TR201502223A2 - Pharmaceutical combinations of dronedarone and dabigatran - Google Patents

Pharmaceutical combinations of dronedarone and dabigatran Download PDF

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TR201502223A2
TR201502223A2 TR2015/02223A TR201502223A TR201502223A2 TR 201502223 A2 TR201502223 A2 TR 201502223A2 TR 2015/02223 A TR2015/02223 A TR 2015/02223A TR 201502223 A TR201502223 A TR 201502223A TR 201502223 A2 TR201502223 A2 TR 201502223A2
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pellets
pharmaceutical combination
tablets
dronedarone
combination according
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TR2015/02223A
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Gökçek Sevgi̇
Türkyilmaz Ali̇
Yelken Gülay
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Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
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Priority to TR2015/02223A priority Critical patent/TR201502223A2/en
Priority to PCT/EP2016/053819 priority patent/WO2016135171A1/en
Publication of TR201502223A2 publication Critical patent/TR201502223A2/en

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Abstract

Mevcut buluş, dronedaron veya farmasotik olarak kabul edilebilir bir tuzu ile birlikte dabigatran veya farmasotik olarak kabul edilebilir bir tuzu veya polimorfu ve en az bir farmasotik olarak kabul edilebilir bir ekspiyan içeren farmasotik bir kombinasyon ile ilgilidir.The present invention relates to a pharmaceutical combination comprising dabigatran or a pharmaceutically acceptable salt or polymorph and at least one pharmaceutically acceptable excipient together with dronedarone or a pharmaceutically acceptable salt thereof.

Description

Tarifname DRONEDARONUN VE DABIGATRANIN FARMASÖTIK KOMBINASYONLARI Bulusun alani Mevcut bulus, dabigatran veya onun farmasötik olarak kabul edilebilir bir tuzu veya farkli bir polimorfu ile birlikte dronedaron veya onun farmasötik olarak kabul edilebilir bir tuzunu ve en az bir tane farmasötik olarak kabul edilebilir yardimci maddeyle içeren farmasötik bir kombinasyonla ilgilidir. specification PHARMACEUTICAL COMBINATIONS OF DRONEDARON AND DABIGATRAN field of invention The present invention includes dabigatran or a pharmaceutically acceptable salt thereof or a different dronedarone or a pharmaceutically acceptable salt thereof, together with its polymorph a pharmaceutical product containing at least one pharmaceutically acceptable excipient It's about the combination.

Bulusun geçmisi Dronedaron, antiaritmik özelliklere sahip Iyodinlenmemis (noniyodinize) bir benzofuran türevidir. Dronedaron, amiodarondan bir iyot kisminin atilmasi ve bir metan sülfonil grubunun eklenmesi bakimindan yapisal olarak farkli bir amiodaron analogudur. Bu modifikasyonlar, tiroit üzerine olan etkileri ve diger advers etkileri azaltir ve dronedaronu daha kisa bir yarilanma ömrü ile daha az Iipofilik hale getirir. Dronedaronun kimyasal ismi N-[2-bütiI-3-[4- Formül l: Dronedaron Formül ll: Dronedaron hidroklorür Dronedaron hidroklorür (formül I'de gösterilen), paroksismal veya persistan atriyal fibrilasyon (AF) öyküsü bulunan, sinüs ritminde seyreden hastalarda AF için hospitalize edilme riskini azaltmak üzere endike gösterilen antiaritmik bir ilaçtir. Yemekle verilmesini takiben, bagirsaklardan iyi derecede emilerek kana geçmektedir. FDA tarafindan 2009 yilinda onaylanmistir ve hali hazirda piyasada MULTAQTM ticari ismi altinda satilmaktadir. Tavsiye edilen doz, sabah ve aksam ögünleri ile günde iki defa 400 mg'lik bir tabletin alinmasidir. history of invention Dronedarone is a non-iodinated benzofuran with antiarrhythmic properties. is derivative. Dronedarone consists of removal of an iodine moiety and a methane sulfonyl group from amiodarone. It is a structurally different analogue of amiodarone in terms of addition. These modifications reduces thyroid and other adverse effects and provides a shorter duration of dronedarone. makes it less Lipophilic with a half-life. Chemical name of dronedarone is N-[2-butyl-3-[4- Formula 1: Dronedarone Formula II: Dronedarone hydrochloride Dronedarone hydrochloride (shown in formula I), paroxysmal or persistent atrial fibrillation Risk of being hospitalized for AF in patients with a history of (AF) and in sinus rhythm. It is an antiarrhythmic drug indicated to reduce Following administration with food, It is well absorbed from the intestines and passes into the blood. by the FDA in 2009. has been approved and is currently marketed under the trade name MULTAQTM. Recommendation The recommended dose is to take one 400 mg tablet twice a day, with morning and evening meals.

Teknigin bilinen durumunda dronedaron ve onun farmasötik olarak kabul edilebilir tuzlari EP basvurusu dronedaron HCl'nin tablet formülasyonlarini bildirmektedir. Ayrica agizdan uygulanan dronedaron formülasyonlarini bildiren bir kaç patent basvurusu da vardiri ancak bu basvurulardan hiç birisi agizda dagilan dronedaron tabletleri içermemektedir. State of the art dronedarone and its pharmaceutically acceptable salts EP reports tablet formulations of dronedarone HCl. Also by word of mouth There are also a few patent applications reporting dronedarone formulations applied, but none of these applications contain dronedarone tablets that disintegrate in the mouth.

Günümüzde yaygin olarak bulunan çok sayida antitrombotik ilaç bulunmaktadir ve trombin enzimini dogrudan inhibe etmek suretiyle antikoagülan (kanin pihtilasmasini geciktirici) etkisini sergileyen bir medikasyon sinifi olan Direkt Trombin Inhibitörleri (DTIler) olarak ta isimlendirilmektedir. DTI'ler hirudin, bivalirudin (IV), lepirudin, desirudin, argatroban (IV), dabigatran, dabigatran eteksilat (oral formülasyonu), melagatran, ksimelagatrani (oral formülasyondur, fakat karaciger komplikasyonlari vardir) ve bunlarin ön ilaçlarini kapsamaktadir. There are many antithrombotic drugs widely available today and thrombin anticoagulant by directly inhibiting the enzyme Also known as Direct Thrombin Inhibitors (DTIs), a class of medications that exert is named. DTIs hirudin, bivalirudin (IV), lepirudin, desirudin, argatroban (IV), dabigatran, dabigatran etexilate (oral formulation), melagatran, ximelagatrani (oral formulation) formulation, but with liver complications) and their prodrugs covers.

Daha önceden WO 98/37075 nolu patent basvurusunda bildirilen dabigatran eteksilat (Formül III), trombinin peptid yapida olmayan, yarismali, geri dönüsümsüz bir antagonistidir. dabigatran etexilate previously reported in patent application WO 98/37075 (Formula III) is a non-peptide, competitive, irreversible antagonist of thrombin.

Vasküler olmayan atriyal fibrilasyon hastalarinda inme ve sistemik emboli riskini azaltmak amaciyla endike gösterilen bir direkt trombin inhibitörüdür. Trombin, faktör Xlll'ü aktive ederek fibrinojeni fibrine, çapraz bagli fibrin monomerlerine dönüstüren ve faktör V ve faktör Vlll'ü aktive ederek te trombin üretimini daha da artiran çok fonksiyonlu bir enzimdir. Ayrica plateletleri aktiflestirir, protein C'yi aktive ederek antikoagülan etkinlik olusturur ve çesitli hücresel prosesleri de baslatir. Reducing the risk of stroke and systemic embolism in patients with nonvascular atrial fibrillation It is a direct thrombin inhibitor indicated for Thrombin activates factor XIII converts fibrinogen to fibrin, cross-linked fibrin monomers, and factor V and factor It is a multifunctional enzyme that further increases the production of thrombin by activating VIII. Moreover It activates platelets, activates protein C, creates anticoagulant activity and has various It also initiates cellular processes.

Formül lll: Dabigatran eteksilat Piyasada halihazirda dabigatran eteksilatin PRADAXA® (75, 110, 150mg'lik) markasi altinda ticari olarak satilan metan sülfonik asit ilave tuzu bulunmaktadir ve dabigatran eteksilat mesilatin (DEM) (Formül lV) pellet kompozisyonu ayrica EP1870100 nolu patent basvurusunda da bildirilmektedir. Bu kompozisyon, organik bir asiti içeren çekirdek bir materyal ve çekirdegi kaplayan bir etken katmanla formüle edilmektedir. Formula III: Dabigatran etexilate Dabigatran etexilatine is currently on the market under the brand name PRADAXA® (75, 110, 150mg). commercially available methane sulfonic acid addition salt and dabigatran etexilate mesylatin (DEM) (Formula IV) pellet composition is also patented EP1870100 reported in the application. This composition is a core compound containing an organic acid. It is formulated with an active layer that covers the material and the core.

Formül IV: Dabigatran eteksilat mesilat Teknik alanda temel olarak yaygin bilgiye göre, antiaritmik ilaçlar, kardiyak aritminin özellikle de atriyal fibrilasyonun tedavisinde antikoagülanlarla kombinasyon halinde yaygin olarak kullanilmaktadir. Ancak teknigin bilinen durumunda dronedaron ve dabigatrani tek dozaj formu içerisinde kombine eden formülasyon bulunmamaktadir. Her birini ayri ayri kullanmak yerine, birden fazla molekülün bir dozaj formu halinde kombine edilmesi hastalarin yasam kalitesini ve hasta kompliyansini artirmaktadir. Bu sebeple, teknikte dronedaron ve bir antikoagülan olarak ta dabigatran eteksilati içeren uygun bir farmasötik dozaj Diger taraftan, iki veya fazla molekülü tek dozaj formu içerisinde kombine edilmesi dissolüsyon, geçimlilik ve stabilite problemleri gibi çok sayida soruna da yol açabilir. Her bir ilaç molekülü farkli kimyasal özelliklere ve dissolüsyon özelliklerine sahiptir. Uygulamadan sonra farkli emilim ve çözünme yolaklarini izleyebilirler. Bu nedenle ilaç moleküllerinin, istenen dissolüsyon özelliklerine sahip tek dozaj formu içerisinde kombine edilmesi kolay degildir. Kombine edilen ilaçlar ayrica birbiri ile veya kullanilan diger yardimci maddeler ile reaksiyona girebilir ve istenmeyen stabilite problemlerine yol açabilir. Bunlar haricinde ayni terapötik alanda kullanilan ve hatta ayni endikasyonu tedavi etmek için kullanilan ilaçlarin, asgari e terapötik etkilerin meydana gelmesi ihtimaliyle her zaman için ayni ve etkili dozaj formlari içerisinde kombine edilemedigi iyi bilinmektedir. Formula IV: Dabigatran etexilate mesylate According to widely known technical art, antiarrhythmic drugs are especially effective for cardiac arrhythmias. It is widely used in combination with anticoagulants in the treatment of atrial fibrillation in is used. However, in the state of the art, dronedarone and dabigatrani are single dosage There is no combination formulation in its form. Using each separately Rather, combining more than one molecule into a dosage form can lead to patients' survival. improves quality and patient compliance. For this reason, dronedarone and a A suitable pharmaceutical dosage form containing dabigatran etexilate as an anticoagulant On the other hand, combining two or more molecules in a single dosage form Dissolution can also cause many problems such as compatibility and stability problems. Each drug molecule has different chemical properties and dissolution properties. From the app then they can follow different absorption and dissolution pathways. Therefore, drug molecules easy to combine in a single dosage form with desired dissolution properties is not. Combined drugs can also be combined with each other or with other excipients used. may react and cause undesirable stability problems. Apart from these, the same drugs used in the therapeutic field or even used to treat the same indication, always the same and effective dosage with minimal probability of therapeutic effects to occur It is well known that it cannot be combined in its forms.

Mevcut bulusta, antiaritmik bir ilaç olarak dronedaron ve antikoagülan bir ilaç olarak da dabigatran tek dozaj formu içerisinde kombine edilmektedir ve kardiyovasküler hastaliklarin etkili ve güvenilir tedavisine ulasilmaktadir. In the present invention, dronedarone as an antiarrhythmic drug and also as an anticoagulant drug dabigatran is combined in a single dosage form and is used to treat cardiovascular diseases. effective and reliable treatment is reached.

Bulusun ayrintili açiklamasi Mevcut bulus, dabigatran veya onun farmasötik olarak kabul edilebilir bir tuzu veya farkli bir polimorfu ile birlikte dronedaron veya onun farmasötik olarak kabul edilebilir bir tuzunu ve en az bir tane farmasötik olarak kabul edilebilir yardimci maddele içeren farmasötik bir kombinasyonla ilgilidir. Detailed description of the invention The present invention includes dabigatran or a pharmaceutically acceptable salt thereof or a different dronedarone or a pharmaceutically acceptable salt thereof, together with its polymorph a pharmaceutical product containing at least one pharmaceutically acceptable excipient It's about the combination.

Bir düzenlemeye göre, mevcut bulusta kullanilan dronedaron veya farmasötik olarak kabul edilebilir bir tuzu, dronedaron hidroklorürdür. According to one embodiment, dronedarone used in the present invention or considered pharmaceutical An acceptable salt of it is dronedarone hydrochloride.

Bir düzenlemeye göre, dronedaron hidroklorür (HCI), toplam formülasyonun agirlikça %50 bir miktardadir. arasi ve daha tercihen de 400 ila 800 mg arasi bir miktarda bulunmaktadir. According to one embodiment, dronedarone hydrochloride (HCI) is 50% by weight of the total formulation. is an amount. and more preferably between 400 and 800 mg.

Bir düzenlemeye göre dabigatran veya farmasötik olarak kabul edilebilir bir tuzu veya farkli bir polimorfu, dabigatranin eteksilat veya eteksilat mesilat tuzudur. According to one embodiment, dabigatran or a pharmaceutically acceptable salt or a different a polymorph is the etexilate or mesylate salt of dabigatranin.

Bir düzenlemeye göre dabigatran veya a farmasötik olarak kabul edilebilir bir tuzu, dabigatran eteksilat mesilattir. According to one embodiment, dabigatran or a pharmaceutically acceptable salt thereof, dabigatran etexilate is mesylate.

Bir düzenlemeye göre dabigatran eteksilat mesilat, toplam formülasyonun agirlikça %10 ila miktardadir. mg arasi ve daha tercihen de 50 ila 250 mg arasi bir miktarda bulunmaktadir. According to one embodiment, dabigatran etexilate mesylate comprises from 10% to 10% by weight of the total formulation. amount. mg, and more preferably 50 to 250 mg.

Mevcut bulusta, dronedaron HCI kombinasyon halinde antikoagülan bir ajan olan dabigatran eteksilat mesilat ile birlikte, hastalarda kardiyak aritminin ve kan pihtilasmasinin tedavisinde ve ciddi ve yasami tehdit eden yan etkilerin önlenmesi amaciyla kullanilmaktadir. In the present invention, dronedarone HCl is used in combination with dabigatran, an anticoagulant agent. in combination with etexilate mesylate for the treatment of cardiac arrhythmia and blood coagulation in patients and to prevent serious and life-threatening side effects.

Bir düzenlemede, her bir ilaç molekülü için güvenilir ve etkili dissolüsyon profillerine sahip stabil bir farmasötik kombinasyon saglayan, dabigatran eteksilat mesilat ile birlikte dronedaron HCI içeren farmasötik bir dozaj gelistirilmistir. In one embodiment, they have reliable and effective dissolution profiles for each drug molecule. in combination with dabigatran etexilate mesylate, providing a stable pharmaceutical combination A pharmaceutical dosage containing dronedarone HCl has been developed.

Bir düzenlemeye göre, mevcut bulusta kullanilan oranlar, tedavi edici ve hem dronedaron HCl hem de dabigatran eteksilat mesilat için stabilite saglayan gerekli miktardaki etkili dozlari saglamaktadir. According to one embodiment, the ratios used in the present invention are both therapeutic and dronedarone. Effective doses of HCl and dabigatran etexilate mesylate in the required amount to provide stability it provides.

Bu düzenlemede dronedaron HCl'nin dabigatran eteksilat mesilat'a olan 0.10- 50.0(a/a), formülasyonun bir yandan kombinasyonun stabilitesini sürdürürken bir yandan da hastalar tarafindan kolaylikla yutulabilecek arzu edilen agirlikta bir dozaj formuna kolaylikla islenmesine yardimci oldugu bulunmustur. In this embodiment, the ratio of dronedarone HCl to dabigatran etexilate mesylate is 0.10-50.0(w/w), formulation while maintaining the stability of the combination, while patients readily into a dosage form of desired weight that can be easily swallowed by It has been found to help with processing.

Bir düzenlemede, mevcut bulustaki bir dozaj formunda formüle edilen farmasötik kombinasyon, hem dronedaron HCI hem de dabigatran eteksilat mesilat için istenen dissolüsyon profilini saglamaktadir. In one embodiment, the pharmaceutical formulated in a dosage form of the present invention The combination is desirable for both dronedarone HCl and dabigatran etexilate mesylate. provides the dissolution profile.

Mevcut bulusun bir düzenlemesine göre, farmasötik kombinasyon kati, sivi veya yari kati dozaj formundadir. According to one embodiment of the present invention, the pharmaceutical combination is solid, liquid or semisolid. in dosage form.

Bu düzenlemede, bu farmasötik kombinasyonlar agizdan, parenteral, intranazal, dilalti, transdermal, transmukozal, oftalmik, intravenöz, pulmoner, intramusküler veya rektal uygulama yollari ile uygulanmaktadir ve tercihen de agizdan uygulanmaktadir. In this embodiment, these pharmaceutical combinations are oral, parenteral, intranasal, sublingual, transdermal, transmucosal, ophthalmic, intravenous, pulmonary, intramuscular or rectal It is administered by administration routes and preferably orally.

Bir düzenlemeye göre, farmasötik kombinasyonlar sikistirilmis tabletler, kapli veya kaplanmamis tabletler içeren tabletler, kapsüller, çok katmanli tabletler, agiz içi tabletler, dil alti tabletler, tablet içinde tabletler, in-lay tabletler, efervesan kombinasyonlar, efervesan tabletler, hemen salimli tabletler, modifiye salimli tabletler, ODT (agizda dagilan tablet), film- kapli tabletler, agizda dagilan tabletler, midede dagilan tabletler, haplar, sert veya yumusak jelatin kapsüller, tozlar, mini tabletler, pelletler, kapli boncuk sistemleri, granüller, mikrosferler, iyon degistirici reçine sistemleri, steril solüsyonlar veya süspansiyonlar, steril oküler solüsyonlar, aerosoller, spreyler, damlalar, ampuller,suppozituarlar, oküler sistemler, parenteral sistemler, kremler, jeller, merhemler, drajeler, kaseler; filmler, agizdan uygulanabilen filmler, agizdan uygulanabilen filmler, solüsyonlar, solidler; eliksirler, tentürler, süspansiyonlar, suruplar, kolloidal dispersiyonlar, dispersiyonlar ve emülsiyonlar formundadir Bir düzenlemede, bahsedilen farmasötik kombinasyon tablet veya kapsül veya çok katmanli tablet formunda formüle edilmektedir. According to one embodiment, pharmaceutical combinations are compressed tablets, coated or tablets containing uncoated tablets, capsules, multilayer tablets, oral tablets, lingual six tablets, tablets in tablets, in-lay tablets, effervescent combinations, effervescent tablets, immediate-release tablets, modified-release tablets, ODT (mouth dispersal tablet), film- Coated tablets, orodispersible tablets, gastro-dispersal tablets, pills, hard or soft gelatin capsules, powders, mini tablets, pellets, coated bead systems, granules, microspheres, ion exchange resin systems, sterile solutions or suspensions, sterile ocular solutions, aerosols, sprays, drops, ampoules, suppositories, ocular systems, parenteral systems, creams, gels, ointments, dragees, bowls; movies by mouth applicable films, orally applicable films, solutions, solids; elixirs, tinctures, in the form of suspensions, syrups, colloidal dispersions, dispersions and emulsions In one embodiment, said pharmaceutical combination is a tablet or capsule or a multilayer It is formulated in tablet form.

Bir düzenlemede, bahsedilen farmasötik kombinasyon dronedaron HCI pelletleri ve dabigatran eteksilat mesilat pelletleri içeren tablet veya kapsül veya çok katmanli tablet Dronedaron, bagirsaklardan iyi emilen bir ilaç molekülüdür ve dabigatran ise mideden iyi emilen bir ilaç molekülüdür. Mevcut bulusun bu kombinasyonunda midede çözünmeyen bagirsaklarda çözünen dronedaron HCI pelletler ve midedede çözünen dabigatran eteksilat mesilat pelletler elde edilmektedir. In one embodiment, said pharmaceutical combination is dronedarone HCl pellets and tablet or capsule or multilayer tablet containing dabigatran etexilate mesylate pellets Dronedarone is a drug molecule that is well absorbed from the intestines, and dabigatran is well absorbed from the stomach. It is an absorbed drug molecule. In this combination of the present invention, the insoluble gut soluble dronedarone HCl pellets and stomach soluble dabigatran etexilate mesylate pellets are obtained.

Bir düzenlemedei bahsedilen farmasötik kombinasyon, enterik bir kaplama içeren dronedaron HCl pelletler içermektedir. In one embodiment, said pharmaceutical combination contains an enteric coating. Contains dronedarone HCl pellets.

Bir düzenlemeye göre, mevcut bulusta kullanilan enterik kaplama dronedaron HCI'nin mideden emilmesini degil de, bagirsaklardan emilmesini saglamaktadir. According to one embodiment, the enteric coating dronedarone HCl used in the present invention is It ensures that it is not absorbed from the stomach, but from the intestines.

Mevcut bulus, dronedaron HCI katmanini kaplayan ve dabigatran eteksilat mesilat ile dronedaron HCI katmanlarini birbirinden ayiran enterik bir kaplama içeren farmasötik bir kombinasyon saglamaktadir. Enterik kaplama, dronedaron HCl'nin midede stabil kalmasini saglar ve ayni zamanda enterik kaplama sayesinde dabigatran eteksilat mesilat ve dronedaron HCi molekülleri arasindaki etkilesim de engellenmis olur. Baska bir önemli sebep te farkli salim profillerine sahip ilaç moleküllerinin enterik kaplama ile ayni dozaj formu içerisinde verilebilmesidir. Bu sebeple dabigatran eteksilat mesilat ve dronedaron HCI molekülleri etkilesime girmeyen bir tarzda formüle edilmektedir ve ayni zamanda bu moleküllerin kendi formlarinda stabil kalmalarini da saglar. Ayrica kardiyovasküler hastaliklarin güvenilir ve etkili bir tedavisi yönünden de her bir ilaç molekülünün arzu edilen salim profillerine de ulasilmis olur. The present invention covers the dronedarone HCl layer with dabigatran etexilate mesylate. dronedarone is a pharmaceutical product containing an enteric coating that separates the HCl layers. provides combination. Enteric coating allows dronedarone HCl to remain stable in the stomach. and at the same time, thanks to the enteric coating, dabigatran etexilate mesylate and The interaction between dronedarone HCi molecules is also inhibited. Another important reason The same dosage form with enteric coating of drug molecules with different release profiles can be given in. For this reason, dabigatran etexilate mesylate and dronedarone HCl molecules are formulated in a non-interacting manner and at the same time this It also ensures that the molecules remain stable in their own form. Also cardiovascular In terms of a reliable and effective treatment of diseases, each drug molecule is desired. release profiles can also be reached.

Mevcut bulusun bu düzenlemesinde, dronedaron HCI pelletler selüloz asetat fitalat, metakrilik asit kopolimerleri (Eudragit L tipleri (metakrilik asit, etil akrilat kopolimerleri), Eudragit RL ve R8 tipleri (etil akrilat, metil metakrilat ve amonyum metakrilat kopolimeri), Eudragit-S tipleri (Metakrilik asit, metil metakrilat kopolimeri)), hidroksipropil metilselüloz fitalat (HPMCP), hidroksipropil metilselüloz asetat süksinat, polivinil asetat fitalat ve metakrilik asit ko-polimeri tip C'yi içeren gruptan seçilen enterik bir kaplama içermektedir. In this embodiment of the present invention, dronedarone HCl pellets are made from cellulose acetate phthalate, methacrylic acid copolymers (Eudragit L types (methacrylic acid, ethyl acrylate copolymers), Eudragit RL and R8 types (ethyl acrylate, methyl methacrylate and ammonium methacrylate copolymer), Eudragit-S types (Methacrylic acid, methyl methacrylate copolymer)), hydroxypropyl methylcellulose phthalate (HPMCP), co-polymer of hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and methacrylic acid containing an enteric coating selected from the group consisting of type C.

Mevcut bulusun bu düzenlemesinde, bahsedilen farmasötik kombinasyon ayri pelletler veya çift katmanli pelletler veya çok katmanli pelletler halindeki dabigatran eteksilat mesilat pelletleri ve dronedaron HCI pelletleri içeren tablet veya kapsül veya çok katmanli tablet formundadir. In this embodiment of the present invention, said pharmaceutical combination is used as separate pellets or dabigatran etexilate mesylate in bilayer pellets or multilayer pellets tablet or capsule or multilayer tablet containing pellets and dronedarone HCl pellets is in the form.

Mevcut bulusun bir düzenlemesinde, bahsedilen dronedaron HCl pelletler farmasötik olarak kabul edilebilir yardimci maddeler olarak mannitol veya prejelatinize nisasta veya karbomer veya kroskarmelloz sodyum veya polivinilpirolidon (PVP) veya polivinil alkol veya seker pellet veya mikrokristalize selüloz (MCC) pellet veya hidroksipropil selüloz veya renklendirici ajan veya bunlarin karisimlarini içermektedir. In one embodiment of the present invention, said dronedarone HCl pellets are pharmaceutically mannitol or pregelatinized starch or carbomer as acceptable excipients or croscarmellose sodium or polyvinylpyrrolidone (PVP) or polyvinyl alcohol or sugar pellets or microcrystalline cellulose (MCC) pellet or hydroxypropyl cellulose or coloring agent or mixtures thereof.

Mevcut bulusun bu düzenlemesinde, bahsedilen dabigatran eteksilat mesilat pelletler farmasötik olarak kabul edilebilir yardimci maddeler olarak polivinil alkol (PVA) veya izopropil alkol (IPA) veya sodyum aljinat veya metakrilik asit-etil akrilat kopolimeri (Eudragit EPO) veya propilen glikol veya laktoz monohidrat veya mannitol veya seker pellet veya polivinilpirolidon (PVP) veya bunlarin karisimlarini içermektedir. In this embodiment of the present invention, said dabigatran etexilate mesylate pellets polyvinyl alcohol (PVA) or isopropyl as pharmaceutically acceptable excipients alcohol (IPA) or sodium alginate or methacrylic acid-ethyl acrylate copolymer (Eudragit EPO) or propylene glycol or lactose monohydrate or mannitol or sugar pellets or polyvinylpyrrolidone (PVP) or mixtures thereof.

Bu nedenle yukarida bahsedilen sorunlara göre yardimci maddelerin seçimi önemlidir. Bu düzenlemeye göre, bir veya daha fazla sayida farmasötik olarak kabul edilebilir yardimci madde tamponlayici ajanlar, stabilizörler, baglayicilar, seyrelticiler, disperze edici ajanlar, kayganlastiricilar, glidanlar, dagiticilar, plastiklestiriciler, koruyucular, tatlandiricilar, aroma katici ajanlar, renklendirici ajanlar veya bunlarin karisimlarini içeren gruptan seçilmektedir. For this reason, the selection of excipients according to the problems mentioned above is important. This one or more pharmaceutically acceptable excipients, according to regulation substance buffering agents, stabilizers, binders, diluents, dispersing agents, lubricants, glidants, dispersants, plasticizers, preservatives, sweeteners, flavorings are selected from the group consisting of additives, coloring agents or mixtures thereof.

Uygun tamponlayici ajanlar alkali metal sitrat, sitrik asit/sodyum sitrat, tartarik asit, fumarik asit, sorbik asit, sitrik asit, süksinikasit, adipik asit, askorbik asit, sorbik asit, glutarik asit, potasyum hidrojen tartarat, sodyum hidrojen tartarat, potasyum hidrojen fitalat, sodyum hidrojen fitalat, potasyum dihidrojen fosfat, sodyum dihidrojen fosfat, disodyum hidrojen fosfat, hidroklorik asit/sodyum hidroksit veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir ve tercihen sitrik asit, fumarik asit, askorbik asit, sodyum dihidrojen fosfat veya bunlarin karisimlaridir. Suitable buffering agents are alkali metal citrate, citric acid/sodium citrate, tartaric acid, fumaric acid, sorbic acid, citric acid, succinic acid, adipic acid, ascorbic acid, sorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen may contain phosphate, hydrochloric acid/sodium hydroxide or mixtures thereof, but not limited and preferably citric acid, fumaric acid, ascorbic acid, sodium dihydrogen phosphate or are mixtures of these.

Uygun stabilizörler sitrik asit, fumarik asit, tartarik asit, sodyum sitrat, sodyum benzoat, sodyum dihidrojen fosfat, kalsiyum karbonat, magnezyum karbonat, arjinin, lizin, meglamin, tokoferol, bütilhidroksianizol (BHA), bütilhidroksianitoluen (BHT), askorbik asit, gallik asit esterleri veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir ve tercihen de sitrik asit, fumarik asit, arjinin veya bunlarin karisimlaridir. Suitable stabilizers are citric acid, fumaric acid, tartaric acid, sodium citrate, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, arginine, lysine, meglamine, tocopherol, butylhydroxyanisole (BHA), butylhydroxyanitoluene (BHT), ascorbic acid, gallic acid esters or mixtures thereof, but not limited to, and preferably citric acid, fumaric acid, arginine or mixtures thereof.

Uygun baglayicilar ksantan zamki, prejelatinize nisasta, polivinilpirolidon, polietilen glikol, polivinil alkol, nisasta, glikoz, glikoz surubu, dogal zamklar, sükroz, sodyum aljinat, hidroksipropil metil selüloz, hidroksipropil selüloz, karboksi metil selüloz, metil selüloz gibi selüloz türevleri, jelatin, karragenan, guar zamki, karbomer, polimetakrilatlar, metakrilat polimerleri, kollajenler, jelatin gibi proteinler, agar, aljinat, aiginik asit, hiyaluronik asit, pektin, polisakkaritler, karbomer, polokzamer, poliakrilamid, alüminyum hidroksit, laponit, bentonit, polioksietilen-alkil eter, polidekstroz, polietilen oksit veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir. Suitable binders are xanthan gum, pregelatinized starch, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose cellulose derivatives, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, collagens, proteins such as gelatin, agar, alginate, aiginic acid, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, laponite, bentonite, may contain polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof, but not angry with them.

Uygun seyrelticiler mannitol, laktoz, mikrokristalize selüloz, spreyle kurutulmus mannitol, nisasta, dekstroz, sükroz, fruktoz, maltoz, sorbitol, ksilitol, inozitol, kaolin, inorganik tuzlar, kalsiyum tuzlari, polisakkaritler, dikalsiyum fosfat, sodyum klorür, dekstratlar, laktilol, maltodekstrin, sükroz-maltodekstrin karisimi, trehaloz, sodyum karbonat, sodyum bikarbonat, kalsiyum karbonat veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir. Suitable diluents are mannitol, lactose, microcrystalline cellulose, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactilol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, may contain, but is not limited to, calcium carbonate or mixtures thereof.

Uygun disperze edici ajanlar kalsiyum silikat, magnezyum alüminyum silikat veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir. Suitable dispersing agents are calcium silicate, magnesium aluminum silicate or their may include, but is not limited to.

Uygun kayganlastiricilar magnezyum stearat, kalsiyum stearat, çinko stearat, talk, mumlar, borik asit, hidrojenize bitkisel yag, sodyum klorat, magnezyum lauril sülfat, sodyum oleat, sodyum asetat, sodyum benzoat, polietilen glikol, stearik asit, yag asidi, fumarik asit, gliseril palmito sülfat, sodyum stearil fumarat, sodyum lauril sülfat veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir. Suitable lubricants are magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyceryl palmito sulfate, sodium stearyl fumarate, sodium lauryl sulfate or mixtures thereof. may include, but is not limited to.

Uygun glidanlar talk, alüminyum silikat, kolloidal silika, nisasta veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir. Suitable glidants include talc, aluminum silicate, colloidal silica, starch or mixtures thereof. may include, but is not limited to.

Uygun dagiticilar prejelatinize nisasta, çapraz bagli polivinil pirolidon (krospovidon), povidon, çapraz bagli karboksimetil selüloz (kroskarmelloz sodyum), düsük-susbtitüe hidroksipropil selüloz, sodyum karboksimetil selüloz, kalsiyum karboksimetil selüloz, karboksimetil selüloz, dokuzat sodyum, guar zamki, düsük-susbtitüe hidroksipropil selüloz, poliakrilin potasyum, sodyum aljinat, misir nisastasi, sodyum nisasta glikollat, aljinik asit, aljinatlar, iyon-degistirici reçineler, magnezyum alüminyum silika, sodyum dodesil sülfat, polokzamer, sodyum glisin karbonat, sodyum Iauril sülfat veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir. Suitable dispersants are pregelatinized starch, cross-linked polyvinyl pyrrolidone (crospovidone), povidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, nineate sodium, guar gum, low-substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, sodium starch glycollate, alginic acid, alginates, ion-exchanger resins, magnesium aluminum silica, sodium dodecyl sulfate, poloxamer, sodium glycine may contain, but not limited to, carbonate, sodium lauryl sulfate, or mixtures thereof. is not.

Uygun plastiklestiriciler farkli moleküler agirliklarda polietilen glikoller, propilen glikol, gliserin, trietil sitrat (TEC), triasetin, dietil fitalat (DEP), dibütil fitalat (DBP), tribütil sitrat (TBC), kastor yagi, dibütil sebasat (DBS), diasetillenmis monogliseridler veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir. Suitable plasticizers are polyethylene glycols of different molecular weights, propylene glycol, glycerine, triethyl citrate (TEC), triacetin, diethyl phthalate (DEP), dibutyl phthalate (DBP), tributyl citrate (TBC), castor oil, dibutyl sebacate (DBS), diacetylated monoglycerides or mixtures thereof. may include, but is not limited to.

Uygun koruyucular metil paraben, propil paraben ve onlarin tuzlari (sodyum, potasyum gibi), sodyum benzoat, sitrik asit, benzoik asit, bütillenmis hidroksitoluen, borik asit, sorbik asit, benzil alkol, benzalkonyum klorür, parahidroksibenzoik asitler veya bütillenmis hidroksianizol ve benzerlerini veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir. Suitable preservatives are methyl paraben, propyl paraben and their salts (such as sodium, potassium), sodium benzoate, citric acid, benzoic acid, butylated hydroxytoluene, boric acid, sorbic acid, benzyl alcohol, benzalkonium chloride, parahydroxybenzoic acids or butylated hydroxyanisole and the like, or mixtures thereof, but are not limited to.

Uygun tatlandiricilar aspartam, potasyum asesülfam, sodyum sakkarinat, neohesperidin dihidrokalkon, sükraloz, sakkarin, sükroz, glikoz, laktoz, früktoz gibi sekerler veya mannitol, sorbitol, ksiIitol, eritritol gibi seker alkollerini veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir. Suitable sweeteners are aspartame, potassium acesulfame, sodium saccharinate, neohesperidin sugars such as dihydrochalcone, sucralose, saccharine, sucrose, glucose, lactose, fructose or mannitol, may contain sugar alcohols such as sorbitol, xylitol, erythritol or mixtures thereof, but not angry with them.

Uygun aroma katici ajanlar mentol, nane, tarçin, çikolata, vanilya veya visne, portakal, çilek, üzüm, siyah frenküzümü, ahududu, muz, kirmizi meyveler, yabani meyveler gibi meyve esanslari veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir. Suitable flavoring agents are menthol, mint, cinnamon, chocolate, vanilla or cherry, orange, strawberry, fruit such as grapes, black currant, raspberry, banana, red berries, wild berries may include, but is not limited to, essences or mixtures thereof.

Uygun renklendirici ajanlar ferrik oksit, titanyum dioksit, Food, Drug & Cosmetic (FD&C) boyalari (FD&C mavisi, FD&C yesili, FD&C kirmizisi, FD&C sarisi, FD&C koyu kirmizisi gibi), poncau, indigo Drug & Cosmetic (D&C) mavisi, indigotin FD&C mavisi, karmoizin indigotin (indigo Karmin); demir oksitler (kirmizi, sari, siyah demir oksit gibi), kinolin sarisi, ates kirmizisi, karmin, karmoizin, gün batimi sarisi boyalarini veya bunlarin karisimlarini içerebilir, ancak bunlarla sinirli degildir. Suitable coloring agents are ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C dark red etc.), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoizine indigotine (indigo Carmine); iron oxides (such as red, yellow, black iron oxide), quinoline yellow, paints fire red, carmine, carmoizine, sunset yellow or their mixtures. may include, but is not limited to.

Bilesenler Miktar (%) Dronedaron HCl pelletler ' dronedaron HCl 5.00 - 98.00 mannitol 5.00 - 90.00 prejelatinize nisasta 5.00 - 90.00 Enterik kaplama selüloz asetat fitalat 0.10 - 30.00 Dabigatran eteksilat mesilat pelletler dabigatran eteksilat mesilat 1.00 - 85.00 adipik asit veya sorbik asit 5.00 - 95.00 veya süksinik asit veya glutarik asit polivinil alkol (PVA) veya 0.05 - 20.00 izopropil alkol (IPA) sodyum aljinat 0.05 - 20.00 metakrilik asit-Etil akrilat 0.05 - 40.00 kopolimeri (Eudragit EPO) veya PVA xanthan gum 0.05 - 5.00 silikon dioksit 0.10 -1.00 magnezyum stearat 0.10 - 3.00 Dronedaron HCI pelletlerin üretim prosesi: Dronedaron HCI, mannitol ve prejelatinize nisasta önce hep bir arada karistirilir, sonrasinda da polivinil pirolidon solüsyonunun püskürtülmesiyle islak bir kütle olusturulur. Ekstrüzyon/sferonizasyon pelletleme teknigi ile bu islak kütleden pelletler üretilmektedir. Enterik kaplama olarak selüloz asetat fitalat eklenerek bir solüsyon/dispersiyon hazirlanir ve dronedaron HCl pelletler bu karisimin püskürtülmesi ile kaplanir. Components Quantity (%) Dronedarone HCl pellets' dronedarone HCl 5.00 - 98.00 mannitol 5.00 - 90.00 pregelatinized starch 5.00 - 90.00 enteric coating cellulose acetate phthalate 0.10 - 30.00 Dabigatran etexilate mesylate pellets dabigatran etexilate mesylate 1.00 - 85.00 adipic acid or sorbic acid 5.00 - 95.00 or succinic acid or glutaric acid polyvinyl alcohol (PVA) or 0.05 - 20.00 isopropyl alcohol (IPA) sodium alginate 0.05 - 20.00 methacrylic acid-Ethyl acrylate 0.05 - 40.00 copolymer (Eudragit EPO) or PVA xanthan gum 0.05 - 5.00 silicon dioxide 0.10 -1.00 magnesium stearate 0.10 - 3.00 Production process of Dronedarone HCl pellets: Dronedarone HCl, mannitol and pregelatinized The starch is first mixed together, and then the polyvinyl pyrrolidone solution is mixed. A wet mass is formed by spraying. With the extrusion/spheronization pelletizing technique, this Pellets are produced from the wet mass. By adding cellulose acetate phthalate as enteric coating A solution/dispersion is prepared and dronedarone HCl pellets are made by spraying this mixture. is covered.

Dabigatranla kaplianmis organik asit pelletlerin üretim prosesi: Adipik asit veya sorbik asit veya süksinik asit veya glutarik asit ve ksantan zamki birarada karistirilir. Bu karisimin üzerine alkollü polivinil alkol (PVA) veya lPA (izopropil alkol) solüsyonu püskürtülür ve akiskan yatakli peletleme teknigi ile pelletler üretilir. Pelletler, akiskan yatakta sodyum aljinat ile kaplanir ve böylece pelletler üretilmis olur. DEM (dabigatran etaksilat mesilat) alkollü metakrilik asit-etil akrilat kopolimeri (Eudragit EPO) veya polivinil alkol (PVA) solüsyonu içerisinde çözdürülür. Bu solüsyoni akiskan yatakli pelletleme teknigi ile asit pelletler üzerine püskürtülür, böylelikle çok katmanli pelletler üretilmis olur. Production process of organic acid pellets coated with dabigatran: Adipic acid or sorbic acid or succinic acid or glutaric acid and xanthan gum mixed together. on this mix alcoholic solution of polyvinyl alcohol (PVA) or IPA (isopropyl alcohol) sprayed and fluidized bed Pellets are produced by the pelleting technique. The pellets are coated with sodium alginate in a fluidized bed and Thus, pellets are produced. DEM (dabigatran ethoxylate mesylate) alcohol methacrylic acid-ethyl It is dissolved in a solution of acrylate copolymer (Eudragit EPO) or polyvinyl alcohol (PVA). This The solution is sprayed on the acid pellets with the fluidized bed pelletizing technique, so that it is very layered pellets are produced.

DEM ve dronedaron HCl pelletler önce silikon dioksit ile sonra da magnezyum stearat ile karistirilir. Son olarak pelletler, tabletler halinde basilir veya kapsüllerin içerisinde doldurulur. DEM and dronedarone HCl pellets were mixed first with silicon dioxide and then with magnesium stearate. is mixed. Finally, the pellets are compressed into tablets or filled into capsules.

Bilesenler Miktar (%) Dronedaron HCI pelletler dronedaron HCI 5.00 - 98.00 mannitol 5.00 - 90.00 prejelatinize nisasta 5.00 - 90.00 karbomer 0.10 - 30.00 Enterik kaplama ve amonyum metakrilat kopolimeri Dabigatran eteksilat mesilat pelletler dabigatran eteksilat mesilat 1.00 - 85.00 adipik asit veya sorbik asit 5.00 - 95.00 veya süksinik asit veya glutarik asit metakrilik asit-Etil akrilat 0.05 - 40.00 kopolimeri (Eudragit EPO) veya PVA mannitol 5.0 - 90.00 ksantan zamki 0.05 - 5.00 magnezyum stearat 0.10 - 3.00 silikon dioksit 0.10 -1.00 Dronedaron HCI pelletlerin üretim prosesi: Dronedaron HCI, mannitol ve prejelatinize nisasta önce hep bir arada karistirilir, sonrasinda da karbomer solüsyonunun püskürtülmesiyle islak bir kütle olusturulur. Ekstrüzyon/sferonizasyon pelletleme teknigi ile bu islak kütleden pelletler üretilmektedir. Enterik kaplama olarak etil akrilat, metil metakrilat ve amonyum metakrilat kopolimeri eklenerek bir solüsyon/dispersiyon hazirlanir ve dronedaron HCI pelletler akiskan yatakta bu karisimin püskürtülmesi ile kaplanir. Components Quantity (%) Dronedarone HCl pellets dronedarone HCI 5.00 - 98.00 mannitol 5.00 - 90.00 pregelatinized starch 5.00 - 90.00 carbomer 0.10 - 30.00 enteric coating and ammonium methacrylate copolymer Dabigatran etexilate mesylate pellets dabigatran etexilate mesylate 1.00 - 85.00 adipic acid or sorbic acid 5.00 - 95.00 or succinic acid or glutaric acid methacrylic acid-Ethyl acrylate 0.05 - 40.00 copolymer (Eudragit EPO) or PVA mannitol 5.0 - 90.00 xanthan gum 0.05 - 5.00 magnesium stearate 0.10 - 3.00 silicon dioxide 0.10 -1.00 Production process of Dronedarone HCl pellets: Dronedarone HCl, mannitol and pregelatinized starch It is first mixed all together, then wet by spraying the carbomer solution. mass is created. Pellets from this wet mass by extrusion/spheronization pelletizing technique is produced. Ethyl acrylate, methyl methacrylate and ammonium methacrylate as enteric coating A solution/dispersion is prepared by adding the copolymer and dronedarone HCl pellets are fluidized. The bed is covered by spraying this mixture.

Dabigatran pelletlerin üretim prosesi: DEM ve mannitol birarada karistirilir. Bu karisimin üzerine alkolik metakrilik asit-etil akrilat kopolimeri (Eudragit EPO) veya polivinil alkol (PVA) solüsyonu püskürtülür ve akiskan yatakli pelletleme teknigi ile pelletler üretilir. Adipik asit veya sorbik asit veya süksinik asit veya glutarik asit ve ksantan zamki ile bir solüsyon hazirlanir. Bu solüsyon, akiskan yatakli pelletleme teknigi ile asit pelletler üzerine püskürtülür, böylelikle çok katmanli pelletler üretilmis olur. Production process of dabigatran pellets: DEM and mannitol are mixed together. This is my wife alcoholic methacrylic acid-ethyl acrylate copolymer (Eudragit EPO) or polyvinyl alcohol (PVA) solution is sprayed and pellets are produced by fluidized bed pelletizing technique. adipic acid or A solution is prepared with sorbic acid or succinic acid or glutaric acid and xanthan gum. This The solution is sprayed onto the acid pellets by the fluidized bed pelletizing technique, thus making it very layered pellets are produced.

DEM ve dronedaron HCl pelletler ilk olarak silikon dioksit ile daha sonra da magnezyum stearat ile karistirilir. Son olarak pelletler, tabletler halinde basilir veya kapsüllerin içerisinde doldurulur. DEM and dronedarone HCl pellets were first mixed with silicon dioxide and then magnesium stearate. mixed with. Finally, the pellets are compressed into tablets or filled into capsules.

Bilesenler Miktar (%) Dronedaron HCI pelletler dronedaron HCl 5.00 - 98.00 mannitol 5.00 - 90.00 kroskarmelloz sodyum 5.00 - 40.00 karbomer 0.10 - 30.00 Enterik kaplama metakrilat kopolimeri Dabigatran eteksilat mesilat pelletler dabigatran eteksilat mesilat 1.00 - 85.00 seker pelleti 5.00 - 90.00 polivinilpirolidon (PVP) 0.10 - 30.00 kopolimeri (Eudragit EPO) veya PVA Inorganik asit pelletler nitrik asit '0.05 - 10.00 Mikrokristalize selüloz veya 5.0 ±- 40.00 mannitol veya Iaktoz silikon dioksit 0.1 - 0.20 kopolimeri (Eudragit EPO) veya PVA silikon dioksit 0.10 - 1.00 magnezyum stearat 0.10 - 3.00 Dronedaron HCI pelletlerin üretim prosesi: Dronedaron HCI, mannitol ve kroskarmelloz sodyum birarada karistirilir, sonrasinda karbomer solüsyonunun püskürtülmesiyle islak bir kütle olusturulur. Ekstrüzyon/sferonizasyon pelletleme teknigi ile bu islak kütleden pelletler üretilir. Components Quantity (%) Dronedarone HCl pellets dronedarone HCl 5.00 - 98.00 mannitol 5.00 - 90.00 croscarmellose sodium 5.00 - 40.00 carbomer 0.10 - 30.00 enteric coating methacrylate copolymer Dabigatran etexilate mesylate pellets dabigatran etexilate mesylate 1.00 - 85.00 sugar pellet 5.00 - 90.00 polyvinylpyrrolidone (PVP) 0.10 - 30.00 copolymer (Eudragit EPO) or PVA Inorganic acid pellets nitric acid '0.05 - 10.00 Microcrystalline cellulose or 5.0 ± 40.00 mannitol or lactose silicon dioxide 0.1 - 0.20 copolymer (Eudragit EPO) or PVA silicon dioxide 0.10 - 1.00 magnesium stearate 0.10 - 3.00 Production process of Dronedarone HCl pellets: Dronedarone HCl, mannitol and croscarmellose sodium is mixed together, then a wet mass is formed by spraying the carbomer solution. is created. Pellets are produced from this wet mass by the extrusion/spheronization pelletizing technique.

Enterik kaplama olarak metakrilik asit, metil metakrilatkopolimeri eklenerek bir solüsyon hazirlanir ve dronedaron HCl pelletler bu karisimin püskürtülmesi ile kaplanir. Methacrylic acid as enteric coating, adding methyl methacrylate copolymer to form a solution is prepared and dronedarone HCl pellets are coated by spraying this mixture.

Dabigatran pelletlerin üretim prosesi: DEM ve PVP eklenerek alkolik solüsyon/dispersiyon hazirlanir. Seker pelletler, bu solüsyon/dispersiyon ile kaplanir._ Etken madde ile kaplanan seker pelletler, önce metakrilik asit-etil akrilat kopolimeri (Eudragit EPO veya Polivinil alkol (PVA)) sonra da PVP solüsyonu ile kaplanir ve böylece DEM pelletler üretilmis olur. Production process of dabigatran pellets: Alcoholic solution/dispersion by adding DEM and PVP is prepared. Sugar pellets are coated with this solution/dispersion._ Sugar coated with active ingredient pellets, first methacrylic acid-ethyl acrylate copolymer (Eudragit EPO or Polyvinyl alcohol (PVA)) then coated with PVP solution and thus DEM pellets are produced.

Inorganik asit pelletlerin üretim prosesi: Mikrokristalize selüloz veya mannitol veya laktoz ve silikon dioksit harmanlanir, sonra seyreltilmis nitrik asit solüsyonu püskürtülerek yüksek parçalayicili granülatör veya akiskan yatak granülatör ile islak bir kütle olusturulur. Pelletler, akiskan yatakta metakrilik asit-etil akrilat kopolimer (Eudragit EPO) veya polivinil alkol (PVA) solüsyonu ile kaplanir, böylece inorganik asit pelletler üretilmis olur. Production process of inorganic acid pellets: Microcrystalline cellulose or mannitol or lactose and Silicon dioxide is blended, then diluted nitric acid solution is sprayed to high A wet mass is formed with a crusher granulator or a fluidized bed granulator. pellets, methacrylic acid-ethyl acrylate copolymer (Eudragit EPO) or polyvinyl alcohol (PVA) in a fluidized bed covered with a solution of inorganic acid, thus producing inorganic acid pellets.

Dronedaron HCl pelletler ve Dabigatran eteksilat mesilat pelletler ve inorganik asit pelletleri karistirilir. Pelletler ilk önce silikon dioksit ile daha sonra da magnezyum stearat ile karistirilir. Dronedarone HCl pellets and Dabigatran etexilate mesylate pellets and inorganic acid pellets is mixed. The pellets are mixed first with silicon dioxide and then with magnesium stearate.

Pelletler son olarak tabletler halinde basilir veya kapsüller içerisine doldurulur. Pellets are finally pressed into tablets or filled into capsules.

Bilesenler Miktar (%) Dronedaron HCI pelletler dronedaron HCI 5.00 - 98.00 polivinilpirolidon (PVP) 0.10 - 30.00 seker pellet 5.00 - 90.00 Enterik kaplama polivinil asetat fitalat 0.10 - 30.00 Dabigatran eteksilat mesilat pelletler dabigatran eteksilat mesilat 1.00 - 85.00 adipik asit veya sorbik asit 5.00 - 95.00 veya süksinik asit veya glutarik asit metakrilik asit-Etil akrilat 0.05- 40.00 kopolimeri (Eudragit EPO) veya PVA mannitol 5.00 - 90.00 ksantan zamki 0.05 - 5.00 polivinil alkol (PVA) 0.05 - 20.00 silikon dioksit 0.10 - 1.00 magnezyum stearat 0.10 - 3.00 Çok katmanli pelletlerin üretim prosesi: Dronedaron ve PVP eklenerek bir solüsyon hazirlanir. Seker pelletler bu solüsyon/dispersiyonla kaplanir. dronedaron HCI ile kaplanan seker pelletler, polivinil asetat fitalat ile kaplanir ve böylelikle dronedaron HCl pelletler üretilmis olur. DEM ve mannitol, alkolik metakrilik asit-etil akrilat kopolimeri (Eudragit EPO) veya polivinil alkol (PVA) solüsyonu ile karistirilir. Bu karisim, dronedaron HCl pelletler üzerine püskürtülür. Components Quantity (%) Dronedarone HCl pellets dronedarone HCI 5.00 - 98.00 polyvinylpyrrolidone (PVP) 0.10 - 30.00 sugar pellets 5.00 - 90.00 enteric coating polyvinyl acetate phthalate 0.10 - 30.00 Dabigatran etexilate mesylate pellets dabigatran etexilate mesylate 1.00 - 85.00 adipic acid or sorbic acid 5.00 - 95.00 or succinic acid or glutaric acid methacrylic acid-Ethyl acrylate 0.05- 40.00 copolymer (Eudragit EPO) or PVA mannitol 5.00 - 90.00 xanthan gum 0.05 - 5.00 polyvinyl alcohol (PVA) 0.05 - 20.00 silicon dioxide 0.10 - 1.00 magnesium stearate 0.10 - 3.00 Production process of multi-layer pellets: Dronedarone and PVP are added to make a solution is prepared. Sugar pellets are coated with this solution/dispersion. coated with dronedarone HCI The sugar pellets were coated with polyvinyl acetate phthalate and thus dronedarone HCl pellets were produced. It is possible. DEM and mannitol, alcoholic methacrylic acid-ethyl acrylate copolymer (Eudragit EPO) or polyvinyl mixed with an alcohol (PVA) solution. This mixture is sprayed onto dronedarone HCl pellets.

Adipik asit veya sorbik asit veya süksinik asit veya glutarik asit ve ksantan zamki eklenerek bir solüsyon hazirlanir. Bu solüsyonun pelletler pelletlerin üzerine püskürtülür ve böylelikle çok katmanli pelletler üretilmis olur. Çok katmanli pelletler, son olarak PVA ile kaplanir. Çok katmanli pelletler önce silikon dioksit ile, daha sonra da magnezyum stearat ile karistirilir. Pelletler tabletler halinde basilir veya kapsüller içerisine doldurulur. Adding adipic acid or sorbic acid or succinic acid or glutaric acid and xanthan gum solution is prepared. The pellets of this solution are sprayed onto the pellets and thus very layered pellets are produced. Multilayer pellets are finally coated with PVA. The multilayer pellets are pre-mixed with silicon dioxide. and then mixed with magnesium stearate. Pellets are pressed into tablets or filled into capsules.

Bilesenler Miktar (%) Dronedaron HCI pelletler dronedaron HCI 5.00 - 98.00 polivinilpirolidon (PVP) 0.10 - 30.00 Seker pellet 5.00 - 90.00 Enterik kaplama metakrilik asit ko-polimeri tip 0.10 - 30.00 Dabigatran eteksilat mesilat pelletler dabigatran eteksilat mesilat 1.00 - 85.00 metakrilik asit-Etil akrilat 0.05 - 40.00 kopolimeri (Eudragit EPO) veya PVA mannitol 5.00 - 90.00 adipik asit veya sorbik asit 5.00 - 95.00 veya süksinik asit veya glutarik asit ksantan zamki 0.05 - 5.00 silikon dioksit 0.10 - 1.00 magnezyum stearat 0.10 - 3.00 Dronedaron HCI pelletlerin üretim prosesi: Dronedaron HCI ve PVP'nin eklenmesi ile bir solüsyon/dispersiyon hazirlanir. Seker pelletler bu solüsyon/dispersiyonla kaplanir. Etken madde ile kaplanan seker pelletler, metakrilik asit ko-polimeri tip C ile hazirlanir ve böylelikle Dronedaron HCI pelletler üretilmis olur. Components Quantity (%) Dronedarone HCl pellets dronedarone HCI 5.00 - 98.00 polyvinylpyrrolidone (PVP) 0.10 - 30.00 Sugar pellets 5.00 - 90.00 enteric coating methacrylic acid co-polymer type 0.10 - 30.00 Dabigatran etexilate mesylate pellets dabigatran etexilate mesylate 1.00 - 85.00 methacrylic acid-Ethyl acrylate 0.05 - 40.00 copolymer (Eudragit EPO) or PVA mannitol 5.00 - 90.00 adipic acid or sorbic acid 5.00 - 95.00 or succinic acid or glutaric acid xanthan gum 0.05 - 5.00 silicon dioxide 0.10 - 1.00 magnesium stearate 0.10 - 3.00 Production process of Dronedarone HCl pellets: With the addition of Dronedarone HCl and PVP, a the solution/dispersion is prepared. Sugar pellets are coated with this solution/dispersion. Active The sugar pellets coated with the substance are prepared with the methacrylic acid co-polymer type C and thus Dronedarone HCl pellets are produced.

Dabigatran pelletlerin üretim prosesi: DEM ve mannitol monohidrat birarada karistirilir. Bu karisimin üzerine alkolik metakrilik asit-etil akrilat kopolimeri (Eudragit EPO) veya polivinil alkol (PVA) solüsyonu püskürtülür ve akiskan yatakli pelletleme teknigi ile pelletler üretilir. Adipik asit veya sorbik asit veya süksinik asit veya glutarik asit ve ksantan zamki eklenerek bir solüsyon hazirlanir. Bu solüsyon, akiskan yatakli pelletleme teknigi ile DEM pelletler üzerine püskürtülür ve böylelikle çok katmanli pelletler üretilmis olur. Production process of dabigatran pellets: DEM and mannitol monohydrate are mixed together. This alcoholic methacrylic acid-ethyl acrylate copolymer (Eudragit EPO) or polyvinyl alcohol on the mixture (PVA) solution is sprayed and pellets are produced by fluidized bed pelletizing technique. adipic acid or a solution by adding sorbic acid or succinic acid or glutaric acid and xanthan gum is prepared. This solution is sprayed onto DEM pellets by fluidized bed pelletizing technique. and thus multi-layered pellets are produced.

Dabigatran eteksilat mesilat ve dronedaron HCl pelletler ilk olarak silikon dioksit ile daha sonra da magnezyum stearat ile karistirilir. Son olarak pelletler, özel tablet baski makinesi ile üretilen çok katmanli döner tablet basim makinesi ile sikistirilir veya özel tablet baski makinesi ile çekirdek üzerinde dronedaron HCI pelletlere sahip kuru tablet içinde tablet veya inlay tabletler üretilmektedir. Dabigatran etexilate mesylate and dronedarone HCl pellets were first mixed with silicon dioxide and then mixed with magnesium stearate. Finally, the pellets are produced with a special tablet press machine. Compressed with multilayer rotary tablet press machine or with special tablet press machine dry tablet-in-tablet or inlay tablets with dronedarone HCl pellets on the core is produced.

Claims (1)

ISTEMLER Dronedaron veya onun farmasötik olarak kabul edilebilir bir tuzu ile birlikte dabigatran veya farmasötik olarak kabul edilebilir bir tuzunu veya farkli bir polimorfunu içeren farmasötik bir kombinasyon olup, en az bir tane farmasötik olarak kabul edilebilir yardimci madde içermesidir. Istem 1'e göre farmasötik bir kombinasyon olup özelligi, dronedaron veya farmasötik olarak kabul edilebilir tuzunun dronedaron hidroklorür olmasidir. istem 1 veya 2'ye göre farmasötik bir kombinasyon olup özelligi, dronedaron hidroklorürün toplam formülasyonun agirlikça %5 ila %98'i arasi, tercihen %20 ila istem 3'e göre farmasötik bir kombinasyon olup özelligi, dronedaron hidroklorürün 800 mg arasi bir miktarda bulunmasidir. Istem 1'e göre farmasötik bir kombinasyon olup özelligi, dabigatran veya farmasötik olarak kabul edilebilir bir tuzu veya polimorfunun, dabigatranin eteksilat veya eteksilat mesilat tuzu olmasidir. istem 5'e göre farmasötik bir kombinasyon olup özelligi, dabigatran veya farmasötik olarak kabul edilebilir bir tuzunun, dabigatranin eteksilat mesilat tuzu olmasidir. istem 1'e göre farmasötik bir kombinasyon olup özelligi, dabigatran eteksilat mesilatin toplam formülasyonun agirlikça %10 ila %85'i arasi, tercihen %10 ila Istem 7'ye göre farmasötik bir kombinasyon olup özelligi, dabigatran eteksilat ila 250 mg arasi bir miktarda bulunmasidir. istem 1'e göre farmasötik bir kombinasyon olup özelligi, dronedaron HCl'nin dabigatran eteksilat mesilata oraninin 0.10 - 50.0 (ala) arasinda, tercihen 1.0 - 35.0 (a/a) arasinda veya daha tercihen 1.0 - 30.0 (a/a) arasinda olmasidir. Istem 1'e göre farmasötik bir kombinasyon olup özelligi, bahsedilen farmasötik kombinasyonun kati, sivi veya yarikati dozaj formunda olmasidir. Istem 10'a göre farmasötik bir kombinasyon olup özelligi, bahsedilen farmasötik kombinasyonun sikistirilmis tabletler, kapli veya kaplanmamis tabletler içeren tabletler, kapsüller, çok katmanli tabletler, agiz içi tabletler, dil alti tabletler, tablet içinde tabletler, in-Iay tabletler, efervesan kombinasyonlar, efervesan tabletler, hemen salimli tabletler, modifiye salimli tabletler, agizda dagilan tablet, film-kapli tabletler, agizda dagilan tabletler, midede dagilan tabletler, haplar, sert veya yumusak jelatin kapsüller, tozlar, mini tabletler, pelletler, kapli boncuk sistemleri, granüller, mikrosferler, iyon degistirici reçine sistemleri, sterile solüsyonlar veya süspansiyonlar, steril oküler solüsyonlar, aerosoller, Spreyler, damlalar, ampuller, suppozituarlar, oküler sistemler, parenteral sistemler, kreamler, jeller, merhemler, drajeler, kaseler; filmler, agizdan uygulanabilen filmler, agizdan uygulanabilen filmler, solüsyonlar, solidler; eliksirler, tentürler, süspansiyonlar, suruplar, kolloidal dispersiyonlar, dispersiyonlar ve emülsiyonlar olarak formüle edilmesidir. Istem 11”e göre farmasötik bir kombinasyon olup özelligi, bahsedilen farmasötik kombinasyonun tercihen tablet veya kapsül veya çok katmanli tablet formunda formüle edilmesidir. Istem 12'ye göre farmasötik bir kombinasyon olup özelligi, bahsedilen farmasötik kombinasyonun dabigatran eteksilat mesilat pelletleri ve dronedaron HCl pelletleri içeren tablet veya kapsül veya çok katmanli tablet formunda formüle edilmesidir. Istem 13'e göre farmasötik bir kombinasyon olup özelligi, bahsedilen dronedaron HCl pelletlerin enterik bir kaplama içermesidir. Istem 14'e göre farmasötik bir kombinasyon olup özelligi, enterik kaplamanin selüloz asetat fitalat, metakrilik asit kopolimerleri, metakrilik asit, etil akrilat kopolimerleri, etil akrilat, metil metakrilat ve amonyum metakrilat kopolimerleri; metakrilik asit, metil metakrilat kopolimeri, metakrilik asit kopolimerleri, hidroksipropil metilselüloz fitalat, hidroksipropil metilselüloz asetat süksinat, polivinil asetat fitalat ve metakrilik asit kopolimeri tip C'yi içeren gruptan seçilmis olmasidir. , istem 13'e göre farmasötik bir kombinasyon olup özelligi, bahsedilen farmasötik kombinasyonun ayrilmis pelletler veya çift katmanli pelletler veya çok katmanli pelletler halinde dronedaron HCI pelletleri ve dabigatran eteksilat mesilat pelletlerini içeren tablet veya kapsül veya çok katmanli tablet formunda olmasidir. Istem 1'e göre farmasötik kombinasyon olup, özelligi en az bir veya daha fazla sayida farmasötik olarak kabul edilebilir yardimci maddenin tamponlayici ajanlar, stabilizörler, baglayicilar, seyrelticiler, disperze edici ajanlar, kayganlastiricilar, glidanlar, dagiticilar, plastiklestiriciler, koruyucular, tatlandiricilar, aroma katici ajanlar, renklendirici ajanlar veya bunlarin karisimlarini içeren gruptan seçilmis olmasidir. Istem 16'ya göre farmasötik bir kombinasyon olup özelligi, bahsedilen dronedaron HCI pelletlerin mannitol veya prejelatinize nisasta veya karbomer veya kroskarmelloz sodyum veya polivinilpirolidon veya polivinil alkol veya seker pellet veya mikrokristalize selüloz pellet veya hidroksipropil selüloz veya renklendirici ajan veya bunlarin karisimlarini içeren farmasötik olarak kabul edilebilir yardimci madde içermesidir. istem 16'ya göre farmasötik bir kombinasyon olup özelligi, bahsedilen dabigatran eteksilat mesilat pelletlerin polivinil alkol veya izopropil alkol veya sodyum aljinat veya metakrilik asit-etil akrilat kopolimeri veya propilen glikol veya Iaktoz monohidrat veya mannitol veya seker pellet veya polivinilpirolidon veya bunlarin karisimlarini içermesidir. Istem 1'e göre farmasötik bir kombinasyon olup özelligi, hastalarda kardiyak aritmi ve kan pihtilasmasinin tedavisinde ve ciddi veya yasami tehdit eden yari etkilerin önlenmesinde kullanima yönelik olmasidir.CLAIM A pharmaceutical combination comprising dronedarone or a pharmaceutically acceptable salt thereof with dabigatran or a pharmaceutically acceptable salt or different polymorph thereof, comprising at least one pharmaceutically acceptable excipient. A pharmaceutical combination according to claim 1, characterized in that dronedarone or its pharmaceutically acceptable salt is dronedarone hydrochloride. A pharmaceutical combination according to claim 1 or 2, characterized in that dronedarone hydrochloride is present in an amount of between 5% and 98%, preferably 20% by weight, of the total formulation of dronedarone hydrochloride in an amount of 800 mg. . A pharmaceutical combination according to claim 1, characterized in that dabigatran or a pharmaceutically acceptable salt or polymorph is the etexilate or etexylate mesylate salt of dabigatran. A pharmaceutical combination according to claim 5, characterized in that dabigatran or a pharmaceutically acceptable salt is the mesylate mesylate salt of dabigatran. A pharmaceutical combination according to claim 1, characterized in that dabigatran etexilate mesylate is present in an amount of 10 to 85% by weight of the total formulation, preferably 10% to a pharmaceutical combination according to claim 7, of dabigatran etexilate to 250 mg . A pharmaceutical combination according to claim 1, characterized in that the ratio of dronedarone HCl to dabigatran etexilate mesylate is between 0.10 and 50.0 (w/w), preferably between 1.0 and 35.0 (w/w), or more preferably between 1.0 and 30.0 (w/w). . A pharmaceutical combination according to claim 1, characterized in that said pharmaceutical combination is in solid, liquid or semi-solid dosage form. It is a pharmaceutical combination according to claim 10, wherein said pharmaceutical combination is compressed tablets, tablets containing coated or uncoated tablets, capsules, multilayered tablets, oral tablets, sublingual tablets, tablets in tablets, in-Iay tablets, effervescent combinations, effervescent tablets, immediate release tablets, modified release tablets, mouth dispersible tablet, film-coated tablets, mouth dispersible tablets, stomach dispersible tablets, pills, hard or soft gelatin capsules, powders, mini tablets, pellets, coated bead systems, granules, microspheres , ion exchange resin systems, sterile solutions or suspensions, sterile ocular solutions, aerosols, Sprays, drops, ampoules, suppositories, ocular systems, parenteral systems, creams, gels, ointments, dragees, bowls; films, oral films, oral films, solutions, solids; It is formulated as elixirs, tinctures, suspensions, syrups, colloidal dispersions, dispersions and emulsions. It is a pharmaceutical combination according to claim 11, characterized in that said pharmaceutical combination is preferably formulated in the form of tablets or capsules or multilayered tablets. A pharmaceutical combination according to claim 12, characterized in that said pharmaceutical combination is formulated in tablet or capsule or multilayer tablet form containing dabigatran etexilate mesylate pellets and dronedarone HCl pellets. A pharmaceutical combination according to claim 13, characterized in that said dronedarone HCl pellets contain an enteric coating. A pharmaceutical combination according to claim 14, characterized in that the enteric coating consists of cellulose acetate phthalate, methacrylic acid copolymers, methacrylic acid, ethyl acrylate copolymers, ethyl acrylate, methyl methacrylate and ammonium methacrylate copolymers; methacrylic acid, methyl methacrylate copolymer, methacrylic acid copolymers, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and methacrylic acid copolymer type C. A pharmaceutical combination according to claim 13, characterized in that said pharmaceutical combination is in the form of tablets or capsules or multilayered tablets containing dronedarone HCl pellets and dabigatran etexilate mesylate pellets as separated pellets or bilayer pellets or multilayer pellets. Pharmaceutical combination according to claim 1, characterized in that at least one or more pharmaceutically acceptable excipients are buffering agents, stabilizers, binders, diluents, dispersing agents, lubricants, glidants, dispersants, plasticizers, preservatives, sweeteners, flavorings. agents, coloring agents or their mixtures. A pharmaceutical combination according to claim 16, characterized in that said dronedarone HCl pellets are pharmaceuticals containing mannitol or pregelatinized starch or carbomer or croscarmellose sodium or polyvinylpyrrolidone or polyvinyl alcohol or sugar pellets or microcrystalline cellulose pellets or hydroxypropyl cellulose or coloring agent or mixtures of these which are acceptable as coloring agents. contains an excipient. A pharmaceutical combination according to claim 16, characterized in that said dabigatran etexilate mesylate pellets contain polyvinyl alcohol or isopropyl alcohol or sodium alginate or methacrylic acid-ethyl acrylate copolymer or propylene glycol or lactose monohydrate or mannitol or sugar pellets or polyvinylpyrrolidone or mixtures thereof. It is a pharmaceutical combination according to claim 1, characterized in that it is for use in the treatment of cardiac arrhythmia and blood coagulation in patients and for the prevention of serious or life-threatening side effects.
TR2015/02223A 2015-02-25 2015-02-25 Pharmaceutical combinations of dronedarone and dabigatran TR201502223A2 (en)

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FR2665444B1 (en) 1990-08-06 1992-11-27 Sanofi Sa AMINO-BENZOFURAN, BENZOTHIOPHENE OR INDOLE DERIVATIVES, THEIR PREPARATION PROCESS AND THE COMPOSITIONS CONTAINING THEM.
PE121699A1 (en) 1997-02-18 1999-12-08 Boehringer Ingelheim Pharma BICYCLE HETERO CYCLES DISSTITUTED AS INHIBITORS OF THROMBIN
FR2764800B1 (en) 1997-06-23 1999-09-10 Sanofi Sa SOLID PHARMACEUTICAL COMPOSITION CONTAINING BENZOFURAN DERIVATIVES
PT1870100E (en) 2002-03-07 2012-04-17 Boehringer Ingelheim Int Ethyl 3-(2-(4-(hexyloxycarbonylamidino)phenylaminomethyl)-1-methyl-1h-benzimidazole-5-carbonyl)-2-pyridylamino)propionate methansulfonate
US20110136779A1 (en) * 2009-11-23 2011-06-09 Milner Peter G Methods for stroke reduction in atrial fibrillation patients
WO2012023024A2 (en) * 2010-08-17 2012-02-23 Lupin Limited Controlled release formulations of dronedarone

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