Salofalk tabletlerininkine benzer davranis gösterdigi, yukaridaki grafiklerde gösterilmistir. Ürün, yemekten bir saat önce alinmalidir, böylelikle FaSSCoF çalismasindan elde edilen in- vivo salim patemini açikça tahmin eder. Mevcut bulusta tablet iki katmandan olusuyor olup, burada bir katman Eudragit L-100 ve ilgili eksipiyanlari içermekte, diger katman Eudragit L-100, Eudragit S-100 ve ayrica enterik kapli bir tablet ile ilgili eksipiyanlari içermektedir. Mevcut bulusa göre farmasötik kompozisyonun bilesenleri, Örnek 1'de gösterildigi gibi oral uygulamaya yönelik enterik kapli bir tablette bir araya getirilir. Örnek 1,de verilen kompozisyon, yalnizca örnekleme amaçlidir. Örnek 1: 1000 mg Mesalamin enterik kapli tablet kompozisyonu Mesalamin Etken madde 1000 67,80 Mikrokristal selüloz 101 Seyreltici N/A N/A Povidon Baglayici N/A N/A Mikrokristal selüloz 102 Seyreltici N/A N/A Kroskarmeloz sodyum Disintegrant N/A N/A Kolloidal silikon dioksit Glidant N/A N/A Kalsiyum stearat Lubrikant N/A N/A Distile su Çözücü N/A N/A Çekirdek Tablet Kütlesi 1306,00 mg - polymer PEG 6000 Plastizer N/A N/A Talk Glidant N/A N/A Etanol Çözücü N/A N/A Birinci Katman Kütlesi 135 8,80 mg - polimeri polimeri PEG 6000 Plastizer N/A N/A Talk Glidant N/A N/A Etanol Çözücü N/A N/A Ikinci Katman Kütlesi i440,00 mg Kaplama malzemesi Film kaplama N/A N/A Distile su Çözücü N/A N/A Toplam Tablet Kütlesi 1475 ,00 mg 100 Mesalamin 1 g enterik film kapli tablet kompozisyonu hazirlama prosedürü; Basamak: Karistirma ve Granülasyon Mesalamin, mikrokristal selüloz ve povidon karistirilip granül hale getirilir. Basamak: Eleme, Lubrikasyon ve Tablet Basimi Mikrokristal selüloz, kroskarmeloz sodyum ve kolloidal silikon dioksit elenir ve kalsiyum stearat ile lubrikasyon gerçeklestirilir. Basamak: Enterik Kaplama - 1 Eudragit L-100, ethanol, PEG 6000 ve talk ile ilk enterik kaplama yapilir. Basamak: Enterik Kaplama - 2 yapilir. Basamak: Film Kaplama Film kaplama malzemesi ile kaplanir. TR TR DESCRIPTION PHARMACEUTICAL COMPOSITIONS CONTAINING MESALAMIN AND RELATED EXCIPIENTS Field of the Invention The present invention relates to the preparation of pharmaceutical compositions containing mesalamine and related excipients and having an improved formulation design for an enteric coated tablet production method. State of the Art Aminosalicylate drugs such as mesalamine are used in the treatment of mild and moderate inflammatory bowel disease (IBD). Mesalamine, also known as 5-aminosalicylic acid (5-ASA), is an anti-inflammatory drug used to treat gastrointestinal tract disorders such as inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Mesalamine; It has the appearance of a pinkish-white crystal or purplish-bronze powder and is odorless. Its chemical name is 5-Amino-2-hydroxybenzoic acid and its molecular weight is 153.135 g/mol. Its chemical structure is shown in Figure 1. Figure 1: Mesalamine Mesalamine has been used for many years, primarily in its treatment. Dosage forms available on the market so far are tablets, enemas, suppositories, capsules, granules or powder. Inflammatory bowel disease is a term that encompasses Crohn's disease and ulcerative colitis, which are characterized by chronic inflammation of the gastrointestinal (GI) tract. Crohn's disease is a chronic inflammatory disease of the digestive system and its symptoms include abdominal pain, fever, fatigue, severe diarrhea, and weight loss. Although there is no known cure for Crohn's disease, treatments can greatly reduce the signs and symptoms of the disease. Ulcerative colitis is one of the inflammatory bowel diseases (IBD) that causes long-term inflammation and ulcers in the digestive tract. The main symptoms of this disease are abdominal pain, bloody diarrhea, weight loss, fever and anemia. It causes irritation, inflammation and ulcers in the lining of the large intestine and rectum. Enteric coated tablet, also known as gastro-resistant coating tablet; It is a type of tablet coated with active ingredient(s) that prevents the release of the medicine until it reaches the small intestine where it can be absorbed. Most enteric-coated tablets have a surface that is stable against the highly acidic pH of the stomach, but rapidly disintegrate at a less acidic (relatively more basic) pH in the intestinal tract. Enteric-coated tablets can dissolve in the small intestine. Parameters sought in enteric coated materials such as resistance to the stomach environment, permeability to intestinal fluids, high compatibility, non-toxic activity and ability to form a continuous film are critical for an enteric coated tablet product. Excipients must be selected based on these parameters as well as the properties of the active ingredient. Enteric coating; It is used to protect drugs from the damaging effects of stomach acidity, to protect the gastric mucosa from irritation, and to control the transport of certain drugs to the intestines to increase absorption. The main polymers used for enteric release film coating are; cellulose acetate phthalate, cellulose acetate trimellitate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, polyvinyl acetate phthalate and methacrylic acid copolymers. When combined oral and rectal application of mesalamine was used, the rate of improvement in symptoms was found to be 88%; However, in treatments where only rectal applications were used, this recovery rate was found to be 54%. These results "Double-blind comparison of the use of oral and rectal mesalamine and their combined treatment in the treatment of distal ulcerative colitis" Summary of the Invention The present invention relates to an improved formulation design for preparing enteric coated pharmaceutical tablet compositions containing mesalamine and related excipients. The present invention provides an enteric coated pharmaceutical tablet composition containing mesalamine. In the composition in question, the enteric coating polymer in the first layer is Eudragit L100. The enteric coating polymers in the second layer are Eudragit 8100 and Eudragit L100. The total tablet mass is between 1400 and 2000 mg. Detailed Description of the Invention The present invention relates to an improved formulation design for the preparation of enteric coated pharmaceutical tablet compositions containing mesalamine and related excipients. In the present invention, which provides a pharmaceutical composition containing mesalamine; The enteric coating polymer Eudragit L100 in the first layer is in the range of the enteric coating in the second layer. The present invention relates to a mesalamine pharmaceutical composition comprising; a) A first layer containing Eudragit L100 as an enteric coating polymer and at least one pharmaceutically acceptable excipient, b) A second layer containing Eduragit 8100 and Eudragit L100 as enteric coating polymers and at least one pharmaceutically acceptable excipient, wherein enteric The weight of coated pharmaceutical tablets is within a certain range. The present invention relates to an enteric coated pharmaceutical tablet composition comprising mesalamine; a) a first layer comprising Eudragit L100 as an enteric coating polymer and at least one pharmaceutically acceptable excipient, wherein the ratio of the weight of Eudragit L100 in the first layer to the total tablet weight is between 2.5 and 5.0. b) a second layer comprising Eduragit 8100 and Eudragit L100 as enteric coating polymers and at least one pharmaceutically acceptable excipient, wherein the ratio of the weight of Eudragit S100 to the weight of Eudragit L100 in the second layer is between 0.5 and 0.8. Here, the enteric coated pharmaceutical tablet weight is between 1400mg and 2000mg. Enteric coating is a type of oral medicine using polymers. These polymers act as a barrier to prevent gastric acids in the stomach from dissolving or breaking down the medications after swallowing the tablets. If enteric protection is not used in pharmaceutical products, most drugs are rapidly broken down by stomach acids. The enteric polymer coating provides a delayed release for tablet dosage forms. As a result of this process, drugs are targeted to the small intestine or other stages of digestion that need to be reached. The present invention relates to an enteric coated pharmaceutical tablet composition with Eudragit L100 enteric coating polymer in the first layer and Eudragit 8100 and Eudragit L100 enteric coating polymers in the second layer. The present invention relates to a pharmaceutical composition in which the ratio of the weight of Eudragit L100 in the first layer to the total tablet weight is between 2.5 and 5.0. The present invention relates to a pharmaceutical composition; wherein the ratio of the weight of Eudragit L100 in the first layer to the total tablet weight is preferably between 2.7 and 3.5, more preferably 2.84. The present invention relates to a pharmaceutical composition; Here, the ratio of the weight of Eudragit SlOO in the second layer to the weight of Eudragit L100 is between 0.5 and 0.8. The present invention relates to a pharmaceutical composition; where the one in the second layer is preferably 0.68. The present invention relates to a pharmaceutical composition comprising mesalamine and related excipients in an enteric-coated tablet dosage form. With this dosage form, the release of active substance from mesalamine tablets begins after 3-4 hours. It reaches maximum plasma concentration after approximately 5 hours. In case of fasting, it reaches the region between the ileum and the large intestine in 3-4 hours, and the upper part of the colon in 4-5 hours. It remains in the colon for approximately 17 hours. The present invention relates to Eudragit and its variants. Eudragit has a structure containing methacrylic acid copolymers. Methacrylic acid copolymers are widely used in enteric coating tablets because they contain free carboxylic acid groups. These enteric polymers are marketed exclusively by Evonik (formerly Röhm GmbH) under the registered trademark Eudragit. Many types of Eudragit enteric polymers are commercially available in different physical forms such as aqueous dispersion, organic solution, granules and powders. Eudragites are anionic copolymers based on methacrylic acid and methyl methacrylate. Eudragit L100 is Poly(metacyclic acid-co-methyl methacrylate) 1:1. Eudragit S100 is Poly(metacyclic acid-co-methyl methacrylate) 1:2. In general, Eudragit products used for enteric coatings consist of anionic polymers of methacrylic acid and methacrylates. It is soluble between pH=5.5 and 7. Some Eudragit products can be seen in Table 1. Table 1: Properties of Eudragit products Application Eudragit ® Class Appearance Dissolution Properties Drug transport in the jejunum Eudragit L100 Powder Dissolution above pH 6.0 Drug transport in the ileum Eudragit SlOO Powder Dissolution above pH 7.0 Some of the prominent properties of Eudragit products in enteric coating: pH-dependent drug release, protection of active substances sensitive to gastric fluid, protection of the gastric mucosa from aggressive active substances, increased drug efficacy, good storage stability, targeting the gastrointestinal tract and colon. The present invention relates to an enteric-coated tablet composition where the product target is the colon region of the human body. The present invention relates to an enteric coated tablet composition having two layers consisting of mesalamine, enteric coating polymers and related excipients. The present invention provides a pharmaceutical composition comprising mesalamine and related excipients, wherein said pharmaceutical composition has two layers, a "first layer" and a "second layer". The present invention relates to an enteric-coated tablet composition in which Eudragit L100 is used as an enteric polymer in the first layer. The present invention relates to an enteric coated tablet composition wherein Eudragit L100 and Eudragit S100 are used as enteric polymers in the second layer of the composition. The present invention provides a pharmaceutical composition comprising mesalamine and related excipients in an enteric coated tablet with a total tablet mass of between 1400 mg and 2000 mg. In one application; It is a pharmaceutical composition containing mesalamine and related excipients, the total tablet weight in the enteric coated tablet is between 1400 mg and 1800 mg. It has been found that when the ratio of the weight of Eudragit enteric polymers (Eudragit L100 and Eudragit S100) to the total tablet weight is within the specific ranges specified in the above paragraphs, the synergistic effect is observed and also provides an optimum formulation design for the enteric coated tablet product in question. In one embodiment, the enteric-coated tablet composition containing mesalamine is used for the treatment of inflammatory bowel disease, including Crohn's disease and ulcerative colitis. One of the objects of the present invention is to provide a pharmaceutical composition in oral dosage form as an enteric-coated tablet that provides immediate release of the drug exhibiting acceptable bioavailability results. In one embodiment, the process of preparing the stable pharmaceutical composition includes the following steps: - preparation of a first enteric layer containing Eudragit L100 and pharmaceutically acceptable excipients, - preparation of a second enteric layer containing Eudragit L100, Eudragit 8100 and pharmaceutically acceptable excipients, - followed by compression of the enteric coated tablet and - covering with a protective layer. In another embodiment, the pharmaceutical composition further includes at least one excipient selected from a diluent, a binder, a disintegrant, a glidant, a lubricant, a plasticizer, an enteric coating polymer, and a film coating material. Advantages By using enteric polymers such as Eudragit L100 and Eudragit 8100 in one enteric tablet, optimum total tablet weight suitable for patient use is achieved. The pharmaceutical compositions of the invention are particularly suitable for oral administration. The present invention exhibits good physical properties due to stability properties in suitable excipients. It shows good properties to provide basic physical stability. The present invention provides pharmaceutical composition comprising mesalamine and related excipients in enteric coated dosage form; i) A simple and unique production process ii) Stable formulation The enteric tablet dosage form is suitable for use in intestinal diseases such as ulcerative colitis in the gastrointestinal (GI) system, therefore patient compliance is high. The enteric coating polymer layer protects the bioactive substance against degradation in the gastrointestinal tract. The present invention is based on i) well-designed tablet formation, controlling/scheduling the release of active ingredients, having an enteric coated dosage form, containing mesalamine and related excipients, where the product target is the colon region in the human body, and ii) a smart and well-designed tablet. production process In the present invention, an enteric tablet product suitable for use in intestinal diseases has been obtained by using enteric polymers such as Eudragit L100 and Eudragit 8100 and minimum auxiliary substances in the formulation. The present invention provides pharmaceutical composition comprising mesalamine and related excipients; wherein the composition is suitable for use with a total tablet weight between 1400 mg and 2000 mg for an enteric coated composition. Tablets larger than 2000mg are not suitable for patients due to swallowing problems. In the present invention, the term "composition" is used to refer to a pharmaceutical composition, or a medical device composition, or a supplement composition, or a food composition. means any treatment, including: 1) preventing or protecting against the disease or condition, i.e. causing clinical symptoms not to develop; 2) prevention of the disease or condition, that is, stopping or suppressing the development of clinical symptoms; and/or 3) alleviate the disease or condition, i.e., cause regression of clinical symptoms. The pharmaceutical compositions of the present invention may contain one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients may include, but are not limited to, diluents, disintegrants, glidants, plasticizers, binders, surfactants, lubricants, enteric coating polymers, solvents, and mixtures thereof to facilitate the physical formulation of various dosage forms for oral administration, such as tablets. Diluents; calcium hydrogen phosphate calcium carbonate, calcium phosphate, calcium sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, maltodextrin, mannitol, microcrystalline cellulose, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium may be selected from, but not limited to, phosphate and xylitol materials, or a mixture thereof. The preferred diluent is microcrystalline cellulose. Bindings; methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone (Povidone), gelatin, polyvinyl alcohol, compressible sugar, liquid glucose, dextrates, dextrin, dextrose, maltodextrin, magnesium aluminum silicate, crylates , sorbitol, or a mixture thereof, but is not limited to. The preferred binder is polyvinylpyrrolidone. Disintegrants; Alginic acid, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidones, polacriline potassium, starch, pregelatinized starch, sodium alginate, hydroxypropyl starch. or one of these can be chosen as a mix, but is not limited to these. The preferred disintegrant is croscarmellose sodium. Glidants; colloidal silicon dioxide, colloidal silica, corn starch, talc, calcium silicate, magnesium silicate, magnesium trisilicate, amorphous silica, colloidal silicone, silicone hydrogel, powdered cellulose, silicon dioxide, talc, tribasic calcium phosphate or similar substances within the state of the art. can be chosen from, but is not limited to. Preferred glidants are talc and colloidal silicon dioxide. Lubricants include, but are not limited to, vegetable oils such as hydrogenated vegetable oil or hydrogenated castor oil, polyethylene glycols; stearic acid; stearic acid derivatives such as magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate and sodium stearyl fumarate; mineral salts such as talc; and polyVinyl alcohols, microcrystalline cellulose, sodium lauryl sulfate, silica, colloidal silica, corn starch, calcium silicate, magnesium silicate, silicone hydrogel materials. The preferred lubricant is calcium stearate. Plasticizers; acetylated monoglycerides, triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, trioctyl citrate, acetyl trioctyl citrate, trihexyl citrate, acetyl trihexyl citrate, butyryl trihexyl citrate, trimethyl citrate, PEG, epoxidized vegetable oils, bis(2-ethylhexyl) adipate, dimethyl adipate, monomethyl adipate, dioctyl adipate, dibutyl sebacate, tributyl sebacate, dibutyl maleate, diisobutyl maleate or similar substances within the prior art, but is not limited to them. The preferred plaster is PEG 6000. Enteric coating polymers; Among, but not limited to, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, polyVinyl acetate phthalate, methacrylic acid copolymers (Eudragit L-100, Eudragit S-100) or prior art can be selected from similar items including, but not limited to. Preferred Enteric coating polymers are Eudragit L-100 and Eudragit S-100. Solvents may be selected from, but are not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, distilled water or similar prior art substances. The preferred solvent is distilled water. The active ingredient mesalamine is a BCS IV class molecule with low solubility and low permeability. During the development of this product; In Vitro studies were designed using buffers prepared with colon-targeted biosimilar chemicals. After the active ingredient and its excipients are determined using the appropriate method; Products of prototype formulations are subjected to dissolution tests simulating body fluids in buffers of different pH. It has been studied with buffers of different pH values; pH: 1.2, pH:4.5 acetate buffer, pH:6.0 phosphate buffer, FaSSCoF and FeSSCoF. * 400 I I DURATION (MINUTES) Figure 2: Comparison of the dissolution profiles of the reference product and the test product (0.1N HCl followed by pH 6.0 Phosphate buffer, pH 7.2 Phosphate buffer (QC environment) 96 DRUG RELEASE DURATION (MINUTES) Figure 3 : Comparison of the dissolution profiles of the reference product and the test product in biorelevant media (FaSSCoF). The test product was tested at all gastrointestinal pH ranges between 1.2 - 7.5 and satisfactory results were obtained in the QC environment with FaSSCoF. Similar behavior to that of 1g Salofalk tablets is shown in the graphs above. The product should be taken one hour before a meal, thus clearly predicting the in vivo release pattern obtained from the FaSSCoF study. In the present invention the tablet consists of two layers, one layer containing Eudragit L-100 and the corresponding The components of the pharmaceutical composition according to the present invention are combined in an enteric coated tablet for oral administration as shown in Example 1. The composition given in Example 1 is for illustration purposes only. Example 1: 1000 mg Mesalamine enteric coated tablet composition Mesalamine Active ingredient 1000 67.80 Microcrystalline cellulose 101 Diluent N/A N/A Povidone Binder N/A N/A Microcrystalline cellulose 102 Diluent N/A N/A Croscarmellose sodium Disintegrant N/A N/A Colloidal silicon dioxide Glidant N/A N/A Calcium stearate Lubricant N/A N/A Distilled water Solvent N/A N/A Core Tablet Mass 1306,00 mg - polymer PEG 6000 Plasticizer N/A N/A Talc Glidant N/A N/A Ethanol Solvent N/A N/A First Layer Mass 135 8,80 mg - polymer polymer PEG 6000 Plasticizer N/A N/A Talc Glidant N/A N/A Ethanol Solvent N/A N/A Second Layer Mass i440,00 mg Coating material Film coating N/A N/A Distilled water Solvent N/A N/A Total Tablet Mass 1475,00 mg 100 Mesalamine 1 g enteric film-coated tablet composition preparation procedure; Step: Mixing and Granulation Mesalamine, microcrystalline cellulose and povidone are mixed and granulated. Step: Sieving, Lubrication and Tablet Pressing Microcrystalline cellulose, croscarmellose sodium and colloidal silicon dioxide are sieved and lubrication is performed with calcium stearate. Step: Enteric Coating - 1 Initial enteric coating is made with Eudragit L-100, ethanol, PEG 6000 and talc. Step: Enteric Coating - 2 is done. Step: Film Coating It is coated with film coating material.TR TR
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Publications (1)
Publication Number | Publication Date |
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TR2023003089T2 true TR2023003089T2 (en) | 2023-08-21 |
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