TR2022021199A2

TR2022021199A2 - Pharmaceutical Composition Containing Edoxaban and Preparation Method

Info

Publication number: TR2022021199A2
Application number: TR2022/021199
Authority: TR
Inventors: Yunkul Furkan; Uslu Abdullah; Lksen Gucarslan Turkan
Original assignee: Nobel İlaç Sanayi̇i̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇
Filing date: 2022-12-29
Publication date: 2024-07-22

Abstract

Mevcut buluş, edoksaban ile dolgu materyali bileşimini içeren bir farmasötik dozaj formu ve hazırlanış yöntemi ile ilgilidir.The present invention relates to a pharmaceutical dosage form containing a composition of edoxaban and a filler material and its preparation method.

Description

TARIFNAME Edoksaban Içeren Farmasötik Bilesim ve Hazirlanis Yöntemi Bulusun ilgili oldugu teknik saha Mevcut bulus, edoksaban ile dolgu materyali bilesimini içeren bir farmasötik dozaj formu ve hazirlanis yöntemi ile ilgilidir. Teknigin bilinen durumu Edoksaban, faktör Xa inhibitörü gibi islev gören bir antitrombotik ajandir. Antitrombotik ajanlar kanin pihtilasmasini engelleyerek ya da olusan pihtinin erimesini saglayarak etki gösterir. Edoksaban, antitrombotik aktivite için antitrombin III'e gereksinim duymaz. Serbest faktör Xa'yi ve protrombinaz aktivitesini inhibe eder. Faktör Xa'nin inhibisyonu sonucunda trombin olusumunu azaltir. Edoksabanin trombosit agregasyonu üstünde direkt etkisi yoktur. Fakat, edoksaban, trombin ile uyarilan trombosit agregasyonunu indirekt olarak inhibe eder. Edoksaban, valvular kalp hastaligi ile iliskisi olmayan atriyal fibriasyonlu hastalarda inme ve sistemik emboli riskinin azaltilmasi ve daha önce enjektabl antikoagülan ile tedavi görmüs hastalarda derin ven trombozu (DVT) ve pulmoner embolizmin (PE) tedavisinde kullanilir. Edoksaban ilk kez EPl405 852 numarali patent dokümaninda açiklanmistir. Kimyasal adi N1- c]piridin-2-il)karbonil]amino}siklohekzil)etandiamid olup yapisi formül l,de görüldügü 50 Formül 1 g/mol, dür. numarali patent ile açiklanmistir. Edoksaban, Biopharmaceutics Classification System (BCS),a göre Class IVate yer almaktadir. Yani düsük çözünürlüge ve düsük permeabiliteye sahip bir ilaç etken maddesidir. Edoksabanin mutlak oral biyoyararlanimi %62 civarindadir. Teknigin bilinen durumu degerlendirildiginde; EP2140867 numarali patent dokümaninda açiklanan bilgide laktoz kullanilan formülasyonlarda çözünme hizinin iyi sonuç vermedigi belirtilmistir. Ilgili dokümanda bahsedilen referans üründe yardimci madde olarak mannitol ve prejelatinize misir nisastasi kullanilmistir ve bitmis ürün film kaplama materyali ile kaplanmistir. Teknigin bilinen durumunda belirtilen formülasyonun yardimci madde olarak laktoz kullanilarak elde edilecek formülasyondan daha yüksek çözünürlük hizina sahip oldugu belirtilmistir. Sekilleri Açiklanmasi Sekil 1- FG-l, FG-3, FG-4, FG-5 karsilastirmali çözünme hizi grafigi Bulusun Detayli Açiklanmasi Bulus, edoksaban ile dolgu materyali bilesimini içeren bir farmasötik dozaj formu ve hazirlanis yöntemi ile ilgilidir. Teknigin bilinen durumunda açiklanan bilgide laktoz kullanilan formülasyonlarda çözünme hizinin iyi sonuç vermedigi belirtilmis ancak gelistirilen formülasyonda, sasirtici sekilde formülasyona bir seker alkolü ve/veya su varliginda sisen bir yardimci maddesi ilavesi ile; ya da bir veya daha fazla kaplama materyali ile kaplanarak elde edilen kati preparasyonun çözünme hizi sonuçlarinin iyilestigi bulunmustur bilgisini içermektedir. Bu bilgi dogrultusunda referans üründe mannitol ve prejelatinize misir nisastasi kullanilmistir ve bitmis ürün film kaplama materyali ile kaplanmistir. Bulusta, teknigin bilinen durumunda açiklanan bilginin aksine bulusumuzda sasirtici sekilde formülasyon yardimci madde olarak laktoz monohidratin belirli bir aralikta kullanildiginda çözünme hizi sonuçlarinin daha iyi sonuç verdigini bulmustur. Çözünme hizi sonuçlarina bakildiginda teknigin bilinen durumunda bahsedildigi gibi laktozun kullaniminin çözünme hizina olumsuz bir etkisi bulunmadigi aksine laktoz varliginda çözünme hizinin iyi sonuç verdigi görülmektedir. Yas granülasyon yöntemi ile hazirlanan formülasyonda dolgu materyali olarak %45 veya daha fazla laktoz monohidrat kullanildiginda düsük çözünme hizi sonuçlari elde edilmistir. Ayni sekilde yas granülasyon yöntemi ile hazirlanan formülasyonda dolgu materyali olarak gözlenmistir. Mevcut bulus yukaridaki belirtilen sorunlari ortadan kaldiran ve ilave bazi avantajlar getiren edoksaban içeren farmasötik dozaj formu ve hazirlanis yöntemi ile ilgilidir. Yas granülasyon yöntemi ile hazirlanan formülasyonda laktoz monohidrat ve mikrokristalin selüloz bilesimi birlikte kullanilarak basilabilirlik sorunu çözülmüs, ayrica yüksek çözünme hizi sonucu elde edilmistir. materyali ile hazirlanan formülasyonlarda, basilabilirlik ve çözünme probleminin yasanmadigi bulunmustur. Söz konusu bulusta %20-45 araliginda laktoz monohidrat ve %15-40 araliginda mikrokristalin selüloz kullanildiginda uygun fizikofarmasötik özelliklere sahip tabletler ve yüksek çözünme hizi sonuçlari elde edilmistir. Bunlara ilaveten yas granülasyon ile hazirlanan formülasyonda lubrikan olarak magnezyum stearat orani %0.5,in altinda oldugunda tabletlerin çözünme hizi sonuçlarinin magnezyum stearat orani %0.5 ,in üstünde olan tabletlere göre daha iyi oldugu bulunmustur. Ancak %0.5 ,in altinda magnezyum stearat kullanildiginda tabletlerde yapisma problemi gözlenmistir. Bu sorun da formülasyona lubrikan olarak gliseril dibehenat ilave edilerek çözülmüstür. Gliseril dibehenatin çözünme hizi sonuçlari üzerine herhangibir olumsuz etkisi olmamistir. Mevcut bulus; edoksaban veya farmasötik açidan uygun bir tuzunu içeren, farmasötik olarak kabul edilebilir yardimci maddeler olarak da en az bir dolgu maddesi, en az bir dagitici, en az bir baglayici ve en az bir lubrikan içermektedir. Bu bulusta etken madde tablet agirliginin %15 ila %25 arasinda bulunmaktadir. Yardimci maddelerin miktarina bakildiginda %50 ila %75 arasinda dolgu maddesi, tablet agirliginin %3 ila %8 arasinda dagitici, tablet agirliginin %1 ila Edoksaban veya farmasötik açidan uygun bir tuzunu içeren formülasyonda dolgu maddesi olarak laktoz monohidrat, mikrokristalin selüloz ve prejelatinize misir nisastasi; dagitici olarak kroskarmelloz sodyum, krospovidon, misir nisastasi, prejelatinize misir nisastasi, sodyum nisasta glikolat veya bunlarin karisimi arasindan tercihen dagitici olarak krospovidon; baglayici olarak povidon, kopovidon, hidroksipropil selüloz, hidroksipropil metil selüloz, karboksi metil selüloz sodyum, polietilen glikol, poliVinil alkol, jelatin, sukroz veya bunlarin karisimi arasindan tercihen hidroksipropil selüloz ve lubrikan olarak gliseril dibehenat ve magnezyum stearat bilesimi bulunmaktadir. Örnekler, Deneysel Veriler ve Çizimler: Mevcut bulus asagidaki örnekler araciligiyla daha ayrintili bir sekilde tarif edilmektedir. Tablo 1. Hazirlanan tabletlerin birim formülleri Içerik FG-l FG-2 FG-3 FG-4 FG-S Fonksiyonu Prejelatinize Misir 0 0 0 0 0 . Film Kaplama Materyali y.m y.m y.m y.m y.m * Üretim asamasinda uçtugundan hesaplamalarda dikkate alinmaz. Üretim Yöntemi (FG-1) Edoksaban tosilat monohidrat, laktoz monohidratin bir kismi, prejelatinize misir nisastasi, krospovidon, hidroksipropil selüloz elekten elenir, karistirilir. Saf su ile granülasyonu yapilir. Yas granüller kurutulur ve elenir. Laktoz monohidratin kalan kismi kuru granüllere eklenir ve karistirilir. Gliseril dibehenat karisima eklenir ve karistirilir. Magnezyum stearat eklenir ve karistirilir. Final toz karisimi tablet baski makinesinde basilir. Tercihen çekirdek tabletler film kaplama materyali ile kaplanir. Üretim Yöntemi (FG-2) Edoksaban tosilat monohidrat, mikrokristalin selüloz, prejelatinize misir nisastasi, krospovidon, hidroksi propil selüloz elekten elenir, karistirilir. Saf su ile granülasyonu yapilir. Yas granüller kurutulur ve elenir. Laktoz monohidrat kuru granüllere eklenir ve karistirilir. Gliseril dibehenat karisima eklenir ve karistirilir. Magnezyum stearat eklenir ve karistirilir. Final toz karisimi tablet baski makinesinde basilir. Tercihen çekirdek tabletler film kaplama materyali ile kaplanir. Üretim Yöntemi (FG-3/FG-4/FG-5) Edoksaban tosilat monohidrat, mikrokristalin selüloz, prejelatinize misir nisastasi, krospovidon, hidroksi propil selüloz elekten elenir, karistirilir. Saf su ile granülasyonu yapilir. Yas granüller kurutulur ve elenir. Laktoz monohidrat,in kalan kismi kuru granüllere eklenir ve karistirilir. Gliseril dibehenat karisima eklenir ve karistirilir. Magnezyum stearat eklenir ve karistirilir. Final toz karisimi tablet baski makinesinde basilir. Tercihen çekirdek tabletler film kaplama materyali ile kaplanir. Tablo 2. FG- 1, FG-3, FG-4 ve FG-5,te hazirlanan çekirdek tabletlerin pH 6.8 Fosfat tamponunda edoksaban çözünme hizi sonuçlari (50 rpm) Edoksaban 60 mg Çekirdek Tablet Süre (dk) (% çözünme) FG-l, FG-2, FG-3, FG-4 ve FG-5 çekirdek tabletlerine ait birim formülasyonlar Tablo 1,de verilmistir. Tablo 1,de verilen miktarlara bakildiginda FG-l çekirdek tableti olusturulurken dolgu materyali olarak laktoz monohidrat kullanilirken mikrokristalin selüloz kullanilmamistir. Dolgu materyali olarak kullanilan laktoz monohidratin miktari %57.36,dir. Kullanilan miktar bulus konusunun belirtmis oldugu araliktan fazladir. Bu dogrultuda Sekil 1,de yer alan edoksabanin % çözünmesi ile ilgili grafige baktigimizda FG-l çekirdek tabletinin % çözünmesinin laktoz monohidrat ve beraberinde mikrokristalin selüloz içeren FG-3, FG-4 ve FG-5 çekirdek tabletlerine göre daha düsüktür. FG-2 çekirdek tabletinin birim formülasyonu incelendiginde, dolgu maddesi olarak laktoz monohidrat miktari %10.20 olup mikrokristalin selüloz miktari ise %47.16,dir. Mikrokristalin selüloz miktari bulus konusunda yer alan %15-40 araligindan fazla oldugu için FG-2 tableti basilabilirlik sorunu gözlenmistir. FG-3, FG-4 ve FG-5 çekirdek tabletlerinin birim formülasyonu incelendiginde ise, bu tabletlerde dolgu materyali olarak laktoz monohidrat ve mikrokristalin selüloz bilesimi kullanilmis olup; laktoz monohidrat miktari %20-45 araliginda ve mikrokristalin selüloz miktari %15-40 araligindadir. Belirtilen aralikta kullanilan dolgu materyali bilesimi sayesinde çözünme hizi teknigin bilinen durumunda bahsedilenden iyi sonuç vermistir. TR TR TR TR TR TR TR TR TR TRDESCRIPTION Pharmaceutical Composition Containing Edoxaban and Its Preparation Method Technical Field to which the Invention Relates The present invention relates to a pharmaceutical dosage form comprising a composition of edoxaban and a filling material and its preparation method. Prior Art Edoxaban is an antithrombotic agent that functions as a factor Xa inhibitor. Antithrombotic agents act by preventing blood clotting or dissolving the formed clot. Edoxaban does not require antithrombin III for its antithrombotic activity. It inhibits free factor Xa and prothrombinase activity. As a result of inhibition of factor Xa, it reduces thrombin formation. Edoxaban has no direct effect on platelet aggregation. However, edoxaban indirectly inhibits thrombin-induced platelet aggregation. Edoxaban is used to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation unrelated to valvular heart disease and to treat deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients previously treated with injectable anticoagulants. Edoxaban was first disclosed in patent document numbered EP1405 852. Its chemical name is N1- c [pyridin-2-yl]carbonyl]amino]cyclohexyl]ethanediamide, and its structure is described in patent numbered 50. The formula is 1 g/mol, as seen in formula 1. Edoxaban is Class IVate according to the Biopharmaceutics Classification System (BCS). This means that it is a pharmaceutical active ingredient with low solubility and low permeability. The absolute oral bioavailability of edoxaban is approximately 62%. When the state of the art is evaluated; it is stated that the dissolution rate in formulations using lactose does not give good results in the information disclosed in the patent document numbered EP2140867. In the reference product mentioned in the relevant document, mannitol and pregelatinized corn starch were used as excipients and the finished product was coated with a film coating material. It has been stated that the formulation specified in the state of the art has a higher dissolution rate than the formulation obtained using lactose as excipient. Explanation of the Figures Figure 1- Comparative dissolution rate graph of FG-1, FG-3, FG-4, FG-5 Detailed Description of the Invention The invention relates to a pharmaceutical dosage form containing edoxaban and a filling material composition and its preparation method. The information disclosed in the state of the art indicated that dissolution rates in formulations using lactose were not satisfactory. However, in the developed formulation, surprisingly, the dissolution rate results of the solid preparation obtained by adding a sugar alcohol and/or an excipient that swells in the presence of water to the formulation, or by coating with one or more coating materials, were found to be improved. In line with this information, mannitol and pregelatinized corn starch were used in the reference product, and the finished product was coated with a film coating material. In the invention, contrary to the information disclosed in the state of the art, it was surprisingly found that the dissolution rate results were better when lactose monohydrate was used as a formulation excipient within a certain range. When examining the dissolution rate results, it is observed that the use of lactose does not have a negative effect on dissolution rate, as mentioned in the state of the art. On the contrary, the presence of lactose yields good dissolution rate results. Low dissolution rate results were obtained when 45% or more lactose monohydrate was used as a filler material in formulations prepared by the wet granulation method. A similar effect was observed as a filler material in formulations prepared by the wet granulation method. The present invention relates to a pharmaceutical dosage form containing edoxaban and its preparation method that eliminates the aforementioned problems and provides some additional advantages. By using lactose monohydrate and microcrystalline cellulose together in the wet granulation method, the compressibility problem was resolved, and a high dissolution rate was also achieved. It has been found that there are no compressibility and dissolution problems in the formulations prepared with the material. In the present invention, when lactose monohydrate in the range of 20-45% and microcrystalline cellulose in the range of 15-40% were used, tablets with appropriate physicopharmaceutical properties and high dissolution rate results were obtained. In addition, it has been found that when the magnesium stearate ratio as a lubricant in the formulation prepared by wet granulation is below 0.5%, the dissolution rate results of the tablets are better than the tablets with the magnesium stearate ratio above 0.5%. However, when magnesium stearate is used below 0.5%, a sticking problem was observed in the tablets. This problem was solved by adding glyceryl dibehenate to the formulation as a lubricant. Glyceryl dibehenate did not have any negative effect on the dissolution rate results. The present invention; It contains edoxaban or a pharmaceutically acceptable salt thereof, and at least one filler, at least one disintegrant, at least one binder and at least one lubricant as pharmaceutically acceptable excipients. In this invention, the active substance is present between 15% and 25% of the tablet weight. When the amount of excipients is considered, the filler is between 50% and 75%, the disintegrant is between 3% and 8% of the tablet weight, the formulation contains edoxaban or a pharmaceutically acceptable salt thereof as 1% of the tablet weight, lactose monohydrate, microcrystalline cellulose and pregelatinized corn starch as fillers; croscarmellose sodium, crospovidone, corn starch, pregelatinized corn starch, sodium starch glycolate or a mixture thereof, preferably crospovidone as a disintegrant; povidone, crospovidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxy methyl cellulose sodium, polyethylene glycol, polyVinyl alcohol, gelatin, sucrose or a mixture thereof, preferably hydroxypropyl cellulose, and glyceryl dibehenate and magnesium stearate as lubricants. Examples, Experimental Data and Drawings: The present invention is described in more detail through the examples below. Table 1. Unit formulas of the prepared tablets Content FG-1 FG-2 FG-3 FG-4 FG-S Function Pregelatinized Corn 0 0 0 0 0 . Film Coating Material y.m y.m y.m y.m y.m * It is not taken into account in the calculations because it volatilizes during the production stage. Production Method (FG-1) Edoxaban tosylate monohydrate, some of the lactose monohydrate, pregelatinized corn starch, crospovidone, and hydroxypropyl cellulose are sieved and mixed. Granulation is done with purified water. The wet granules are dried and sieved. The remaining portion of the lactose monohydrate is added to the dry granules and mixed. Glyceryl dibehenate is added to the mixture and mixed. Magnesium stearate is added and mixed. The final powder mixture is compressed on a tablet compression machine. Preferably, the core tablets are coated with a film-coating material. Production Method (FG-2) Edoxaban tosylate monohydrate, microcrystalline cellulose, pregelatinized corn starch, crospovidone, and hydroxy propyl cellulose are sieved and mixed. Granulation is carried out with purified water. Wet granules are dried and sieved. Lactose monohydrate is added to the dry granules and mixed. Glyceryl dibehenate is added to the mixture and mixed. Magnesium stearate is added and mixed. The final powder mixture is compressed on a tablet press. Preferably, the core tablets are coated with a film-coating material. Production Method (FG-3/FG-4/FG-5) Edoxaban tosylate monohydrate, microcrystalline cellulose, pregelatinized corn starch, crospovidone, and hydroxy propyl cellulose are sieved and mixed. Granulation is carried out with purified water. The wet granules are dried and sieved. The remaining portion of lactose monohydrate is added to the dry granules and mixed. Glyceryl dibehenate is added to the mixture and mixed. Magnesium stearate is added and mixed. The final powder mixture is compressed on a tablet pressing machine. Preferably, the core tablets are coated with film-coating material. Table 2. Results of edoxaban dissolution rate of core tablets prepared in FG-1, FG-3, FG-4 and FG-5 in pH 6.8 phosphate buffer (50 rpm) Edoxaban 60 mg Core Tablet Time (min) (% dissolution) The unit formulations of FG-1, FG-2, FG-3, FG-4 and FG-5 core tablets are given in Table 1. Considering the amounts given in Table 1, lactose monohydrate was used as a filler material during the production of the FG-1 core tablet, while microcrystalline cellulose was not. The amount of lactose monohydrate used as a filler material is 57.36%. The amount used is greater than the range specified by the invention. In this regard, when we look at the graph regarding the % dissolution of edoxaban in Figure 1, we see that the % dissolution of the FG-1 core tablet is lower than that of the FG-3, FG-4, and FG-5 core tablets, which contain lactose monohydrate and microcrystalline cellulose. When the unit formulation of the FG-2 core tablet is examined, the amount of lactose monohydrate as a filler is 10.20%, and the amount of microcrystalline cellulose is 47.16%. Because the microcrystalline cellulose content exceeded the 15-40% range specified in the invention, a compressibility problem was observed in the FG-2 tablet. When the unit formulation of the FG-3, FG-4, and FG-5 core tablets was examined, a combination of lactose monohydrate and microcrystalline cellulose was used as filler material in these tablets; the lactose monohydrate content was between 20-45% and the microcrystalline cellulose content was between 15-40%. Thanks to the filler material composition used within the specified range, the dissolution rate was better than that reported in the state of the art.

Claims

Requests

l. It is a composition containing edoxaban or a pharmaceutically acceptable salt thereof, and is characterized by being a composition containing 20% to 45% lactose monohydrate and 15% to 40% microcrystalline cellulose as a filler material.

2. The pharmaceutical composition as claimed in claim 1, wherein the amount of lactose monohydrate is in the range of 20% to 30% and microcrystalline cellulose is in the range of 30% to 35%.

3. Pharmaceutical composition as in claim 1, characterized in that it contains binder in the range of 1% to 5% of the tablet weight and lubricant composition in the range of 0.1% to 2% of the tablet weight from excipients.

4. Pharmaceutical composition according to claim 3, characterized in that the disintegrant is selected from croscarmellose sodium, crospovidone, corn starch, pregelatinized corn starch, sodium starch glycolate or a mixture thereof.

5. Pharmaceutical composition according to claim 4, characterized in that the disintegrant preferably is crospovidone.

6. Pharmaceutical composition as claimed in claim 3, characterized in that the binder is selected from povidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxy methyl cellulose sodium, polyethylene glycol, polyvinyl alcohol, gelatin, sucrose or a mixture of these.

7. Pharmaceutical composition according to claim 6, characterized in that the binder is hydroxypropyl cellulose.

8. The pharmaceutical composition as in claim 1, characterized in that glyceryl dibehenate and magnesium stearate are used together as lubricants.

9. Pharmaceutical composition according to claim 8, characterized in that magnesium stearate is present in the lubricant composition.

10. Pharmaceutical composition according to claim 8, characterized in that the lubricant composition contains glyceryl dibehenatin.

ll. A method for the preparation of a pharmaceutical composition comprising edoxaban, characterized in that, i) Edoxaban tosylate monohydrate, microcrystalline cellulose, pregelatinized corn starch, crospovidone, hydroxy propyl cellulose are sieved and mixed. Granulation is carried out with pure water. ii) Wet granules are dried and sieved. iii) The remaining part of lactose monohydrate is added to the dry granules and mixed. iv) Glyceryl dibehenate is added to the mixture and mixed. V) Magnesium stearate is added and mixed. Vi) The final powder mixture is pressed in a tablet press machine. Vii) Preferably, the core tablets are coated with film coating material.