TR2022002174A2 - A SOLID PHARMACEUTICAL COMPOSITION CONTAINING TOLVAPTAN - Google Patents
A SOLID PHARMACEUTICAL COMPOSITION CONTAINING TOLVAPTANInfo
- Publication number
- TR2022002174A2 TR2022002174A2 TR2022/002174 TR2022002174A2 TR 2022002174 A2 TR2022002174 A2 TR 2022002174A2 TR 2022/002174 TR2022/002174 TR 2022/002174 TR 2022002174 A2 TR2022002174 A2 TR 2022002174A2
- Authority
- TR
- Turkey
- Prior art keywords
- tolvaptan
- pharmaceutical composition
- solid pharmaceutical
- crystalline polymorph
- composition according
- Prior art date
Links
- 229960001256 tolvaptan Drugs 0.000 title claims abstract description 69
- GYHCTFXIZSNGJT-UHFFFAOYSA-N tolvaptan Chemical compound CC1=CC=CC=C1C(=O)NC(C=C1C)=CC=C1C(=O)N1C2=CC=C(Cl)C=C2C(O)CCC1 GYHCTFXIZSNGJT-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 239000007787 solid Substances 0.000 title claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 30
- 239000002245 particle Substances 0.000 claims abstract description 41
- 239000000203 mixture Substances 0.000 claims abstract description 29
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 10
- 229920002261 Corn starch Polymers 0.000 claims description 15
- 239000008120 corn starch Substances 0.000 claims description 15
- 239000007884 disintegrant Substances 0.000 claims description 11
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 9
- 229960001021 lactose monohydrate Drugs 0.000 claims description 9
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- 229920002472 Starch Polymers 0.000 claims description 7
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- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- 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 6
- 239000011230 binding agent Substances 0.000 claims description 6
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- 229940097275 indigo Drugs 0.000 claims description 2
- COHYTHOBJLSHDF-UHFFFAOYSA-N indigo powder Natural products N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 claims description 2
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- 238000000034 method Methods 0.000 abstract description 11
- 239000002270 dispersing agent Substances 0.000 abstract description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 10
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 102000004136 Vasopressin Receptors Human genes 0.000 description 2
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- 239000004176 azorubin Substances 0.000 description 2
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- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
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Abstract
Mevcut buluş, tolvaptan veya bunun kristalin polimorfunu ve famasötik olarak kabul edilebilir en az bir eksipiyan içeren, dağıtıcıların tolvaptan veya bunun kristalin polimorfuna ağırlık oranının 0.3 ile 2.5 arasında olduğu ve tolvaptan veya bunun kristalin polimorfunun 150 µm'den daha küçük bir d (0.9) parçacık boyutuna sahip olduğu katı bir farmasötik kompozisyon ile ilgilidir. Ayrıca kompozisyon, etkili bir proses kullanılarak elde edilir.The present invention comprises tolvaptan or its crystalline polymorph and at least one pharmaceutically acceptable excipient, wherein the weight ratio of the dispersants to tolvaptan or its crystalline polymorph is between 0.3 and 2.5 and the tolvaptan or its crystalline polymorph has a d (0.9) particle size of less than 150 µm. It relates to a solid pharmaceutical composition having a size Moreover, the composition is obtained using an efficient process.
Description
TARIFNAME TOLVAPTAN IÇEREN KATI BIR FARMASÖTIK KOMPOZISYON Bulusun Alani Mevcut bulusi tolvaptan veya bunun kristalin polimorfunu ve famasötik olarak kabul edilebilir en az bir eksipiyan içeren, dagiticilarin tolvaptan veya bunun kristalin polimorfuna agirlik oraninin 0.3 ile 2.5 arasinda oldugu ve tolvaptan veya bunun kristalin polimorfunun 150 pm'den daha küçük bir d (0.9) parçacik boyutuna sahip oldugu kati bir farmasötik kompozisyon ile ilgilidir. Ayrica kompozisyon, etkili bir proses kullanilarak elde edilir. Bulusun Arka Plani Tolvaptan, hiponatremiyi tedavi etmek için kullanilabilen, oral olarak biyoyararli, seçici, arginin vazopressin reseptör 2 (V2, AVPRZ) antagonistidir. Oral uygulama üzerine tolvaptan, renal toplayici kanallarin vaskülatür ve luminal membranlarinin duvarlarinda bulunan V2 reseptörüne seçici ve rekabetçi bir sekilde baglanir ve bunlari bloke eder, böylece vazopressinin V2 reseptörüne baglanmasini önler. Bu, böbreklerde su emilimini önlerve böbrekleryoluyla elektrolit içermeyen suyun atilimini arttirir. Bu, intravasküler hacmi azaltir ve serum sodyum konsantrasyonlarini ve ozmolaliteyi Tolvaptan, kimyasal olarak N-(4-(7-Kloro-5-hidroksi-2,3,4,5-tetrahidro-lH-benzo[b]azepin-1-karbonil)- 3-metilfenil)-2-metilbenzamid olarak tanimlanir. Ampirik formülü, C25H25CIN203 olup, yapisal formülü asagidaki gibidir: Formül I: Tolvaptan Tolvaptan, klinik olarak anlamli hipervolemik ve övolemik hiponatreminin tedavisi için Otsuka America Pharmaceutical tarafindan SAMSCA® ticari adiyla piyasaya sürülen 15 mg ve 30 mg tolvaptan içeren oral tabletler olarak mevcuttur. Tolvaptan, BCS siniflandirmasinda bir sinif lV ilacidir, yani çözünürlügü düsük ve hipotonik bir ilaçtir. Az çözünür ilaçlar için, çözünmesi, emilim hizini sinirlayan bir süreçtir ve genellikle biyoyararlanimini ,258,510 no'lu ABD Patenti, tolvaptani açiklar. W, tolvaptan kati dispersiyonunu ve hazirlama yöntemini açiklar. Kati dispersiyon, 1:0.05-20 agirlik oraninda tolvaptan ve çapraz bagli polivinilpirolidon içerir. Ayrica bu basvuru, polivinilpirrolidon, hidroksipropilselüloz, hidroksietilselüloz veya metilselüloz gibi suda çözünür polimerleri açiklar. W, tolvaptan ve agirlikça %50 veya daha fazla miktarda bir hidroksipropoksil grubu içeren hidroksipropilselüloz içeren bir farmasötik kati preparasyonu açiklar. Önceki teknikte tolvaptani oral farmasötik dozaj formlarinda açiklayan birkaç patent de bulunmaktadir. Ancak tolvaptanin çözünme problemine ragmen etkili bir formülasyon ve yöntem ortaya konmamistir. Teknikte yüksek çözünürlüge, mükemmel farmakomekanik özelliklere ve buna bagli olarak yüksek bir biyoyararlanim ve yine etkili bir proses kullanilarak elde edilen uzun vadeli bir stabiliteye sahip olan, tolvaptan veya bunun kristalin polimorfunu içeren iyilestirilmis kati bir farmasötik kompozisyonun saglanmasina hala ihtiyaç vardir. Bulusun Ayrintili Açiklamasi Mevcut bulusun ana amaci, istenen düzeyde çözünme hizina ve yüksek stabiliteye ve akiskanlik, sikistirilabilirlik ve içerik tekdüzeligi gibi mükemmel farmakomekanik özelliklere sahip olan, yukarida açiklanmis olan önceki teknige ait problemlerin üstesinden gelen ve onlara göre ilave avantajlara sahip olan, tolvaptan veya bunun kristalin polimorfunu içeren kati bir farmasötik kompozisyon saglamaktir. Mevcut bulusun baska bir amaci, tolvaptan veya bunun kristalin polimorfunu içeren bir tablet kompozisyonu için bir proses saglamaktir. Proses, basit, hizli, uygun maliyetli, zaman kazandiran ve endüstriyel olarak uygun bir yöntemdir. Tolvaptan, suda az çözünürdür. Bu, çözünme profili veya biyoyararlanim problemlerine sebep olur. Mevcut bulusta bu problemlerin ortaya çikmamasi için bazi çalismalar yapilmistir. Düsük çözünürlük problemlerinden muzdarip etkin maddeler için düsük parçacik boyutunun kullanilmasi önceki teknikten bilinmektedir. Bu bulusta, kullanilan tolvaptan parçacik boyutunun yani sira kullanilan dagiticilarin tolvaptana oraninin da önemli oldugu bulunmustur. Bu bulusun bir düzenlemesine göre kati bir farmasötik kompozisyon, tolvaptan veya bunun kristalin polimorfunu ve famasötik olarak kabul edilebilir en az bir eksipiyani içermekte olup, dagiticilarin tolvaptan veya bunun kristalin polimorfuna agirlik orani 0.3 ile 2.5 arasindadir ve tolvaptan veya bunun kristalin polimorfu, 150 um'den daha küçük bir d (0.9) parçacik boyutuna sahiptir. Bu özellikler istenen çözünme profilini ve dagilma oranini saglar. Dagiticinin tolvaptana orani, belirtilen degerlerde kullanilir, tercih edilen form tablet ise istenen sertlik ve sikistirilabilirligi saglar. Bu bulusun bir düzenlemesine göre dagiticilarin tolvaptan veya bunun kristalin polimorfuna agirlik orani, 0.5 ile 2.0, tercihen 0.6 ile 1.8 arasindadir. Uygun dagiticilar, misir nisastasi, nisasta, krospovidon, kroskarmeloz sodyum, düsük ikameli hidroksipropil selüloz, karboksimetil selüloz, sodyum karboksimetil selüloz, kalsiyum karboksimetil selüloz, sodyum karboksimetil nisasta, hidroksimetil nisasta veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre dagitici, misir nisastasidir. Misir nisastasi reaktif bir maddedir, diger eksipiyanlar ve etkin madde ile etkilesime girmez. Misir nisastasi, kirilgan özellik gösteren bazi eksipiyanlar (MCC ve laktoz monohidrat gibi) ile birlikte kullanildiginda formülasyona avantaj saglayan plastik deformasyon özelligi gösterir. Bu bulusta istenen sikistirilabilirlik misir nisastasi ile saglanmaktadir. Bu bulusun bir düzenlemesine göre dagitici miktari toplam kompozisyonun agirlikça %1.0 ile %35.0'i Bu bulusun bir düzenlemesine göre tolvaptan veya bunun kristalin polimorfunun miktari, toplam arasindadir. Asagidaki parçacik boyutlarina sahip tolvaptanin formülasyon için önemli oldugunu bulduk. Çok küçük parçacik boyutlari, örnegin yapistirma veya film kaplama yöntemiyle üretilebilirligi etkiler. Öte yandan çok büyük parçaciklar, farmasötik kompozisyonun ve dozaj formunun çözünme özelliklerini ve dolayisiyla biyoyararlanimi olumsuz etkiler. Parçacik boyutu dagiliminin tercih edilen araliklari asagida tarif edilmektedir. Burada kullanildigi sekliyle "parçacik boyutu dagilimi", lVlalvern Mastersizer 2000 lazer kirinim parçacik boyutu analiz cihazi ekipmani tarafindan belirlenen lazer kirinim yöntemi olan geleneksel olarak kabul edilen bir yöntemle test edilen kümülatif hacim boyut dagilimi ile tanimlanir. "D (08)" veya "d90", parçaciklarin hacimce %90'inin daha ince oldugu boyutu, d (0.1), parçaciklarin hacimce %10'unun daha ince oldugu boyutu ve C] (0.5), parçaciklarin hacimce %50'sinin daha ince oldugu boyutu ifade eder. Bu bulusta tolvaptanin d(0.9) veya d(0.5) veya D(0.1) degerinin parçacik boyutu dagilimi, kati numuneler ile ölçülmüs ve bu degerler Malvern Mastersizer 2000 lazer kirinim parçacik boyutu analiz cihazi ile belirlenmistir. Mevcut bulusun bu düzenlemesine göre tolvaptan veya bunun kristalin polimorfu, 2 um ile 100 pm arasinda veya 3 pm ile 50 pm arasinda veya 3 pm ile 30 pm arasinda bir d (0.9) parçacik boyutuna sahiptir. Mevcut bulusun bu düzenlemesine göre tolvaptan veya bunun kristalin polimorfu, 3 pm ile 30 pm arasinda veya 3 um ile 25 um arasinda veya 3 um ile 20 um arasinda bir d (0.9) parçacik boyutuna sahiptir. Mevcut bulusun bu düzenlemesine göre, tolvaptan veya bunun kristalin polimorfu, 4 um ile 15 pm arasinda bir 01 (0.9) parçacik boyutuna sahiptir. Mevcut bulusun bu düzenlemesine göre tolvaptan veya bunun kristalin polimorfu, 75 pm'den daha küçük bir d (0.5) parçacik boyutuna sahiptir. Mevcut bulusun bu düzenlemesine göre tolvaptan veya bunun kristalin polimorfu, 1 um ile 50 um arasinda veya 1 um ile 30 um arasinda bir d (0.5) parçacik boyutuna sahiptir. Mevcut bulusun bu düzenlemesine göre tolvaptan veya bunun kristalin polimorfu, 1 um ile 25 um arasinda veya 1 pm ile 15 um arasinda veya 1 pm ile 8 um arasinda bir d (0.5) parçacik boyutuna sahiptir. Mevcut bulusun bu düzenlemesine göre tolvaptan veya bunun kristalin polimorfu, 1 pm ile 5 pm arasinda bir d (0.5) parçacik boyutuna sahiptir. Mevcut bulusun bu düzenlemesine göre tolvaptan veya bunun kristalin polimorfu, 25 pm'den daha küçük bir d (0.1) parçacik boyutuna sahiptir. Mevcut bulusun bu düzenlemesine göre tolvaptan veya bunun kristalin polimorfu, 0.1 pm ile 20 pm arasinda veya 0.1 pm ile 12 um arasinda veya 0.1 pm ile 8 um arasinda bir cl (0.1) parçacik boyutuna sahiptir. Mevcut bulusun bu düzenlemesine göre tolvaptan veya bunun kristalin polimorfu, 0.1 pm ile 4 pm arasinda bir cl (0.1) parçacik boyutuna sahiptir. Mevcut bulusun bu düzenlemesine göre, tolvaptan veya bunun kristalin polimorfu, 2 um ile 100 um arasinda bir d (0.9) parçacik boyutuna sahiptir, tolvaptan veya bunun kristalin polimorfu, 1 pm ile 30 um arasinda bir d (0.5) parçacik boyutuna sahiptir, tolvaptan veya bunun kristalin polimorfu, 0.1 um ile 12 um arasinda bir d (0.1) parçacik boyutuna sahiptir. Tolvaptan veya bunun kristalin polimorfunun bu parçacik boyutlari, tolvaptani çözerek istenen çözünme profilini saglamaya yardimci olur. Mevcut bulusun bir düzenlemesine göre kati farmasötik kompozisyon sunlari içerir: - tolvaptan veya bunun kristalin polimorfu, 150 um'den daha küçük bir d (0.9) parçacik boyutuna sahiptir. - misir nisastasinin tolvaptan veya bunun kristalin polimorfuna agirlik orani 0.3 ile 2.5 arasindadir. Tolvaptan, suda az çözünürdir. Tabletlerin fiili üretiminde, genellikle düsük çözünme veya hatta niteliksiz problemlerle karsilasilmaktadir. Ayrica, tolvaptan veya bunun kristalin polimorfu, tek tek kompozisyon birimlerinde etkin madde içeriginin tek düzeligi ile ilgili olarak kompozisyonun imalati sirasinda önemli problemlere yol açabilecek küçük oranlarda kullanilir. Içerigin tekdüzeligi problemleri nedeniyle, etkin madde birkaç eksipiyan ile etkilesime girebilir. Bu, içerik tekdüzeliginin ilacin çözünmesinde önemli rol oynadigini yansitir. Mevcut bulusun bir düzenlemesine göre kompozisyon ayrica dolgu maddeleri, baglayicilar, lubrikantlar, renklendirici maddeler veya bunlarin karisimlarindan olusan gruptan seçilen farmasötik olarak kabul edilebilir en az bir eksipiyan içerir. Uygun dolgu maddeleri, mikrokristalin selüloz, laktoz monohidrat, amonyum aljinat, kalsiyum karbonat, kalsiyum fosfat, kalsiyum fosfat dehidrat, nötr peletler, kalsiyum sülfat, selüloz, selüloz asetat, sikistirilabilir seker, dekstratlar, dekstrin, dekstroz, etilselüloz, fruktoz, gliseril palmitostearat, laktoz, Iaktitol, mannitol, magnezyum karbonat, magnezyum oksit, maltodekstrin, maltoz, orta zincirli trigliseritler, polidekstroz, polimetakrilatlar, simetikon, sodyum aljinat, sodyum klorür, sorbitol, sukroz, seker küreleri, sülfobütileter beta-siklodekstrin, talk, kitre, trehaloz, ksilitol veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir baska düzenlemesine göre dolgu maddesi, mikrokristalin selüloz veya laktoz monohidrat veya bunlarin karisimlaridir. Bu bulusun bir düzenlemesine göre dolgu maddesi miktari toplam kompozisyonun agirlikça %500 ile Uygun baglayicilar, polivinilpirolidon , sodyum karboksimetil selüloz, sodyum karboksimetil selüloz, polietilen glikol, nisasta, önceden jelatinize edilmis nisasta, sodyum aljinat, hidroksipropil metil selüloz, hidroksipropil selüloz, karboksi metil selüloz, metil selüloz, jelatin, karagenan, guar zamki, polimetakrilatlar, polimetakrilatlar, pektin, polisakaritler, karbomer, poloksamer, poliakrilamid, alüminyum hidroksit, polioksietilen-alkil eter, polidekstroz, polietilen oksit veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre baglayici, polivinilpirolidondur. Bu istenen akiskanligi saglar. Bu bulusun bir düzenlemesine göre, baglayici miktari toplam kompozisyonun agirlikça %1.0 ile %20.0'si Mevcut bulusun bir düzenlemesine göre kati farmasötik kompozisyon, sunlari içerir: - Tolvaptan veya bunun kristalin polimorfu, 150 pm'den daha küçük bir 01 (0.9) parçacik boyutuna sahiptir, - Misir nisastasi - Polivinilpirolidon K30 - Laktoz Monohidrat - Mikrokristalin selüloz Uygun lubrikantlar, magnezyum stearat, kalsiyum stearat, sodyum stearil fumarat, potasyum stearat, stearik asit, sodyum klorür, sodyum benzoat, sodyum asetat, sodyum oleat, polietilen glikoller veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre lubrikant, magnezyum stearattir. Uygun renklendirici maddeler, indigo karmin alüminyum lake, demir oksit, titanyum dioksit, Gida, Ilaç ve Kozmetik (FD&C) boyalari (FD&C mavisi, FD&C yesili, FD&C kirmizisi, FD&C sarisi, FD&C Iakeleri), poncau, indigo Ilaç ve Kozmetik (D&C) mavisi , indigotin FD&C mavisi, karmoisin indigotin (indigo Karmin); demir oksitler (örnegim demir oksit kirmizisi, sarisi, siyahi), kinolin sarisi, alevli kirmizi, karmin, karmoisin, gün batimi sarisi veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre renklendirici madde indigo karmin alüminyum Iakedir. Bu eksipiyan, redoks indikatörü olarak bilinir. Oksidatif ve indirgeyici maddelere (stres faktörleri) karsi kendi geri dönüsümlü reaksiyonunu vererek etkin maddenin bozulmasini engeller. Reaksiyon tersine çevrilebilir oldugundan kendi bozunmasiyla tamamen tükenmez ve hammadde stres faktörlerinden (Oksidatif ve indirgeyici türler) korunur. Bu da ürünün raf ömrüne olumlu katki saglar. Bu renklendirici madde, istenen stabiliteyi saglar. Mevcut bulusun bir düzenlemesine göre kati farmasötik kompozisyon, kapsül, tablet, serit, toz, pastiller, poset, efervesan kompozisyonlar formundadir. Mevcut bulusun bir düzenlemesine göre kati farmasötik kompozisyon, tablet formundadir. Mevcut bulusun bir düzenlemesine göre kati farmasötik kompozisyon, kapsül formundadir. Ayrica kompozisyon, yas granülasyon yöntemi kullanilarak elde edildiginden basit ve düsük maliyetli bir üretim yöntemi kullanilmistir. Miktar (toplam kompozisyonun agirlikça %) 3.0 - 25.0 polimorfu Polivinilpirolidon K30 1.0-20.0 Misir nisastasi 1.0-35.0 Laktoz Monohidrat 30.0 - 53.0 Mikrokristalin selüloz 20.0 - 32.0 Magnezyum stearat 0.5 - 4.0 Toplam 100 Miktar (toplam kompozisyonun agirlikça %) polimorfu 8.6 Polivinilpirolidon K30 5.2 Misir nisastasi 11.5 Laktoz Monohidrat 47.8 Mikrokristalin selüloz 25.9 Magnezyum stearat 1.0 Toplam 100 Miktar (toplam kompozisyonun agirlikça %) polimorfu Polivinilpirolidon K30 5.2 Misir nisastasi 11.5 Laktoz Monohidrat 39.1 Mikrokristalin selüloz 25.9 Magnezyum stearat 1.0 Toplam 100 Örnek 1 veya 2 veya 3 için bir proses sunlari içerir; a) Tolvaptan veya kristalin polimorfu, laktoz monohidrat, misir nisastasi, mikrosistralin selüloz ve polivinilpirolidonun karistirilmasi, b) (a) adimindaki karisimin saf su ile granüle edilmesi, c) Kurutma ve ardindan eleme, d) Indigo karmin alüminyum lake eklenerek karistirilmasi, e) Magnezyum stearat eklenerek karistirilmasi, f) Karisimin tabletler halinde basilmasi. TR TR TR TR TR TRDESCRIPTION A SOLID PHARMACEUTICAL COMPOSITION COMPRISING TOLVAPTAN Field of the Invention The present invention relates to a solid pharmaceutical composition comprising tolvaptan or a crystalline polymorph thereof and at least one pharmaceutically acceptable excipient, wherein the weight ratio of disintegrants to tolvaptan or a crystalline polymorph thereof is between 0.3 and 2.5 and wherein the tolvaptan or a crystalline polymorph thereof has a d (0.9) particle size of less than 150 pm. Furthermore, the composition is obtained using an effective process. Background of the Invention Tolvaptan is an orally bioavailable, selective, arginine vasopressin receptor 2 (V2, AVPRZ) antagonist that can be used to treat hyponatremia. Upon oral administration, tolvaptan selectively and competitively binds to and blocks the V2 receptor located on the walls of the vasculature and luminal membranes of the renal collecting ducts, thereby preventing vasopressin from binding to the V2 receptor. This inhibits renal water reabsorption and increases renal excretion of non-electrolyte water. This reduces intravascular volume and increases serum sodium concentrations and osmolality. Tolvaptan is chemically designated as N-(4-(7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide. Its empirical formula is C25H25CIN2O3 and its structural formula is as follows: Formula I: Tolvaptan Tolvaptan is available as oral tablets containing 15 mg and 30 mg tolvaptan, marketed under the trade name SAMSCA® by Otsuka America Pharmaceutical for the treatment of clinically significant hypervolemic and euvolemic hyponatremia. Tolvaptan is a Class IV drug in the BCS classification, meaning it is a poorly soluble and hypotonic drug. For poorly soluble drugs, dissolution is a process that limits the rate of absorption and generally reduces bioavailability. U.S. Patent No. 258,510 describes tolvaptan. W describes a tolvaptan solid dispersion and a method of preparation. The solid dispersion contains tolvaptan and cross-linked polyvinylpyrrolidone in a weight ratio of 1:0.05-20. This application also discloses water-soluble polymers such as polyvinylpyrrolidone, hydroxypropylcellulose, hydroxyethylcellulose or methylcellulose. W discloses a pharmaceutical solid preparation comprising tolvaptan and hydroxypropylcellulose containing a hydroxypropoxyl group in an amount of 50% or more by weight. There are also several patents in the prior art that disclose tolvaptan in oral pharmaceutical dosage forms. However, despite the dissolution problem of tolvaptan, an effective formulation and method have not been disclosed. There is still a need in the art to provide an improved solid pharmaceutical composition containing tolvaptan or its crystalline polymorph having high solubility, excellent pharmacomechanical properties and hence high bioavailability and long-term stability achieved using an effective process. Detailed Description of the Invention The main object of the present invention is to provide a solid pharmaceutical composition containing tolvaptan or its crystalline polymorph having desired dissolution rate and high stability and excellent pharmacomechanical properties such as flowability, compressibility and content uniformity, overcoming the problems of the above-described prior art and having additional advantages over them. Another object of the present invention is to provide a process for a tablet composition containing tolvaptan or its crystalline polymorph. The process is simple, fast, cost effective, time saving and industrially suitable. Tolvaptan is poorly soluble in water. This causes dissolution profile or bioavailability problems. In the present invention, some studies have been carried out to avoid these problems. It is known from the prior art that low particle size is used for active substances suffering from low solubility problems. In the present invention, it has been found that the tolvaptan particle size used as well as the ratio of dispersants to tolvaptan used are important. According to one embodiment of the present invention, a solid pharmaceutical composition comprises tolvaptan or a crystalline polymorph thereof and at least one pharmaceutically acceptable excipient, the weight ratio of disintegrants to tolvaptan or a crystalline polymorph thereof being between 0.3 and 2.5 and the tolvaptan or a crystalline polymorph thereof having a particle size of less than 150 µm (d(0.9)). These properties provide the desired dissolution profile and disintegration rate. The ratio of disintegrant to tolvaptan is used at the specified values, the preferred form being a tablet providing the desired hardness and compressibility. According to one embodiment of the present invention, the weight ratio of disintegrants to tolvaptan or a crystalline polymorph thereof being between 0.5 and 2.0, preferably between 0.6 and 1.8. Suitable disintegrants are selected from the group consisting of corn starch, starch, crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxymethyl starch or mixtures thereof. According to one embodiment of the present invention, the disintegrant is corn starch. Corn starch is a reactive substance and does not interact with other excipients and the active substance. Corn starch exhibits plastic deformation properties that provide advantages to the formulation when used together with some excipients that exhibit brittle properties (such as MCC and lactose monohydrate). In the present invention, the desired compressibility is provided by corn starch. According to one embodiment of the present invention, the amount of dispersant is between 1.0 and 35.0 wt% of the total composition. According to one embodiment of the present invention, the amount of tolvaptan or its crystalline polymorph is between 1.0 and 35.0 wt% of the total composition. We have found that tolvaptan having the following particle sizes is important for the formulation. Too small particle sizes affect manufacturability, for example by adhesion or film coating. Too large particles, on the other hand, adversely affect the dissolution properties of the pharmaceutical composition and dosage form and thus the bioavailability. Preferred ranges of particle size distribution are described below. As used herein, "particle size distribution" is defined by the cumulative volume size distribution as tested by a conventionally accepted method, namely the laser diffraction method, as determined by the Vialvern Mastersizer 2000 laser diffraction particle size analyzer equipment. "D(08)" or "d90" means the dimension at which 90 vol.% of the particles are finer, d(0.1) means the dimension at which 10 vol.% of the particles are finer, and C](0.5) means the dimension at which 50 vol.% of the particles are finer. In the present invention, the particle size distribution of tolvaptan d(0.9) or d(0.5) or D(0.1) was measured with solid samples and these values were determined with a Malvern Mastersizer 2000 laser diffraction particle size analyzer. According to this embodiment of the present invention, tolvaptan or its crystalline polymorph has a d(0.9) particle size of 2 µm to 100 pm, or 3 pm to 50 pm, or 3 pm to 30 pm. According to this embodiment of the present invention, tolvaptan or its crystalline polymorph has a d(0.9) particle size of 3 pm to 30 pm, or 3 um to 25 um, or 3 um to 20 um. According to this embodiment of the present invention, tolvaptan or its crystalline polymorph has a d(0.9) particle size of 4 um to 15 pm. According to this embodiment of the present invention, tolvaptan or its crystalline polymorph has a d(0.5) particle size of less than 75 pm. According to this embodiment of the present invention, tolvaptan or its crystalline polymorph has a d(0.5) particle size of 1 um to 50 um, or 1 um to 30 um. According to this embodiment of the present invention, tolvaptan or the crystalline polymorph thereof has a d(0.5) particle size of 1 µm to 25 µm, or 1 pm to 15 µm, or 1 pm to 8 µm. According to this embodiment of the present invention, tolvaptan or the crystalline polymorph thereof has a d(0.5) particle size of 1 pm to 5 pm. According to this embodiment of the present invention, tolvaptan or the crystalline polymorph thereof has a d(0.1) particle size of less than 25 pm. According to this embodiment of the present invention, tolvaptan or the crystalline polymorph thereof has a cl(0.1) particle size of 0.1 pm to 20 pm, or 0.1 pm to 12 µm, or 0.1 pm to 8 µm. According to this embodiment of the present invention, tolvaptan or its crystalline polymorph has a cl (0.1) particle size of between 0.1 pm and 4 pm. According to this embodiment of the present invention, tolvaptan or its crystalline polymorph has a d (0.9) particle size of between 2 µm and 100 µm, tolvaptan or its crystalline polymorph has a d (0.5) particle size of between 1 pm and 30 µm, tolvaptan or its crystalline polymorph has a d (0.1) particle size of between 0.1 µm and 12 µm. These particle sizes of tolvaptan or its crystalline polymorph help to dissolve tolvaptan and provide the desired dissolution profile. According to one embodiment of the present invention, the solid pharmaceutical composition contains: - tolvaptan or its crystalline polymorph having a particle size d (0.9) smaller than 150 µm. - the weight ratio of corn starch to tolvaptan or its crystalline polymorph is between 0.3 and 2.5. Tolvaptan is poorly soluble in water. In the actual production of tablets, problems of low dissolution or even unqualified dissolution are often encountered. Furthermore, tolvaptan or its crystalline polymorph is used in small proportions, which may lead to significant problems during the manufacture of the composition regarding the uniformity of the active substance content in the individual composition units. Due to the problems of uniformity of the content, the active substance may interact with several excipients. This reflects that the uniformity of the content plays an important role in the dissolution of the drug. According to one embodiment of the present invention, the composition further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of fillers, binders, lubricants, coloring agents or mixtures thereof. Suitable fillers are selected from the group consisting of microcrystalline cellulose, lactose monohydrate, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, ethylcellulose, fructose, glyceryl palmitostearate, lactose, lactitol, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, sucrose, sugar spheres, sulfobutylether beta-cyclodextrin, talc, tragacanth, trehalose, xylitol or mixtures thereof. According to another embodiment of the present invention, the filler is microcrystalline cellulose or lactose monohydrate or mixtures thereof. According to one embodiment of the present invention, the amount of filler is 500% by weight of the total composition. Suitable binders are selected from the group consisting of polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, starch, pregelatinized starch, sodium alginate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, polymethacrylates, polymethacrylates, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof. According to one embodiment of the present invention, the binder is polyvinylpyrrolidone. This provides the desired fluidity. According to one embodiment of the present invention, the amount of binder is between 1.0 and 20.0 wt% of the total composition. According to one embodiment of the present invention, the solid pharmaceutical composition comprises: - Tolvaptan or its crystalline polymorph having an 01 (0.9) particle size of less than 150 pm, - Corn starch - Polyvinylpyrrolidone K30 - Lactose Monohydrate - Microcrystalline cellulose Suitable lubricants are selected from the group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate, potassium stearate, stearic acid, sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols or mixtures thereof. According to one embodiment of the present invention, the lubricant is magnesium stearate. Suitable coloring agents are selected from the group consisting of indigo carmine aluminum lake, iron oxide, titanium dioxide, Food, Drug and Cosmetic (FD&C) dyes (FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C Flakes), poncau, indigo Drug and Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo carmine); iron oxides (e.g., iron oxide red, yellow, black), quinoline yellow, flame red, carmine, carmoisine, sunset yellow, or mixtures thereof. According to one embodiment of the present invention, the coloring agent is indigo carmine aluminum flake. This excipient is known as a redox indicator. It prevents the degradation of the active substance by giving its own reversible reaction against oxidative and reducing agents (stress factors). Since the reaction is reversible, it is not completely exhausted by its own degradation and the raw material is protected from stress factors (oxidative and reducing species). This also contributes positively to the shelf life of the product. This coloring agent provides the desired stability. According to an embodiment of the present invention, the solid pharmaceutical composition is in the form of capsules, tablets, strips, powder, lozenges, sachets, effervescent compositions. According to an embodiment of the present invention, the solid pharmaceutical composition is in the form of tablets. According to an embodiment of the present invention, the solid pharmaceutical composition is in the form of capsules. In addition, since the composition is obtained using the wet granulation method, a simple and low-cost production method has been used. Amount (% of total composition by weight) 3.0 - 25.0 polymorph Polyvinylpyrrolidone K30 1.0-20.0 Corn starch 1.0-35.0 Lactose Monohydrate 30.0 - 53.0 Microcrystalline cellulose 20.0 - 32.0 Magnesium stearate 0.5 - 4.0 Total 100 Amount (% of total composition by weight) polymorph 8.6 Polyvinylpyrrolidone K30 5.2 Corn starch 11.5 Lactose Monohydrate 47.8 Microcrystalline cellulose 25.9 Magnesium stearate 1.0 Total 100 Amount (% of total composition by weight) polymorph Polyvinylpyrrolidone K30 5.2 Corn starch 11.5 Lactose Monohydrate 39.1 Microcrystalline cellulose 25.9 Magnesium stearate 1.0 Total 100 A process for Example 1 or 2 or 3 includes; a) Mixing tolvaptan or its crystalline polymorph, lactose monohydrate, corn starch, microcistral cellulose and polyvinylpyrrolidone, b) Granulating the mixture from step (a) with pure water, c) Drying and then sieving, d) Adding indigo carmine aluminium lake and mixing, e) Adding magnesium stearate and mixing, f) Compressing the mixture into tablets. TR TR TR TR TR TR
Claims (1)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TR2022002174A2 true TR2022002174A2 (en) | 2023-08-21 |
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